241. Bakan, I.; Laplante, M. Connecting mTORC1 signaling to SREBP-1 activation. *Curr. Opin. Lipidol.* **2012**, *23*, 226-234, doi:10.1097/MOL.0b013e328352dd03.

242. Huffman, T.A.; Mothe-Satney, I.; Lawrence, J.C., Jr. Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. *Proc. Natl. Acad. Sci. USA* **2002**, *99*, 1047-1052, doi:10.1073/pnas.022634399.

243. Koh, Y.K.; Lee, M.Y.; Kim, J.W.; Kim, M.; Moon, J.S.; Lee, Y.J.; Ahn, Y.H.; Kim, K.S. Lipin1 is a key factor for the maturation and maintenance of adipocytes in the regulatory network with CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma 2. *J. Biol. Chem.* **2008**, *283*, 34896-34906, doi:10.1074/jbc.M804007200.

244. Kim, H.E.; Bae, E.; Jeong, D.Y.; Kim, M.J.; Jin, W.J.; Park, S.W.; Han, G.S.; Carman, G.M.; Koh, E.; Kim, K.S. Lipin1 regulates PPARgamma transcriptional activity. *Biochem. J.* **2013**, *453*, 49-60, doi:10.1042/BJ20121598.

245. Finck, B.N.; Gropler, M.C.; Chen, Z.; Leone, T.C.; Croce, M.A.; Harris, T.E.; Lawrence, J.C., Jr.; Kelly, D.P. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. *Cell Metab.* **2006**, *4*, 199-210, doi:10.1016/j.cmet.2006.08.005.

246. San, Y.Z.; Liu, Y.; Zhang, Y.; Shi, P.P.; Zhu, Y.L. Peroxisome proliferator-activated receptor-gamma agonist inhibits the mammalian target of rapamycin signaling pathway and has a protective effect in a rat model of status epilepticus. *Mol. Med. Rep.* **2015**, *12*, 1877-1883, doi:10.3892/mmr.2015.3641.

247. Purnell, P.; Teepper, C.; Liu, S.; Cardiff, R.; Gregg, J. Induction of PPAR gamma signaling and autophagy as a mechanism mediating acquired rapamycin resistance in breast cancer models. *Cancer Res.* **2008**, *68*.

248. Assumpcao, J.A.F.; Magalhaes, K.G.; Correa, J.R. The role of ppargamma and autophagy in ros production, lipid droplets biogenesis and its involvement with colorectal cancer cells modulation. *Cancer Cell Int.* **2017**, *17*, 82, doi:10.1186/s12935-017-0451-5.

249. Kang, J.H.; Chang, Y.C.; Maurizi, M.R. 4-O-carboxymethyl ascochlorin causes ER stress and induced autophagy in human hepatocellular carcinoma cells. *J. Biol. Chem.* **2012**, *287*, 15661-15671, doi:10.1074/jbc.M112.358473.

250. Pellerito, O.; Notaro, A.; Sabella, S.; De Blasio, A.; Vento, R.; Calvaruso, G.; Giuliano, M. WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARgamma down-regulation. *Apoptosis* **2014**, *19*, 1029-1042, doi:10.1007/s10495-014-0985-0.

251. Weng, J.R.; Bai, L.Y.; Chiu, C.F.; Hu, J.L.; Chiu, S.J.; Wu, C.Y. Cucurbitane Triterpenoid from Momordica charantia Induces Apoptosis and Autophagy in Breast Cancer Cells, in Part, through Peroxisome Proliferator-Activated Receptor gamma Activation. *Evid. Based Complement. Altern. Med.* **2013**, *2013*, 935675, doi:10.1155/2013/935675.

252. Zhou, J.; Zhang, W.; Liang, B.; Casimiro, M.C.; Whitaker-Menezes, D.; Wang, M.; Lisanti, M.P.; Lanza-Jacoby, S.; Pestell, R.G.; Wang, C. PPARgamma activation induces autophagy in breast cancer cells. *Int. J. Biochem. Cell Biol.* **2009**, *41*, 2334-2342, doi:10.1016/j.biocel.2009.06.007.

253. Yan, S.; Yang, X.; Chen, T.; Xi, Z.; Jiang, X. The PPARgamma agonist Troglitazone induces autophagy, apoptosis and necroptosis in bladder cancer cells. *Cancer Gene Ther.* **2014**, *21*, 188-193, doi:10.1038/cgt.2014.16.

254. Cerquetti, L.; Sampaoli, C.; Amendola, D.; Bucci, B.; Masuelli, L.; Marchese, R.; Misiti, S.; De Venanzi, A.; Poggi, M.; Toscano, V.; et al. Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells. *Exp. Cell Res.* **2011**, *317*, 1397-1410, doi:10.1016/j.yexcr.2011.02.014.

255. Teresi, R.E.; Waite, K.A. PPARgamma, PTEN, and the Fight against Cancer. *PPAR Res.* **2008**, *2008*, 932632, doi:10.1155/2008/932632.

256. Patel, L.; Pass, I.; Coxon, P.; Downes, C.P.; Smith, S.A.; Macphee, C.H. Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. *Curr. Biol.* **2001**, *11*, 764-768.

257. Zhang, W.; Wu, N.; Li, Z.; Wang, L.; Jin, J.; Zha, X.L. PPARgamma activator rosiglitazone inhibits cell migration via upregulation of PTEN in human hepatocarcinoma cell line BEL-7404. *Cancer Biol. Ther.* **2006**, *5*, 1008-1014.

258. Lin, C.F.; Young, K.C.; Bai, C.H.; Yu, B.C.; Ma, C.T.; Chien, Y.C.; Chiang, C.L.; Liao, C.S.; Lai, H.W.; Tsao, C.W. Rosiglitazone regulates anti-inflammation and growth inhibition via PTEN. *Biomed. Res. Int.* **2014**, *2014*, 787924, doi:10.1155/2014/787924.

259. Song, M.S.; Salmena, L.; Pandolfi, P.P. The functions and regulation of the PTEN tumour suppressor. *Nat. Rev. Mol. Cell Biol.* **2012**, *13*, 283-296, doi:10.1038/nrm3330.
260. Panasyuk, G.; Espeillac, C.; Chauvin, C.; Pradelli, L.A.; Horie, Y.; Suzuki, A.; Annicotte, J.S.; Fajas, L.; Foretz, M.; Verdeguer, F.; et al. PPARgamma contributes to PKM2 and HK2 expression in fatty liver. *Nat. Commun.* **2012**, *3*, 672, doi:10.1038/ncomms1667.

261. Wang, L.; Yin, Y.; Hou, G.; Kang, J.; Wang, Q. Peroxisome Proliferator-Activated Receptor (PPARgamma) Plays a Protective Role in Cigarette Smoking-Induced Inflammation via AMP-Activated Protein Kinase (AMPK) Signaling. *Med. Sci. Monit.* **2018**, *24*, 5168–5177, doi:10.12659/MSM.909285.

262. He, G.; Sung, Y.M.; Digiovanni, J.; Fischer, S.M. Thiazolidinediones inhibit insulin-like growth factor-i-induced activation of p70S6 kinase and suppress insulin-like growth factor-I tumor-promoting activity. *Cancer Res.* **2006**, *66*, 1873–1878, doi:10.1158/0008-5472.CAN-05-3111.

263. Lee, Y.H.; Lee, H.Y.; Kim, T.G.; Lee, N.H.; Yu, M.K.; Yi, H.K. PPARgamma Maintains Homeostasis through Autophagy Regulation in Dental Pulp. *J. Dent. Res.* **2015**, *94*, 729–737, doi:10.1177/0022034515573833.

264. Xu, F.; Li, J.; Ni, W.; Shen, Y.W.; Zhang, X.P. Peroxisome proliferator-activated receptor-gamma agonist 15d-prostaglandin J2 mediates neuronal autophagy after cerebral ischemia-reperfusion injury. *PLoS ONE* **2013**, *8*, e55080, doi:10.1371/journal.pone.0055080.

265. Li, H.; Zhang, Q.; Yang, X.; Wang, L. PPAR-gamma agonist rosiglitazone reduces autophagy and promotes functional recovery in experimental traumatic spinal cord injury. *Neurosci. Lett.* **2017**, *650*, 89–96, doi:10.1016/j.neulet.2017.02.075.

266. Mahmood, D.F.; Jguirim-Souissi, I.; Khadija, E.H.; Blondeau, N.; Diderot, V.; Amrani, S.; Slimane, M.N.; Syrovets, T.; Simmet, T.; Rouis, M. Peroxisome proliferator-activated receptor gamma induces apoptosis and inhibits autophagy of human monocyte-derived macrophages via induction of cathepsin L: Potential role in atherosclerosis. *J. Biol. Chem.* **2011**, *286*, 28858–28866, doi:10.1074/jbc.M111.273292.

267. Xiao, B.; Sanders, M.J.; Underwood, E.; Heath, R.; Mayer, F.V.; Carmena, D.; Jing, C.; Walker, P.A.; Eccleston, J.F.; Haire, L.F.; et al. Structure of mammalian AMPK and its regulation by ADP. *Nature* **2011**, *472*, 230–233, doi:10.1038/nature09932.

268. Ross, F.A.; MacKintosh, C.; Hardie, D.G. AMP-activated protein kinase: A cellular energy sensor that comes in 12 flavours. *FEBS J.* **2016**, *283*, 2987–3001, doi:10.1111/febs.13698.

269. Suter, M.; Riek, U.; Tuerk, R.; Schlattner, U.; Wallimann, T.; Neumann, D. Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. *J. Biol. Chem.* **2006**, *281*, 32207–32216, doi:10.1074/jbc.M606357200.

270. Davies, S.P.; Helps, N.R.; Cohen, P.T.; Hardie, D.G. 5'-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. *FEBS Lett.* **1995**, *377*, 421–425, doi:10.1016/0014-5793(95)01368-7.

271. Fogarty, S.; Hawley, S.A.; Green, K.A.; Saner, N.; Mustard, K.J.; Hardie, D.G. Calmodulin-dependent protein kinase kinase-beta activates AMPK without forming a stable complex: Synergistic effects of Ca²⁺ and AMP. *Biochem. J.* **2010**, *426*, 109–118, doi:10.1042/BJ20091372.

272. Winder, W.W.; Hardie, D.G. AMP-activated protein kinase, a metabolic master switch: Possible roles in type 2 diabetes. *Am. J. Physiol.* **1999**, *E1–E10*, doi:10.1152/ajpendo.1999.277.1.E1.

273. Koo, S.H.; Flechner, L.; Qi, L.; Zhang, X.; Screaton, R.A.; Jeffries, S.; Hedrick, S.; Xu, W.; Boussouar, F.; Brindle, P.; et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. *Nature* **2005**, *437*, 1109–1111, doi:10.1038/nature03967.

274. Chen, S.; Murphy, J.; Toth, R.; Campbell, D.G.; Morrice, N.A.; Mackintosh, C. Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. *Biochem. J.* **2008**, *409*, 449–459, doi:10.1042/BJ20071114.

275. Geraghty, K.M.; Chen, S.; Harthill, J.E.; Ibrahim, A.F.; Toth, R.; Morrice, N.A.; Vandermoere, F.; Moorhead, G.B.; Hardie, D.G.; MacKintosh, C. Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF, PMA and AICAR. *Biochem. J.* **2007**, *407*, 231–241, doi:10.1042/BJ20070649.

276. Jager, S.; Handschin, C.; St-Pierre, J.; Spiegelman, B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. *Proc. Natl. Acad. Sci. USA* **2007**, *104*, 12017–12022, doi:10.1073/pnas.0705070104.

277. McGee, S.L.; van Denderen, B.J.; Howlett, K.F.; Mollica, J.; Schertzer, J.D.; Kemp, B.E.; Hargreaves, M. AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. *Diabetes* **2008**, *57*, 860–867, doi:10.2337/db07-0843.
278. Davies, S.P.; Sim, A.T.; Hardie, D.G. Location and function of three sites phosphorylated on rat acetyl-CoA carboxylase by the AMP-activated protein kinase. *Eur. J. Biochem.* **1990**, *187*, 183–190.

279. Davies, S.P.; Carling, D.; Munday, M.R.; Hardie, D.G. Diurnal rhythm of phosphorylation of rat liver acetyl-CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. Effects of high fat diets. *Eur. J. Biochem.* **1992**, *203*, 615–623.

280. Li, Y.; Xu, S.; Mihaylova, M.M.; Zheng, B.; Hou, X.; Jiang, B.; Park, O.; Luo, Z.; Lefai, E.; Shyy, J.Y.; et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. *Cell Metab.* **2011**, *13*, 376–388, doi:10.1016/j.cmet.2011.03.009.

281. Muoio, D.M.; Seefeld, K.; Witters, L.A.; Coleman, R.A. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: Evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. *Biochem. J.* **1999**, *338* Pt 3, 783–791.

282. Clarke, P.R.; Hardie, D.G. Regulation of HMG-CoA reductase: Identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. *EMBO J.* **1990**, *9*, 2439–2446.

283. Hoppe, S.; Bierhoff, H.; Cado, I.; Weber, A.; Tiebe, M.; Grummt, I.; Voit, R. AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply. *Proc. Natl. Acad. Sci. USA* **2009**, *106*, 17781–17786, doi:10.1073/pnas.0909873106.

284. Dufer, M.; Noack, K.; Krippeit-Drews, P.; Drews, G. Activation of the AMP-activated protein kinase enhances glucose-stimulated insulin secretion in mouse beta-cells. *Islets* **2010**, *2*, 156–163, doi:10.4161/isl.2.3.11412.

285. Chavez, J.A.; Roach, W.G.; Keller, S.R.; Lane, W.S.; Lienhard, G.E. Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. *J. Biol. Chem.* **2008**, *283*, 9187–9195, doi:10.1074/jbc.M708934200.

286. Marsin, A.S.; Bouzin, C.; Bertrand, L.; Hue, L. The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. *J. Biol. Chem.* **2002**, *277*, 30778–30783, doi:10.1074/jbc.M205213200.

287. Jorgensen, S.B.; Nielsen, J.N.; Birk, J.B.; Olsen, G.S.; Viollet, B.; Andreelli, F.; Schjerling, P.; Vaulont, S.; Hardie, D.G.; Hansen, B.F.; et al. The alpha2-5' AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading. *Diabetes* **2004**, *53*, 3074–3081.

288. Hardie, D.G.; Ross, F.A.; Hawley, S.A. AMPK: A nutrient and energy sensor that maintains energy homeostasis. *Nat. Rev. Mol. Cell Biol.* **2012**, *13*, 251–262, doi:10.1038/nrm3311.

289. Leclerc, I.; Lenzner, C.; Gourdon, L.; Vaulont, S.; Kahn, A.; Viollet, B. Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase. *Diabetes* **2001**, *50*, 1515–1521, doi:10.2337/diabetes.50.7.1515.

290. Lee, J.M.; Seo, W.Y.; Song, K.H.; Chanda, D.; Kim, Y.D.; Kim, D.K.; Lee, M.W.; Ryu, D.; Kim, Y.H.; Noh, J.R.; et al. AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner. *J. Biol. Chem.* **2010**, *285*, 32182–32191, doi:10.1074/jbc.M110.134890.

291. Minokoshi, Y.; Alquier, T.; Furukawa, N.; Kim, Y.B.; Lee, A.; Xue, B.; Mu, J.; Foufelle, F.; Ferre, P.; Birnbaum, M.J.; et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. *Nature* **2004**, *428*, 569–574, doi:10.1038/nature02440.

292. Andersson, U.; Filipsson, K.; Abbott, C.R.; Woods, A.; Smith, K.; Bloom, S.R.; Carling, D.; Small, C.J. AMP-activated protein kinase plays a role in the control of food intake. *J. Biol. Chem.* **2004**, *279*, 12005–12008, doi:10.1074/jbc.C300557200.

293. Steinberg, G.R.; Kemp, B.E. AMPK in Health and Disease. *Physiol. Rev.* **2009**, *89*, 1025–1078, doi:10.1152/physrev.00011.2008.

294. Wang, Z.; Wang, N.; Liu, P.; Xie, X. AMPK and Cancer. *Exp. Suppl.* **2016**, *107*, 203–226, doi:10.1007/978-3-319-43589-3_9.

295. Umezawa, S.; Higurashi, T.; Nakajima, A. AMPK: Therapeutic Target for Diabetes and Cancer Prevention. *Curr. Pharm. Des.* **2017**, *23*, 3629–3644, doi:10.2174/0929867324666170713150440.

296. Greer, E.L.; Dowlatshahi, D.; Banko, M.R.; Villen, J.; Hoang, K.; Blanchard, D.; Gygi, S.P.; Brunet, A. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in *C. elegans*. *Curr. Biol.* **2007**, *17*, 1646–1656, doi:10.1016/j.cub.2007.08.047.
297. Schulz, T.J.; Zarse, K.; Voigt, A.; Urban, N.; Birringer, M.; Ristow, M. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. *Cell Metab.* **2007**, *6*, 280–293, doi:10.1016/j.cmet.2007.08.011.

298. Funakoshi, M.; Tsuda, M.; Muramatsu, K.; Hatsuda, H.; Morishita, S.; Aigaki, T. A gain-of-function screen identifies wdb and lkb1 as lifespan-extending genes in Drosophila. *Biochem. Biophys. Res. Commun.* **2011**, *405*, 667–672, doi:10.1016/j.bbrc.2011.01.090.

299. Stenesen, D.; Suh, J.M.; Seo, J.; Yu, K.; Lee, K.S.; Kim, J.S.; Min, K.J.; Graff, J.M. Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. *Cell Metab.* **2013**, *17*, 101–112, doi:10.1016/j.cmet.2012.12.006.

300. Hardie, D.G.; Carling, D.; Carlson, M. The AMP-activated/SNF1 protein kinase subfamily: Metabolic sensors of the eukaryotic cell? *Annu. Rev. Biochem.* **1998**, *67*, 821–855, doi:10.1146/annurev.biochem.67.1.821.

301. Viollet, B.; Andreelli, F. AMP-activated protein kinase and metabolic control. *Handb. Exp. Pharmacol.* **2011**, *303–330*, doi:10.1007/978-3-642-17214-4_13.

302. Burns, K.A.; Vanden Heuvel, J.P. Modulation of PPAR activity via phosphorylation. *Biochim. Biophys. Acta* **2007**, *1771*, 952–960, doi:10.1016/j.bbalip.2007.04.018.

303. Li, J.; Miller, E.J.; Ninomiya-Tsuji, J.; Russell, R.R., 3rd; Young, L.H. AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart. *Circ. Res.* **2005**, *97*, 872–879, doi:10.1161/01 RES.0000187458.77026.10.

304. Lemieux, K.; Konrad, D.; Klip, A.; Marette, A. The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle. *FASEB J.* **2003**, *17*, 1658–1665, doi:10.1096/fj.02-1125com.

305. Hunter, R.W.; Treebak, J.T.; Wojtaszewski, J.F.; Sakamoto, K. Molecular mechanism by which AMP-activated protein kinase activation promotes glycogen accumulation in muscle. *Diabetes* **2011**, *60*, 766–774, doi:10.2337/db10-1148.

306. Hinds, T.D., Jr.; Burns, K.A.; Hosick, P.A.; McBeth, L.; Nestor-Kalinoski, A.; Drummond, H.A.; AlAmodi, A.A.; Hankins, M.W.; Vanden Heuvel, J.P.; Stec, D.E. Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3beta Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) alpha. *J. Biol. Chem.* **2016**, *291*, 25179–25191, doi:10.1074/jbc.M116.731703.

307. Lee, W.J.; Kim, M.; Park, H.S.; Kim, H.S.; Jeon, M.J.; Oh, K.S.; Koh, E.H.; Won, J.C.; Kim, M.S.; Oh, G.T.; et al. AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1. *Biochem. Biophys. Res. Commun.* **2006**, *340*, 291–295, doi:10.1016/j.bbrc.2005.12.011.

308. Yoon, M.J.; Lee, G.Y.; Chung, J.J.; Ahn, Y.H.; Hong, S.H.; Kim, J.B. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. *Diabetes* **2006**, *55*, 2562–2570, doi:10.2337/db05-1322.

309. Hotta, K.; Funahashi, T.; Arita, Y.; Takahashi, M.; Matsuda, M.; Okamoto, Y.; Iwahashi, H.; Kuriyama, H.; Ouchi, N.; Maeda, K.; et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. *Arterioscler. Thromb. Vasc. Biol.* **2000**, *20*, 1595–1599, doi:10.1161/01.atv.20.6.1595.

310. Gan, Z.; Burkart-Hartman, E.M.; Han, D.H.; Finck, B.; Leone, T.C.; Smith, E.Y.; Ayala, J.E.; Holloszy, J.; Kelly, D.P. The nuclear receptor PPARbeta/delta programs muscle glucose metabolism in cooperation with AMPK and MEF2. *Genes Dev.* **2011**, *25*, 2619–2630, doi:10.1101/gad.178434.111.

311. Bai, F.; Liu, Y.; Tu, T.; Li, B.; Xiao, Y.; Ma, Y.; Qin, F.; Xie, J.; Zhou, S.; Liu, Q. Metformin regulates lipid metabolism in a canine model of atrial fibrillation through AMPK/PPAR-alpha/VLCAD pathway. *Lipids Health Dis.* **2019**, *18*, 109, doi:10.1186/s12944-019-1059-7.

312. Joly, E.; Roduit, R.; Peyot, M.L.; Habinowski, S.A.; Ruderman, N.B.; Witters, L.A.; Prentki, M. Glucose represses PPARalpha gene expression via AMP-activated protein kinase but not via p38 mitogen-activated protein kinase in the pancreatic beta-cell. *J. Diabetes* **2009**, *1*, 263–272, doi:10.1111/j.1753-0407.2009.00043.x.

313. Ravnskjaer, K.; Boergesen, M.; Dalgaard, L.T.; Mandrup, S. Glucose-induced repression of PPARalpha gene expression in pancreatic beta-cells involves PP2A activation and AMPK inactivation. *J. Mol. Endocrinol.* **2006**, *36*, 289–299, doi:10.1677/jme.1.01965.

314. Bronner, M.; Hertz, R.; Bar-Tana, J. Kinase-independent transcriptional co-activation of peroxisome proliferator-activated receptor alpha by AMP-activated protein kinase. *Biochem. J.* **2004**, *384*, 295–305, doi:10.1042/BJ20040955.
315. Sozio, M.S.; Lu, C.; Zeng, Y.; Liangpunsakul, S.; Crabb, D.W. Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells. *Am. J. Physiol. Gastrointest. Liver Physiol.* **2011**, *301*, G739-G747, doi:10.1152/ajpgi.00432.2010.

316. Chanda, D.; Lee, C.H.; Kim, Y.H.; Noh, J.R.; Kim, D.K.; Park, J.H.; Hwang, J.H.; Lee, M.R.; Jeong, K.H.; Lee, I.K.; et al. Fenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate-activated protein kinase-dependent induction of orphan nuclear receptor small heterodimer partner. *Hepatology* **2009**, *50*, 880-892, doi:10.1002/hep.23049.

317. Liangpunsakul, S.; Wou, S.E.; Wineinger, K.D.; Zeng, Y.; Cyganek, I.; Jayaram, H.N.; Crabb, D.W. Effects of WY-14,643 on the phosphorylation and activation of AMP-dependent protein kinase. *Arch. Biochem. Biophys.* **2009**, *485*, 10-15, doi:10.1016/j.abb.2009.02.006.

318. Ren, G.; Rimando, A.M.; Mathews, S.T. AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells. *Biochem. Biophys. Res. Commun.* **2018**, *498*, 640-645, doi:10.1016/j.bbrc.2018.03.035.

319. Murakami, H.; Murakami, R.; Kambe, F.; Cao, X.; Takahashi, R.; Asai, T.; Hirai, T.; Numaguchi, Y.; Okumura, K.; Seo, H.; et al. Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC. *Biochem. Biophys. Res. Commun.* **2006**, *341*, 973-978, doi:10.1016/j.bbrc.2006.01.052.

320. Okayasu, T.; Tomizawa, A.; Suzuki, K.; Manaka, K.; Hattori, Y. PPARalpha activators upregulate eNOS activity and inhibit cytokine-induced NF-kappaB activation through AMP-activated protein kinase activation. *Life Sci.* **2008**, *82*, 884-891, doi:10.1016/j.lfs.2008.02.002.

321. Manio, M.C.; Inoue, K.; Fujitani, M.; Matsumura, S.; Fushiki, T. Combined pharmacological activation of AMPK and PPARdelta potentiates the effects of exercise in trained mice. *Physiol. Rep.* **2016**, *4*, doi:10.14814/phy2.12625.

322. Narkar, V.A.; Downes, M.; Yu, R.T.; Embler, E.; Wang, Y.X.; Banayo, E.; Mihaylova, M.M.; Nelson, M.C.; Zou, Y.; Juguilon, H.; et al. AMPK and PPARdelta agonists are exercise mimetics. *Cell* **2008**, *134*, 405-415, doi:10.1016/j.cell.2008.06.051.

323. Lamontagne, J.; Pepin, E.; Peyot, M.L.; Joly, E.; Ruderman, N.B.; Poitout, V.; Madiraju, S.R.; Nolan, C.J.; Prentki, M. Pioglitazone acutely reduces insulin secretion and causes metabolic deceleration of the pancreatic beta-cell at submaximal glucose concentrations. *Endocrinology* **2009**, *150*, 3465-3474, doi:10.1210/en.2008-1557.

324. Boyle, J.G.; Logan, P.J.; Ewart, M.A.; Reihill, J.A.; Ritchie, S.A.; Connell, J.M.; Cleland, S.J.; Salt, I.P. Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase. *J. Biol. Chem.* **2008**, *283*, 11210-11217, doi:10.1074/jbc.M710048200.

325. Ceolotto, G.; Gallo, A.; Papparella, I.; Franco, L.; Murphy, E.; Iori, E.; Pagnin, E.; Fadini, G.P.; Albiero, M.; Semplicini, A.; et al. Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism. *Arterioscler. Thromb. Vasc. Biol.* **2007**, *27*, 2627-2633, doi:10.1161/ATVBAHA.107.155762.

326. Sun, H.; Zhu, X.; Lin, W.; Zhou, Y.; Cai, W.; Qiu, L. Interactions of TLR4 and PPARgamma, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells. *Cell Physiol. Biochem.* **2017**, *42*, 1227-1239, doi:10.1159/000478920.

327. Wang, X.; Zhou, L.; Shao, L.; Qian, L.; Fu, X.; Li, G.; Luo, T.; Gu, Y.; Li, F.; Li, J.; et al. Troglitazone acutely activates AMP-activated protein kinase and inhibits insulin secretion from beta cells. *Life Sci.* **2007**, *81*, 160-165, doi:10.1016/j.lfs.2007.04.034.

328. LeBrasseur, N.K.; Kelly, M.; Tsao, T.S.; Farmer, S.R.; Saha, A.K.; Ruderman, N.B.; Tomas, E. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. *Am. J. Physiol. Endocrinol. Metab.* **2006**, *291*, E175-E181, doi:10.1152/ajpendo.00453.2005.

329. Shen, Z.; Liang, X.; Rogers, C.Q.; Rideout, D.; You, M. Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice. *Am. J. Physiol. Gastrointest. Liver Physiol.* **2010**, *298*, G364-G374, doi:10.1152/ajpgi.00456.2009.

330. Saha, A.K.; Avilucea, P.R.; Ye, J.M.; Assifi, M.M.; Kraegen, E.W.; Ruderman, N.B. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. *Biochem. Biophys. Res. Commun.* **2004**, *314*, 580-585, doi:10.1016/j.bbrc.2003.12.120.

331. Ye, J.M.; Dzamko, N.; Hoy, A.J.; Iglesias, M.A.; Kemp, B.; Kraegen, E. Rosiglitazone treatment enhances acute AMP-activated protein kinase-mediated muscle and adipose tissue glucose uptake in high-fat-fed rats. *Diabetes* **2006**, *55*, 2797-2804, doi:10.2337/db05-1315.
332. Coletta, D.K.; Sriwijitkamol, A.; Wajcberg, E.; Tantiwong, P.; Li, M.; Prentki, M.; Madiraju, M.; Jenkinson, C.P.; Cersosimo, E.; Musi, N.; et al. Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: A randomised trial. *Diabetologia* **2009**, *52*, 723–732, doi:10.1007/s00125-008-1256-9.

333. Xiao, X.; Su, G.; Brown, S.N.; Chen, L.; Ren, J.; Zhao, P. Peroxisome proliferator-activated receptors gamma and alpha agonists stimulate cardiac glucose uptake via activation of AMP-activated protein kinase. *J. Nutr. Biochem.* **2010**, *21*, 621–626, doi:10.1016/j.jnutbio.2009.03.011.

334. Ratziu, V.; Charlotte, F.; Bernhardt, C.; Giral, P.; Halbron, M.; Lenaour, G.; Hartmann-Heurtier, A.; Bruckert, E.; Poynard, T.; Group, L.S. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. *Hepatology* **2010**, *51*, 445–453, doi:10.1002/hep.23270.

335. Zhang, F.; Dey, D.; Branstrom, R.; Forsberg, L.; Lu, M.; Zhang, Q.; Sjoholm, A. BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner. *Am. J. Physiol. Cell Physiol.* **2009**, *296*, C346–C354, doi:10.1152/ajpcell.00444.2008.

336. Chang, T.J.; Chen, W.P.; Yang, C.; Lu, P.H.; Liang, Y.C.; Su, M.J.; Lee, S.C.; Chuang, L.M. Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the K(ATP) channel and insulin secretion in rats. *Diabetologia* **2009**, *52*, 1112–1121, doi:10.1007/s00125-009-1337-4.

337. Fryer, L.G.; Parbu-Patel, A.; Carling, D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. *J. Biol. Chem.* **2002**, *277*, 25226–25232, doi:10.1074/jbc.M202489200.

338. Gonzalez, E.; McGraw, T.E. The Akt kinases: Isoform specificity in metabolism and cancer. *Cell Cycle* **2009**, *8*, 2502–2508, doi:10.4161/cc.8.16.9335.

339. Oh, W.J.; Jacinto, E. mTOR complex 2 signaling and functions. *Cell Cycle* **2011**, *10*, 2305–2316, doi:10.4161/cc.10.14.16586.

340. Piscitello, D.; Varshney, D.; Lilla, S.; Vizioli, M.G.; Reid, C.; Gorbunova, V.; Seluanov, A.; Gillespie, D.A.; Adams, P.D. AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. *Oncogene* **2018**, *37*, 427–438, doi:10.1038/onc.2017.340.

341. Jia, Y.; Song, W.; Zhang, F.; Yan, J.; Yang, Q. Akt1 inhibits homologous recombination in Brca1-deficient cells by blocking the Chk1-Rad51 pathway. *Oncogene* **2013**, *32*, 1943–1949, doi:10.1038/onc.2012.211.

342. Liu, P.; Gan, W.; Guo, C.; Xie, A.; Gao, D.; Guo, J.; Zhang, J.; Willis, N.; Su, A.; Asara, J.M.; et al. Akt-mediated phosphorylation of XLF impairs non-homologous end-joining DNA repair. *Mol. Cell* **2015**, *57*, 648–661, doi:10.1016/j.molcel.2015.01.005.

343. Haeusler, R.A.; McGraw, T.E.; Accili, D. Biochemical and cellular properties of insulin receptor signalling. *Nat. Rev. Mol. Cell Biol.* **2018**, *19*, 31–44, doi:10.1038/nrm.2017.89.

344. Rowland, A.F.; Fazakerley, D.J.; James, D.E. Mapping insulin/GLUT4 circuitry. *Traffic* **2011**, *12*, 672–681, doi:10.1111/j.1600-0854.2011.01178.x.

345. Bevan, P. Insulin signalling. *J. Cell Sci.* **2001**, *114*, 1429–1430.

346. Siddle, K. Signalling by insulin and IGF receptors: Supporting acts and new players. *J. Mol. Endocrinol.* **2011**, *47*, R1–R10, doi:10.1530/JME-11-0022.

347. Wong, R.H.; Sul, H.S. Insulin signaling in fatty acid and fat synthesis: A transcriptional perspective. *Curr. Opin. Pharmacol.* **2010**, *10*, 684–691, doi:10.1016/j.coph.2010.08.004.

348. Weindruch, R. The retardation of aging by caloric restriction: Studies in rodents and primates. *Toxicol. Pathol.* **1996**, *24*, 742–745, doi:10.1177/019262339602400618.

349. Shimokawa, I.; Komatsu, T.; Hayashi, N.; Kim, S.E.; Kawata, T.; Park, S.; Hayashi, H.; Yamaza, H.; Chiba, T.; Mori, R. The life-extending effect of dietary restriction requires Foxo3 in mice. *Aging Cell* **2015**, *14*, 707–709, doi:10.1111/acel.12340.

350. Kim, D.H.; Park, M.H.; Lee, E.K.; Choi, Y.J.; Chung, K.W.; Moon, K.M.; Kim, M.J.; An, H.J.; Park, J.W.; Kim, N.D.; et al. The roles of FoxOs in modulation of aging by calorie restriction. *Biogerontology* **2015**, *16*, 1–14, doi:10.1007/s10522-014-9519-y.

351. Bluher, M.; Kahn, B.B.; Kahn, C.R. Extended longevity in mice lacking the insulin receptor in adipose tissue. *Science* **2003**, *299*, 572–574, doi:10.1126/science.1078223.
352. Dosch, J.; Meissner, U.; Rascher, W. Prolonged lifespan by defective insulin signalling? *Eur. J. Endocrinol.* **2003**, *148*, 489–490, doi:10.1530/eje.0.1480489.

353. Tatar, M.; Bartke, A.; Antebi, A. The endocrine regulation of aging by insulin-like signals. *Science* **2003**, *299*, 1346–1351, doi:10.1126/science.1081447.

354. Kenyon, C.; Chang, J.; Gensch, E.; Rudner, A.; Tabtiang, R. A *C. elegans* mutant that lives twice as long as wild type. *Nature* **1993**, *366*, 461–464, doi:10.1038/366461a0.

355. Holzenberger, M.; Dupont, J.; Ducos, B.; Leneuve, P.; Geloen, A.; Even, P.C.; Cervera, P.; Le Bouc, Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. *Nature* **2003**, *421*, 182–187, doi:10.1038/nature01298.

356. Taguchi, A.; Wartschow, L.M.; White, M.F. Brain IRS2 signaling coordinates life span and nutrient homeostasis. *Science* **2007**, *317*, 369–372, doi:10.1126/science.1142179.

357. Selman, C.; Lingard, S.; Choudhury, A.I.; Batterham, R.L.; Claret, M.; Clements, M.; Ramadani, F.; Okkenhaug, K.; Schuster, E.; Blanc, E.; et al. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. *FASEB J.* **2008**, *22*, 807–818, doi:10.1096/fj.07-9261com.

358. Coschigano, K.T.; Holland, A.N.; Riders, M.E.; List, E.O.; Flyvbjerg, A.; Kopchick, J.J. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. *Endocrinology* **2003**, *144*, 3799–3810, doi:10.1210/en.2003-0374.

359. Bonkowski, M.S.; Rocha, J.S.; Masternak, M.M.; Al Regaiey, K.A.; Bartke, A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. *Proc. Natl. Acad. Sci. USA* **2006**, *103*, 7901–7905, doi:10.1073/pnas.0600161103.

360. Kurosu, H.; Yamamoto, M.; Clark, J.D.; Pastor, J.V.; Nandi, A.; Gurnani, P.; McGuinness, O.P.; Chikuda, H.; Yamaguchi, M.; Kawaguchi, H.; et al. Suppression of aging in mice by the hormone Klotho. *Science* **2005**, *309*, 1829–1833, doi:10.1126/science.1112766.

361. Erol, A. Insulin resistance is an evolutionarily conserved physiological mechanism at the cellular level for protection against increased oxidative stress. *Bioessays* **2007**, *29*, 811–818, doi:10.1002/bies.20618.

362. Dobbins, R.L.; Chester, M.W.; Stevenson, B.E.; Daniels, M.B.; Stein, D.T.; McGarry, J.D. A fatty acid-dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion. *J. Clin. Investig.* **1998**, *101*, 2370–2376, doi:10.1172/JCI1813.

363. Gremlich, S.; Nolan, C.; Roduit, R.; Burcelin, R.; Peyot, M.L.; Delghingaro-Augusto, V.; Desvergne, B.; Michalik, L.; Prentki, M.; Wahli, W. Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-activated receptor alpha transcriptional up-regulation of fatty acid oxidation. *Endocrinology* **2005**, *146*, 375–382, doi:10.1210/en.2004-0667.

364. Ravnskjaer, K.; Boergesen, M.; Rubi, B.; Larsen, J.K.; Nielsen, T.; Fridriksson, J.; Maechler, P.; Mandrup, S. Peroxisome proliferator-activated receptor alpha (PPARalpha) potentiates, whereas PPARgamma attenuates, glucose-stimulated insulin secretion in pancreatic beta-cells. *Endocrinology* **2005**, *146*, 3266–3276, doi:10.1210/en.2004-1430.

365. Holness, M.J.; Smith, N.D.; Greenwood, G.K.; Sugden, M.C. Acute (24 h) activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) reverses high-fat feeding-induced insulin hypersecretion in vivo and in perifused pancreatic islets. *J. Endocrinol.* **2003**, *177*, 197–205, doi:10.1677/joe.0.1770197.

366. Lalloyer, F.; Vandewalle, B.; Percevault, F.; Torpier, G.; Kerr-Conte, J.; Oosterveer, M.; Paumelle, R.; Fruchart, J.C.; Kuipers, F.; Pattou, F.; et al. Peroxisome proliferator-activated receptor alpha improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets. *Diabetes* **2006**, *55*, 1605–1613, doi:10.2337/db06-0016.

367. Maida, A.; Lamont, B.J.; Cao, X.; Drucker, D.J. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. *Diabetologia* **2011**, *54*, 339–349, doi:10.1007/s00125-010-1937-z.

368. Patsouris, D.; Mandard, S.; Voshol, P.J.; Escher, P.; Tan, N.S.; Havekes, L.M.; Koenig, W.; Marz, W.; Tafuri, S.; Wahli, W.; et al. PPARalpha governs glycerol metabolism. *J. Clin. Investig.* **2004**, *114*, 94–103, doi:10.1172/JCI20468.

369. Wu, P.; Peters, J.M.; Harris, R.A. Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor alpha. *Biochem. Biophys. Res. Commun.* **2001**, *287*, 391–396, doi:10.1006/bbrc.2001.5608.
370. Sugden, M.C.; Greenwood, G.K.; Smith, N.D.; Holness, M.J. Peroxisome proliferator-activated receptor-alpha activation during pregnancy attenuates glucose-stimulated insulin hypersecretion in vivo by increasing insulin sensitivity, without impairing pregnancy-induced increases in beta-cell glucose sensing and responsiveness. *Endocrinology* **2003**, *144*, 146-153, doi:10.1210/en.2002-220811.

371. Ferrari, C.; Frezzati, S.; Romussi, M.; Bertazzoni, A.; Testori, G.P.; Antonini, S.; Paracchi, A. Effects of short-term clofibrate administration on glucose tolerance and insulin secretion in patients with chemical diabetes or hypertriglyceridemia. *Metabolism* **1977**, *26*, 129-139, doi:10.1016/0026-0495(77)90048-8.

372. Murakami, K.; Nambu, S.; Koh, H.; Kobayashi, M.; Shigeta, Y. Clofibrate enhances the affinity of insulin receptors in non-insulin dependent diabetes mellitus. *Br. J. Clin. Pharmacol.* **1984**, *17*, 89-91, doi:10.1111/j.1365-2125.1984.tb05005.x.

373. Kobayashi, M.; Shigeta, Y.; Hirata, Y.; Omori, Y.; Sakamoto, N.; Nambu, S.; Baba, S. Improvement of glucose tolerance in NIDDM by clofibrate. Randomized double-blind study. *Diabetes Care* **1988**, *11*, 495-499, doi:10.2337/diacare.11.6.495.

374. Koh, E.H.; Kim, M.S.; Park, J.Y.; Kim, H.S.; Youn, J.Y.; Park, H.S.; Youn, J.H.; Lee, K.U. Peroxisome proliferator-activated receptor (PPAR)-alpha activation prevents diabetes in OLETF rats: Comparison with PPAR-gamma activation. *Diabetes* **2003**, *52*, 2331-2337, doi:10.2337/diabetes.52.9.2331.

375. Guerre-Millo, M.; Gervois, P.; Raspe, E.; Madsen, L.; Poulain, P.; Derudas, B.; Herbert, J.M.; Winegar, D.A.; Willson, T.M.; Fruchart, J.C.; et al. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. *J. Biol. Chem.* **2000**, *275*, 16638-16642, doi:10.1074/jbc.275.22.16638.

376. Aasum, E.; Belke, D.D.; Severson, D.L.; Riemersma, R.A.; Cooper, M.; Andreassen, M.; Larsen, T.S. Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator. *Am. J. Physiol. Heart Circ. Physiol.* **2002**, *283*, H949-H957, doi:10.1152/ajpheart.00226.2001.

377. Park, C.W.; Zhang, Y.; Zhang, X.; Wu, J.; Chen, L.; Cha, D.R.; Su, D.; Hwang, M.T.; Fan, X.; Davis, L.; et al. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. *Kidney Int.* **2006**, *69*, 1511-1517, doi:10.1038/sj.ki.5000209.

378. Sugden, M.C.; Bulmer, K.; Gibbons, G.F.; Knight, B.L.; Holness, M.J. Peroxisome-proliferator-activated receptor-alpha (PPARalpha) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin. *Biochem. J.* **2002**, *364*, 361-368, doi:10.1042/BJ20011699.

379. Guerre-Millo, M.; Rouault, C.; Poulain, P.; Andre, J.; Poitout, V.; Peters, J.M.; Gonzalez, F.J.; Fruchart, J.C.; Reach, G.; Staels, B. PPAR-alpha-null mice are protected from high-fat diet-induced insulin resistance. *Diabetes* **2001**, *50*, 2809-2814, doi:10.2337/diabetes.50.12.2809.

380. Jo, Y.S.; Ryu, D.; Maida, A.; Wang, X.; Evans, R.M.; Schoonjans, K.; Auwerx, J. Phosphorylation of the nuclear receptor corepressor 1 by protein kinase B switches its corepressor targets in the liver in mice. *Hepatology* **2015**, *62*, 1606-1618, doi:10.1002/hep.27907.

381. Roduit, R.; Morin, J.; Masse, F.; Segall, L.; Roche, E.; Newgard, C.B.; Assimacopoulos-Jeannet, F.; Prentki, M. Glucose down-regulates the expression of the peroxisome proliferator-activated receptor-alpha gene in the pancreatic beta-cell. *J. Biol. Chem.* **2000**, *275*, 35799-35806, doi:10.1074/jbc.M006001200.

382. Blanquart, C.; Mansouri, R.; Paumelle, R.; Fruchart, J.C.; Staels, B.; Glineur, C. The protein kinase C signaling pathway regulates a molecular switch between transactivation and transrepression activity of the peroxisome proliferator-activated receptor alpha. *Mol. Endocrinol.* **2004**, *18*, 1906-1918, doi:10.1210/me.2003-0327.

383. Hostetler, H.A.; Huang, H.; Kier, A.B.; Schroeder, F. Glucose directly links to lipid metabolism through high affinity interaction with peroxisome proliferator-activated receptor alpha. *J. Biol. Chem.* **2008**, *283*, 2246-2254, doi:10.1074/jbc.M705138200.

384. Cohen, G.; Riahi, Y.; Shamni, O.; Guichardant, M.; Chatgilialoglu, C.; Ferreri, C.; Kaiser, N.; Sasson, S. Role of lipid peroxidation and PPAR-delta in amplifying glucose-stimulated insulin secretion. *Diabetes* **2011**, *60*, 2830-2842, doi:10.2337/db11-0347.

385. Iglesias, J.; Barg, S.; Vallois, D.; Lahiri, S.; Roger, C.; Yessoufou, A.; Pradevand, S.; McDonald, A.; Bonal, C.; Reimann, F.; et al. PPARbeta/delta affects pancreatic beta cell mass and insulin secretion in mice. *J. Clin. Investig.* **2012**, *122*, 4105-4117, doi:10.1172/JCI42127.

386. Serrano-Marco, L.; Rodriguez-Calvo, R.; El Kochairi, I.; Palomer, X.; Michalik, L.; Wahli, W.; Vazquez-Carrera, M. Activation of peroxisome proliferator-activated receptor-beta/-delta (PPAR-beta/-delta) ameliorates insulin signaling and reduces SOCS3 levels by inhibiting STAT3 in interleukin-6-stimulated adipocytes. *Diabetes* **2011**, *60*, 1990-1999, doi:10.2337/db10-0704.
387. Serrano-Marco, L.; Barroso, E.; El Kochairi, I.; Palomer, X.; Michalik, L.; Wahli, W.; Vazquez-Carrera, M. The peroxisome proliferator-activated receptor (PPAR) beta/delta agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. *Diabetologia* **2012**, *55*, 743–751, doi:10.1007/s00125-011-2401-4.

388. Salvado, L.; Barroso, E.; Gomez-Foix, A.M.; Palomer, X.; Michalik, L.; Wahli, W.; Vazquez-Carrera, M. PPARbeta/delta prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. *Diabetologia* **2014**, *57*, 2126–2135, doi:10.1007/s00125-014-3331-8.

389. Lee, C.H.; Olson, P.; Hevener, A.; Mehl, I.; Chong, L.W.; Olefsky, J.M.; Gonzalez, F.J.; Ham, J.; Kang, H.; Peters, J.M.; et al. PPARdelta regulates glucose metabolism and insulin sensitivity. *Proc. Natl. Acad. Sci. USA* **2006**, *103*, 3444–3449, doi:10.1073/pnas.0511253103.

390. Oliver, W.R., Jr.; Shenk, J.L.; Snaith, M.R.; Russell, C.S.; Plunket, K.D.; Bodkin, N.L.; Lewis, M.C.; Winegar, D.A.; Sznaidman, M.L.; Lambert, M.H.; et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. *Proc. Natl. Acad. Sci. USA* **2001**, *98*, 5306–5311, doi:10.1073/pnas.091021198.

391. Tanaka, T.; Yamamoto, J.; Iwasaki, S.; Asaba, H.; Hamura, H.; Ikeda, Y.; Watanabe, M.; Magoori, K.; Ioka, R.X.; Tachibana, K.; et al. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. *Proc. Natl. Acad. Sci. USA* **2003**, *100*, 15924–15929, doi:10.1073/pnas.0306981100.

392. Riserus, U.; Sprecher, D.; Johnson, T.; Olson, E.; Hirschberg, S.; Liu, A.; Fang, Z.; Hegde, P.; Richards, D.; Sarov-Blat, L.; et al. Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. *Diabetes* **2008**, *57*, 332–339, doi:10.2337/db07-1318.

393. Cariou, B.; Hanf, R.; Lambert-Porcheron, S.; Zair, Y.; Sauvinet, V.; Noel, B.; Flet, L.; Vidal, H.; Staels, B.; Laville, M. Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. *Diabetes Care* **2013**, *36*, 2923–2930, doi:10.2337/dc12-2012.

394. Buchanan, T.A.; Xiang, A.H.; Peters, R.K.; Kjos, S.L.; Marroquin, A.; Goico, J.; Ochoa, C.; Tan, S.; Berkowitz, K.; Hodis, H.N.; et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. *Diabetes* **2002**, *51*, 2796–2803, doi:10.2337/diabetes.51.9.2796.

395. Knowler, W.C.; Hamman, R.F.; Edelstein, S.L.; Barrett-Connor, E.; Ehrmann, D.A.; Walker, E.A.; Fowler, S.E.; Nathan, D.M.; Kahn, S.E.; Diabetes Prevention Program Research, G. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. *Diabetes* **2005**, *54*, 1150–1156, doi:10.2337/diabetes.54.4.1150.

396. Moitra, J.; Mason, M.M.; Olive, M.; Krylov, D.; Gavrilova, O.; Marcus-Samuels, B.; Feigenbaum, L.; Lee, E.; Aoyama, T.; Eckhaus, M.; et al. Life without white fat: A transgenic mouse. *Genes Dev.* **1998**, *12*, 3168–3181.

397. Larsen, T.M.; Toubro, S.; Astrup, A. PPARgamma agonists in the treatment of type II diabetes: Is increased fatness commensurate with long-term efficacy? *Int. J. Obes. Relat. Metab. Disord.* **2003**, *27*, 147–161, doi:10.1038/sj.ijo.802223.

398. Ye, J.M.; Doyle, P.J.; Iglesias, M.A.; Watson, D.G.; Cooney, G.J.; Kraegen, E.W. Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: Comparison with PPAR-gamma activation. *Diabetes* **2001**, *50*, 411–417, doi:10.2337/diabetes.50.2.411.

399. Collino, M.; Aragno, M.; Castiglia, S.; Miglio, G.; Tomasinelli, C.; Boccuzzi, G.; Thiemermann, C.; Fantozzi, R. Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation. *Br. J. Pharmacol.* **2010**, *160*, 1892–1902, doi:10.1111/j.1476-5381.2010.00671.x.

400. Iwata, M.; Haruta, T.; Usui, I.; Takata, Y.; Takano, A.; Uno, T.; Kawahara, J.; Ueno, E.; Sasaoka, T.; Ishibashi, O.; et al. Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator-activated receptor-gamma. *Diabetes* **2001**, *50*, 1083–1092, doi:10.2337/diabetes.50.5.1083.
401. Smith, U.; Gogg, S.; Johansson, A.; Olausson, T.; Rotter, V.; Svalstedt, B. Thiazolidinediones (PPARgamma agonists) but not PPARalpha agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes. *FASEB J.* **2001**, *15*, 215–220, doi:10.1096/fj.00-0020com.

402. Rieusset, J.; Auwerx, J.; Vidal, H. Regulation of gene expression by activation of the peroxisome proliferator-activated receptor gamma with rosiglitazone (BRL 49653) in human adipocytes. *Biochem. Biophys. Res. Commun.* **1999**, *265*, 265–271, doi:10.1006/bbrc.1999.1657.

403. Baumann, C.A.; Chokshi, N.; Saltiel, A.R.; Ribon, V. Cloning and characterization of a functional peroxisome proliferator activator receptor-gamma-responsive element in the promoter of the CAP gene. *J. Biol. Chem.* **2000**, *275*, 9131–9135, doi:10.1074/jbc.275.13.9131.

404. Ribon, V.; Johnson, J.H.; Camp, H.S.; Saltiel, A.R. Thiazolidinediones and insulin resistance: Peroxisome proliferator-activated receptor gamma activation stimulates expression of the CAP gene. *Proc. Natl. Acad. Sci. USA* **1998**, *95*, 14751–14756, doi:10.1073/pnas.95.25.14751.

405. Liu, J.; DeYoung, S.M.; Hwang, J.B.; O'Leary, E.E.; Saltiel, A.R. The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. *J. Biol. Chem.* **2003**, *278*, 36754–36762, doi:10.1074/jbc.M300664200.

406. Kramer, D.; Shapiro, R.; Adler, A.; Bush, E.; Rondinone, C.M. Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. *Metabolism* **2001**, *50*, 1294–1300, doi:10.1053/meta.2001.27202.

407. Standaert, M.L.; Kanoh, Y.; Sajan, M.P.; Bandyopadhyay, G.; Farese, R.V. Cbl, IRS-1, and IRS-2 mediate effects of rosiglitazone on PI3K, PKC-lambda, and glucose transport in 3T3/L1 adipocytes. *Endocrinology* **2002**, *143*, 1705–1716, doi:10.1210/endo.143.5.8812.

408. Kim, H.I.; Kim, J.W.; Kim, S.H.; Cha, J.Y.; Kim, K.S.; Ahn, Y.H. Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter. *Diabetes* **2000**, *49*, 1517–1524, doi:10.2337/diabetes.49.9.1517.

409. Samaha, F.F.; Szapary, P.O.; Iqbal, N.; Williams, M.M.; Bloedon, L.T.; Kochar, A.; Wolfe, M.L.; Rader, D.J. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. *Arterioscler. Thromb. Vasc. Biol.* **2006**, *26*, 624–630, doi:10.1161/01.ATV.0000200136.56716.30.

410. Rui, L.; Yuan, M.; Frantz, D.; Shoelson, S.; White, M.F. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. *J. Biol. Chem.* **2002**, *277*, 42394–42398, doi:10.1074/jbc.C200444200.

411. Farrell, G.C. Signalling links in the liver: Knitting SOCS with fat and inflammation. *J. Hepatol.* **2005**, *43*, 193–196, doi:10.1016/j.jhep.2005.04.004.

412. Szalkowski, D.; White-Carrington, S.; Berger, J.; Zhang, B. Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. *Endocrinology* **1995**, *136*, 1474–1481, doi:10.1210/endo.136.4.7895657.

413. Pajvani, U.B.; Hawkins, M.; Combs, T.P.; Rajala, M.W.; Doebber, T.; Berger, J.P.; Wagner, J.A.; Wu, M.; Knopps, A.; Xiang, A.H.; et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. *J. Biol. Chem.* **2004**, *279*, 12152–12162, doi:10.1074/jbc.M311113200.

414. Yamauchi, T.; Kamon, J.; Waki, H.; Terauchi, Y.; Kubota, N.; Hara, K.; Mori, Y.; Ide, T.; Murakami, K.; Tsuboyama-Kasaoka, N.; et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. *Nat. Med.* **2001**, *7*, 941–946, doi:10.1038/90984.

415. Armoni, M.; Harel, C.; Karni, S.; Chen, H.; Bar-Yoseph, F.; Ver, M.R.; Quon, M.J.; Karnieli, E. FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity. *J. Biol. Chem.* **2006**, *281*, 19881–19891, doi:10.1074/jbc.M600320200.

416. Fan, W.; Imamura, T.; Sonoda, N.; Sears, D.D.; Patsouris, D.; Kim, J.J.; Olefsky, J.M. FOXO1 transrepresses peroxisome proliferator-activated receptor gamma transactivation, coordinating an insulin-induced feed-forward response in adipocytes. *J. Biol. Chem.* **2009**, *284*, 12188–12197, doi:10.1074/jbc.M808915200.

417. Dowell, P.; Otto, T.C.; Adi, S.; Lane, M.D. Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. *J. Biol. Chem.* **2003**, *278*, 45485–45491, doi:10.1074/jbc.M309069200.

418. Nolan, J.J.; Ludvik, B.; Beerdsen, P.; Joyce, M.; Olefsky, J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. *N. Engl. J. Med.* **1994**, *331*, 1188–1193, doi:10.1056/NEJM199411033311803.
419. Barroso, I.; Gurnell, M.; Crowley, V.E.; Agostini, M.; Schwabe, J.W.; Soos, M.A.; Maslen, G.L.; Williams, T.D.; Lewis, H.; Schafer, A.J.; et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. *Nature* **1999**, *402*, 880–883, doi:10.1038/47254.

420. Savage, D.B.; Tan, G.D.; Acerini, C.L.; Jebb, S.A.; Agostini, M.; Gurnell, M.; Williams, R.L.; Umpleby, A.M.; Thomas, E.L.; Bell, J.D.; et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. *Diabetes* **2003**, *52*, 910–917, doi:10.2337/diabetes.52.4.910.

421. Agarwal, A.K.; Garg, A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. *J. Clin. Endocrinol. Metab.* **2002**, *87*, 408–411, doi:10.1210/jcem.87.1.8290.

422. Hegele, R.A.; Cao, H.; Frankowski, C.; Mathews, S.T.; Leff, T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. *Diabetes* **2002**, *51*, 3586–3590, doi:10.2337/diabetes.51.12.3586.

423. Demir, T.; Onay, H.; Savage, D.B.; Temeloglu, E.; Uzum, A.K.; Kadioglu, P.; Altay, C.; Ozen, S.; Demir, L.; Cavdar, U.; et al. Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor-gamma (PPARG) mutation, H449L: A comparison of people with this mutation and those with classic codon 482 Lamin A/C (LMNA) mutations. *Diabet Med.* **2016**, *33*, 1445–1450, doi:10.1111/dme.13061.

424. Ludtke, A.; Buettner, J.; Schmidt, H.H.; Worman, H.J. New PPARG mutation leads to lipodystrophy and loss of protein function that is partially restored by a synthetic ligand. *J. Med. Genet.* **2007**, *44*, e88, doi:10.1136/jmg.2007.050567.

425. Ludtke, A.; Buettner, J.; Wu, W.; Muchir, A.; Schroeter, A.; Zinn-Justin, S.; Spuler, S.; Schmidt, H.H.; Worman, H.J. Peroxisome proliferator-activated receptor-gamma C190S mutation causes partial lipodystrophy. *J. Clin. Endocrinol. Metab.* **2007**, *92*, 2248–2255, doi:10.1210/jc.2005-2624.

426. Reitman, M.L.; Arioglu, E.; Gavrilova, O.; Taylor, S.I. Lipoatrophy revisited. *Trends Endocrinol. Metab.* **2000**, *11*, 410–416.

427. Jones, J.R.; Barrick, C.; Kim, K.A.; Lindner, J.; Blondeau, B.; Fujimoto, Y.; Shiota, M.; Kesterson, R.A.; Kahn, B.B.; Magnuson, M.A. Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. *Proc. Natl. Acad. Sci. USA* **2005**, *102*, 6207–6212, doi:10.1073/pnas.0306743102.

428. Corton, J.C.; Brown-Borg, H.M. Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. *J. Gerontol. Biol. Sci. Med. Sci.* **2005**, *60*, 1494–1509, doi:10.1093/gerona/60.12.1494.

429. Carvalho, C.R.; Brenelli, S.L.; Silva, A.C.; Nunes, A.L.; Velloso, L.A.; Saad, M.J. Effect of aging on insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of rats. *Endocrinology* **1996**, *137*, 151–159, doi:10.1210/endo.137.1.8536607.

430. Rocchi, S.; Picard, F.; Vamecq, J.; Gelman, L.; Potier, N.; Zeyer, D.; Dubuquoy, L.; Bac, P.; Champy, M.F.; Plunket, K.D.; et al. A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity. *Mol. Cell* **2001**, *8*, 737–747.

431. Dunn, F.L.; Higgins, L.S.; Fredrickson, J.; De Paoli, A.M.; group, I.N.T.S. Selective modulation of PPARgamma activity can lower plasma glucose without typical thiazolidinedione side-effects in patients with Type 2 diabetes. *J. Diabetes Complicat.* **2011**, *25*, 151–158, doi:10.1016/j.jdiacomp.2010.06.006.

432. Beekmann, K.; Rubio, L.; de Haan, L.H.; Actis-Goretta, L.; van der Burg, B.; van Bladeren, P.J.; Rietjens, I.M. The effect of quercetin and kaempferol aglycones and glucuronides on peroxisome proliferator-activated receptor-gamma (PPAR-gamma). *Food Funct.* **2015**, *6*, 1098–1107, doi:10.1039/c5fo00076a.

433. Fang, X.K.; Gao, J.; Zhu, D.N. Kaempferol and quercetin isolated from Euonymus alatus improve glucose uptake of 3T3-L1 cells without adipogenesis activity. *Life Sci.* **2008**, *82*, 615–622, doi:10.1016/j.lfs.2007.12.021.

434. Takahashi, H.; Hara, H.; Goto, T.; Kamakari, K.; Wataru, N.; Mohri, S.; Takahashi, N.; Suzuki, H.; Shibata, D.; Kawada, T. 13-Oxo-9(Z),11(E),15(Z)-octadecatrienoic acid activates peroxisome proliferator-activated receptor gamma in adipocytes. *Lipids* **2015**, *50*, 3–12, doi:10.1007/s11745-014-3972-x.

435. Zhang, Y.; Gu, M.; Cai, W.; Yu, L.; Feng, L.; Zhang, L.; Zang, Q.; Wang, Y.; Wang, D.; Chen, H.; et al. Dietary component isorhamnetin is a PPARgamma antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency. *Sci. Rep.* **2016**, *6*, 19288, doi:10.1038/srep19288.

436. Yamauchi, T.; Waki, H.; Kamon, J.; Murakami, K.; Motojima, K.; Komeda, K.; Miki, H.; Kubota, N.; Terauchi, Y.; Tsuchida, A.; et al. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes. *J. Clin. Investig.* **2001**, *108*, 1001–1013, doi:10.1172/JCI12864.
437. Kubota, N.; Terauchi, Y.; Miki, H.; Tamemoto, H.; Yamauchi, T.; Komeda, K.; Satoh, S.; Nakano, R.; Ishii, C.; Sugiyama, T.; et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. *Mol. Cell* **1999**, *4*, 597-609, doi:10.1016/s1097-2765(00)80210-5.

438. Miles, P.D.; Barak, Y.; He, W.; Evans, R.M.; Olefsky, J.M. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. *J. Clin. Investig.* **2000**, *105*, 287-292, doi:10.1172/JCI8538.

439. Yamauchi, T.; Kamon, J.; Waki, H.; Murakami, K.; Motojima, K.; Komeda, K.; Ide, T.; Kubota, N.; Terauchi, Y.; Tobe, K.; et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. *J. Biol. Chem.* **2001**, *276*, 41245-41254, doi:10.1074/jbc.M103241200.

440. Heikkinen, S.; Argmann, C.; Feige, J.N.; Koutnikova, H.; Champy, M.F.; Dali-Youcef, N.; Schadt, E.E.; Laakso, M.; Auwerx, J. The Pro12Ala PPARgamma2 variant determines metabolism at the gene-environment interface. *Cell Metab.* **2009**, *9*, 88-98, doi:10.1016/j.cmet.2008.11.007.

441. Deeb, S.S.; Fajas, L.; Nemoto, M.; Pihlajamaki, J.; Mykkanen, L.; Kuusisto, J.; Laakso, M.; Fujimoto, W.; Auwerx, J. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. *Nat. Genet.* **1998**, *20*, 284-287, doi:10.1038/3099.

442. Altshuler, D.; Hirschhorn, J.N.; Klannemark, M.; Lindgren, C.M.; Vohl, M.C.; Nemesh, J.; Lane, C.R.; Schaffner, S.F.; Bolk, S.; Brewer, C.; et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. *Nat. Genet.* **2000**, *26*, 76-80, doi:10.1038/79216.

443. Rieusset, J.; Touri, F.; Michalik, L.; Escher, P.; Desvergne, B.; Niesor, E.; Wahli, W. A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity. *Mol. Endocrinol.* **2002**, *16*, 2628-2644, doi:10.1210/me.2002-0036.

444. Mukherjee, R.; Hoener, P.A.; Jow, L.; Bilakovics, J.; Klausing, K.; Mais, D.E.; Faulkner, A.; Croston, G.E.; Paterniti, J.R., Jr. A selective peroxisome proliferator-activated receptor-gamma (PPARgamma) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes. *Mol. Endocrinol.* **2000**, *14*, 1425-1433, doi:10.1210/mend.14.9.0528.

445. Ferrara, N.; Rinaldi, B.; Corbi, G.; Conti, V.; Stiuso, P.; Boccuti, S.; Rengo, G.; Rossi, F.; Filippelli, A. Exercise training promotes SIRT1 activity in aged rats. *Rejuvenation Res.* **2008**, *11*, 139-150, doi:10.1089/rej.2007.0576.

446. Corbi, G.; Conti, V.; Scapagnini, G.; Filippelli, A.; Ferrara, N. Role of sirtuins, calorie restriction and physical activity in aging. *Front. Biosci. (Elite Ed.)* **2012**, *4*, 768-778.

447. Rack, J.G.; Morra, R.; Barkauskaite, E.; Kraehenbuehl, R.; Ariza, A.; Qu, Y.; Ortmayer, M.; Leidecker, O.; Cameron, D.R.; Matic, I.; et al. Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens. *Mol. Cell* **2015**, *59*, 309-320, doi:10.1016/j.molcel.2015.06.013.

448. Liou, G.G.; Tanny, J.C.; Kruger, R.G.; Walz, T.; Moazed, D. Assembly of the SIR complex and its regulation by O-acetyl-ADP-ribose, a product of NAD-dependent histone deacetylation. *Cell* **2005**, *121*, 515-527, doi:10.1016/j.cell.2005.03.035.

449. Vaquero, A.; Scher, M.; Lee, D.; Erdjument-Bromage, H.; Tempst, P.; Reinberg, D. Human SIRT1 interacts with histone H1 and promotes formation of facultative heterochromatin. *Mol. Cell* **2004**, *16*, 93-105, doi:10.1016/j.molcel.2004.08.031.

450. Dang, W. The controversial world of sirtuins. *Drug Discov. Today Technol.* **2014**, *12*, e9-e17, doi:10.1016/j.ddtec.2012.08.003.

451. Houtkooper, R.H.; Pirinen, E.; Auwerx, J. Sirtuins as regulators of metabolism and healthspan. *Nat. Rev. Mol. Cell Biol.* **2012**, *13*, 225-238, doi:10.1038/nrm3293.

452. Shimazu, T.; Hirshey, M.D.; Hua, L.; Dittenhafer-Reed, K.E.; Schwer, B.; Lombard, D.B.; Li, Y.; Bunkenborg, J.; Alt, F.W.; Denu, J.M.; et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. *Cell Metab.* **2010**, *12*, 654-661, doi:10.1016/j.cmet.2010.11.003.

453. Hirshey, M.D.; Shimazu, T.; Goetzman, E.; Jing, E.; Schwer, B.; Lombard, D.B.; Grueter, C.A.; Harris, C.; Biddinger, S.; Ilkayeva, O.R.; et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. *Nature* **2010**, *464*, 121-125, doi:10.1038/nature08778.

454. Qiu, X.; Brown, K.; Hirshey, M.D.; Verdin, E.; Chen, D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. *Cell Metab.* **2010**, *12*, 662-667, doi:10.1016/j.cmet.2010.11.015.

455. Preyat, N.; Leo, O. Sirtuin deacylases: A molecular link between metabolism and immunity. *J. Leukoc. Biol.* **2013**, *93*, 669-680, doi:10.1189/jlb.1112557.
456. Satoh, A.; Brace, C.S.; Ben-Josef, G.; West, T.; Wozniak, D.F.; Holtzman, D.M.; Herzog, E.D.; Imai, S. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. *J. Neurosci.* **2010**, *30*, 10220–10232, doi:10.1523/JNEUROSCI.1385-10.2010.

457. Kaeberlein, M.; McVey, M.; Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. *Genes Dev.* **1999**, *13*, 2570–2580, doi:10.1101/gad.13.19.2570.

458. Whitaker, R.; Faulkner, S.; Miyokawa, R.; Burhenn, L.; Henriksen, M.; Wood, J.G.; Helfand, S.L. Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner. *Aging (Albany NY)* **2013**, *5*, 682–691, doi:10.18632/aging.100599.

459. Lin, S.J.; Defossez, P.A.; Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. *Science* **2000**, *289*, 2126–2128, doi:10.1126/science.289.5487.2126.

460. Rogina, B.; Helfand, S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. *Proc. Natl. Acad. Sci. USA* **2004**, *101*, 15998–16003, doi:10.1073/pnas.0404184101.

461. Tissenbaum, H.A.; Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. *Nature* **2001**, *410*, 227–230, doi:10.1038/35065638.

462. Oberdoerffer, P.; Michan, S.; McVay, M.; Mostoslavsky, R.; Vann, J.; Park, S.K.; Hartlerode, A.; Stegmuller, J.; Hafner, A.; Loerch, P.; et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. *Cell* **2008**, *135*, 907–918, doi:10.1016/j.cell.2008.10.025.

463. Rodgers, J.T.; Lerin, C.; Haas, W.; Gygi, S.P.; Spiegelman, B.M.; Puigserver, P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. *Nature* **2005**, *434*, 113–118, doi:10.1038/nature03354.

464. Nemoto, S.; Fergusson, M.M.; Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. *J. Biol. Chem.* **2005**, *280*, 16456–16460, doi:10.1074/jbc.M501485200.

465. Lagouge, M.; Argmann, C.; Gerhart-Hines, Z.; Meziane, H.; Lerin, C.; Daussin, F.; Messadeq, N.; Milne, J.; Lambert, P.; Elliott, P.; et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. *Cell* **2006**, *127*, 1109–1122, doi:10.1016/j.cell.2006.11.013.

466. Vaziri, H.; Dessain, S.K.; Ng Eaton, E.; Imai, S.I.; Frye, R.A.; Pandita, T.K.; Guarente, L.; Weinberg, R.A. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. *Cell* **2001**, *107*, 149–159, doi:10.1016/s0092-8674(01)00527-x.

467. Luo, J.; Nikolaev, A.Y.; Imai, S.; Chen, D.; Su, F.; Shiloh, A.; Guarente, L.; Gu, W. Negative control of p53 by Sir2alpha promotes cell survival under stress. *Cell* **2001**, *107*, 137–148, doi:10.1016/s0092-8674(01)00524-4.

468. Daitoku, H.; Hatta, M.; Matsuzaki, H.; Aratani, S.; Ohshima, T.; Miyagishi, M.; Nakajima, T.; Fukamizu, A. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. *Proc. Natl. Acad. Sci. USA* **2004**, *101*, 10042–10047, doi:10.1073/pnas.0400593101.

469. van der Horst, A.; Tertoolen, L.G.; de Vries-Smits, L.M.; Frye, R.A.; Medema, R.H.; Burgering, B.M. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). *J. Biol. Chem.* **2004**, *279*, 28873–28879, doi:10.1074/jbc.M401138200.

470. Accili, D.; Arden, K.C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. *Cell* **2004**, *117*, 421–426, doi:10.1016/s0092-8674(04)00452-0.

471. Martins, R.; Lithgow, G.J.; Link, W. Long live FOXO: Unraveling the role of FOXO proteins in aging and longevity. *Aging Cell* **2016**, *15*, 196–207, doi:10.1111/acel.12427.

472. Gross, D.N.; van den Heuvel, A.P.; Birnbaum, M.J. The role of FoxO in the regulation of metabolism. *Oncogene* **2008**, *27*, 2320–2336, doi:10.1038/onc.2008.25.

473. Frescas, D.; Valenti, L.; Accili, D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. *J. Biol. Chem.* **2005**, *280*, 20589–20595, doi:10.1074/jbc.M412357200.

474. Brunet, A.; Sweeney, L.B.; Sturgill, J.F.; Chua, K.F.; Greer, P.L.; Lin, Y.; Tran, H.; Ross, S.E.; Mostoslavsky, R.; Cohen, H.Y.; et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. *Science* **2004**, *303*, 2011–2015, doi:10.1126/science.1094637.

475. Bordone, L.; Motta, M.C.; Picard, F.; Robinson, A.; Jhala, U.S.; Apfeld, J.; McDonagh, T.; Lemieux, M.; McBurney, M.; Szilvasi, A.; et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. *PLoS Biol.* **2006**, *4*, e31, doi:10.1371/journal.pbio.0040031.
476. Moynihan, K.A.; Grimm, A.A.; Plueger, M.M.; Bernal-Mizrachi, E.; Ford, E.; Cras-Meneur, C.; Permutt, M.A.; Imai, S. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. *Cell Metab.* **2005**, *2*, 105–117, doi:10.1016/j.cmet.2005.07.001.

477. Haigis, M.C.; Mostoslavsky, R.; Haigis, K.M.; Fahie, K.; Christodoulou, D.C.; Murphy, A.J.; Valenzuela, D.M.; Yancopoulos, G.D.; Karow, M.; Blander, G.; et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. *Cell* **2006**, *126*, 941–954, doi:10.1016/j.cell.2006.06.057.

478. Bae, N.S.; Swanson, M.J.; Vassilev, A.; Howard, B.H. Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10. *J. Biochem.* **2004**, *135*, 695–700, doi:10.1093/jb/mvh084.

479. North, B.J.; Marshall, B.L.; Borra, M.T.; Denu, J.M.; Verdin, E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. *Mol. Cell* **2003**, *11*, 437–444, doi:10.1016/s1097-2765(03)00038-8.

480. Wang, F.; Nguyen, M.; Qin, F.X.; Tong, Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. *Aging Cell* **2007**, *6*, 505–514, doi:10.1111/j.1474-9726.2007.00304.x.

481. Jing, E.; Gesta, S.; Kahn, C.R. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. *Cell Metab.* **2007**, *6*, 105–114, doi:10.1016/j.cmet.2007.07.003.

482. Dryden, S.C.; Nahhas, F.A.; Nowak, J.E.; Goustin, A.S.; Tainsky, M.A. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. *Mol. Cell Biol.* **2003**, *23*, 3173–3185, doi:10.1128/mcb.23.9.3173-3185.2003.

483. Sinclair, D.A.; Guarente, L. Extrachromosomal rDNA circles--a cause of aging in yeast. *Cell* **1997**, *91*, 1033–1042, doi:10.1016/s0092-8674(00)80493-6.

484. Starai, V.J.; Celic, I.; Cole, R.N.; Boeke, J.D.; Escalante-Semerena, J.C. Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. *Science* **2002**, *298*, 2390–2392, doi:10.1126/science.1077650.

485. Onyango, P.; Celic, I.; McCaffery, J.M.; Boeke, J.D.; Feinberg, A.P. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. *Proc. Natl. Acad. Sci. USA* **2002**, *99*, 13653–13658, doi:10.1073/pnas.222538099.

486. Shi, T.; Wang, F.; Stieren, E.; Tong, Q. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. *J. Biol. Chem.* **2005**, *280*, 13560–13567, doi:10.1074/jbc.M414670200.

487. Rose, G.; Dato, S.; Altomare, K.; Bellizzi, D.; Garasto, S.; Greco, V.; Passarino, G.; Feraco, E.; Mari, V.; Barbi, C.; et al. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. *Exp. Gerontol.* **2003**, *38*, 1065–1070, doi:10.1016/s0531-5565(03)00209-2.

488. Nasrin, N.; Wu, X.; Fortier, E.; Feng, Y.; Bare, O.C.; Chen, S.; Ren, X.; Wu, Z.; Streeper, R.S.; Bordone, L. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. *J. Biol. Chem.* **2010**, *285*, 31995–32002, doi:10.1074/jbc.M110.124164.

489. Michishita, E.; Park, J.Y.; Burneskis, J.M.; Barrett, J.C.; Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. *Mol. Biol. Cell* **2005**, *16*, 4623–4635, doi:10.1091/mbc.e05-01-0033.

490. McCord, R.A.; Michishita, E.; Hong, T.; Berber, E.; Boxer, L.D.; Kusumoto, R.; Guan, S.; Shi, X.; Gozani, O.; Burlingame, A.L.; et al. SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. *Aging (Albany NY)* **2009**, *1*, 109–121, doi:10.18632/aging.100011.

491. Mostoslavsky, R.; Chua, K.F.; Lombard, D.B.; Pang, W.W.; Fischer, M.R.; Gellon, L.; Liu, P.; Mostoslavsky, G.; Franco, S.; Murphy, M.M.; et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. *Cell* **2006**, *124*, 315–329, doi:10.1016/j.cell.2005.11.044.

492. Kanfi, Y.; Naiman, S.; Amir, G.; Peshti, V.; Zinman, G.; Nahum, L.; Bar-Joseph, Z.; Cohen, H.Y. The sirtuin SIRT6 regulates lifespan in male mice. *Nature* **2012**, *483*, 218–221, doi:10.1038/nature10815.

493. Luo, L.L.; Chen, X.C.; Fu, Y.C.; Xu, J.J.; Li, L.; Lin, X.H.; Xiang, Y.F.; Zhang, X.M. The effects of caloric restriction and a high-fat diet on ovarian lifespan and the expression of SIRT1 and SIRT6 proteins in rats. *Aging Clin. Exp. Res.* **2012**, *24*, 125–133, doi:10.3275/7660.

494. Ford, E.; Voit, R.; Liszt, G.; Magin, C.; Grummt, I.; Guarente, L. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. *Genes Dev.* **2006**, *20*, 1075–1080, doi:10.1101/gad.1399706.

495. Vazquez, B.N.; Thackray, J.K.; Simonet, N.G.; Kane-Goldsmith, N.; Martinez-Redondo, P.; Nguyen, T.; Bunting, S.; Vaquero, A.; Tischfield, J.A.; Serrano, L. SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair. *EMBO J.* **2016**, *35*, 1488–1503, doi:10.15252/embj.201593499.
496. Geng, Y.Q.; Li, T.T.; Liu, X.Y.; Li, Z.H.; Fu, Y.C. SIRT1 and SIRT5 activity expression and behavioral responses to calorie restriction. *J. Cell Biochem.* **2011**, *112*, 3755–3761, doi:10.1002/jcb.23315.

497. Ran, M.; Li, Z.; Yang, L.; Tong, L.; Zhang, L.; Dong, H. Calorie restriction attenuates cerebral ischemic injury via increasing SIRT1 synthesis in the rat. *Brain Res.* **2015**, *1610*, 61–68, doi:10.1016/j.brainres.2015.03.043.

498. Nisoli, E.; Tonello, C.; Cardile, A.; Cozzi, V.; Bracale, R.; Tedesco, L.; Falcone, S.; Valerio, A.; Cantoni, O.; Clementi, E.; et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. *Science* **2005**, *310*, 314–317, doi:10.1126/science.1117728.

499. Yu, W.; Zhou, H.F.; Lin, R.B.; Fu, Y.C.; Wang, W. Shortterm calorie restriction activates SIRT14 and 7 in cardiomyocytes in vivo and in vitro. *Mol. Med. Rep.* **2014**, *9*, 1218–1224, doi:10.3892/mmr.2014.1944.

500. Yu, W.; Qin, J.; Chen, C.; Fu, Y.; Wang, W. Moderate calorie restriction attenuates ageassociated alterations and improves cardiac function by increasing SIRT1 and SIRT3 expression. *Mol. Med. Rep.* **2018**, *18*, 4087–4094, doi:10.3892/mmr.2018.9390.

501. Chen, L.L.; Deng, X.Q.; Li, N.X. [Effects of calorie restriction on SIRT1 expression in liver of nonalcoholic fatty liver disease: Experiment with rats]. *Zhonghua Yi Xue Za Zhi* **2007**, *87*, 1434–1437.

502. Boily, G.; Seifert, E.L.; Bevilacqua, L.; He, X.H.; Sabourin, G.; Estey, C.; Moffat, C.; Crawford, S.; Saliba, S.; Jardine, K.; et al. SIRT1 regulates energy metabolism and response to caloric restriction in mice. *PLoS ONE* **2008**, *3*, e1759, doi:10.1371/journal.pone.0001759.

503. Bordone, L.; Cohen, D.; Robinson, A.; Motta, M.C.; van Veen, E.; Czopik, A.; Steele, A.D.; Crowe, H.; Marmor, S.; Luo, J.; et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. *Aging Cell* **2007**, *6*, 759–767, doi:10.1111/j.1474-9726.2007.00335.x.

504. Bhullar, K.S.; Hubbard, B.P. Lifespan and healthspan extension by resveratrol. *Biochim. Biophys. Acta* **2015**, *1852*, 1209–1218, doi:10.1016/j.bbadis.2015.01.012.

505. Howitz, K.T.; Bitterman, K.J.; Cohen, H.Y.; Lamming, D.W.; Lavu, S.; Wood, J.G.; Zipkin, R.E.; Chung, P.; Kisielewski, A.; Zhang, L.L.; et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. *Nature* **2003**, *425*, 191–196, doi:10.1038/nature01960.

506. Wood, J.G.; Rogina, B.; Lavu, S.; Howitz, K.; Helfand, S.L.; Tatar, M.; Sinclair, D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. *Nature* **2004**, *430*, 686–689, doi:10.1038/nature02789.

507. Baur, J.A.; Pearson, K.J.; Price, N.L.; Jamieson, H.A.; Lerin, C.; Kalra, A.; Prabhu, V.V.; Allard, J.S.; Lopez-Lluch, G.; Lewis, K.; et al. Resveratrol improves health and survival of mice on a high-calorie diet. *Nature* **2006**, *444*, 337–342, doi:10.1038/nature05354.

508. Timmers, S.; Konings, E.; Bilet, L.; Houtkooper, R.H.; van de Weijer, T.; Goossens, G.H.; Hoeks, J.; van der Krieken, S.; Ryu, D.; Kersten, S.; et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. *Cell Metab.* **2011**, *14*, 612–622, doi:10.1016/j.cmet.2011.10.002.

509. Barger, J.L.; Kayo, T.; Vann, J.M.; Arias, E.B.; Wang, J.; Hacker, T.A.; Wang, Y.; Raederstorff, D.; Morrow, J.D.; Leeuwenburgh, C.; et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. *PLoS ONE* **2008**, *3*, e2264, doi:10.1371/journal.pone.0002264.

510. Laurent, G.; de Boer, V.C.; Finley, L.W.; Sweeney, M.; Lu, H.; Schug, T.T.; Cen, Y.; Jeong, S.M.; Li, X.; Sauve, A.A.; et al. SIRT4 represses peroxisome proliferator-activated receptor alpha activity to suppress hepatic fat oxidation. *Mol. Cell Biol.* **2013**, *33*, 4552–4561, doi:10.1128/MCB.00087-13.

511. Purushotham, A.; Schug, T.T.; Xu, Q.; Surapureddi, S.; Guo, X.; Li, X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. *Cell Metab.* **2009**, *9*, 327–338, doi:10.1016/j.cmet.2009.02.006.

512. Oka, S.; Zhai, P.; Yamamoto, T.; Ikeda, Y.; Byun, J.; Hsu, C.P.; Sadoshima, J. Peroxisome Proliferator Activated Receptor-alpha Association With Silent Information Regulator 1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart. *Circ. Heart Fail.* **2015**, *8*, 1123–1132, doi:10.1161/CIRCHEARTFAILURE.115.002216.

513. Oka, S.; Alcendor, R.; Zhai, P.; Park, J.Y.; Shao, D.; Cho, J.; Yamamoto, T.; Tian, B.; Sadoshima, J. PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. *Cell Metab.* **2011**, *14*, 598–611, doi:10.1016/j.cmet.2011.10.001.

514. Oka, S.; Zhai, P.; Alcendor, R.; Park, J.Y.; Tian, B.; Sadoshima, J. Suppression of ERR targets by a PPARalpha/Sirt1 complex in the failing heart. *Cell Cycle* **2012**, *11*, 856–864, doi:10.4161/cc.11.5.19210.
515. Planavila, A.; Iglesias, R.; Giralt, M.; Villarroya, F. Sirt1 acts in association with PPARalpha to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. *Cardiovasc. Res.* **2011**, *90*, 276-284, doi:10.1093/cvr/cvq376.

516. Okazaki, M.; Iwasaki, Y.; Nishiyama, M.; Taguchi, T.; Tsugita, M.; Nakayama, S.; Kambayashi, M.; Hashimoto, K.; Terada, Y. PPARbeta/delta regulates the human SIRT1 gene transcription via Sp1. *Endocr. J.* **2010**, *57*, 403-413, doi:10.1507/endocrj.k10e-004.

517. Barroso, E.; Eyre, E.; Palomer, X.; Vazquez-Carrera, M. The peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) agonist GW501516 prevents TNF-alpha-induced NF-kappaB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1. *Biochem. Pharmacol.* **2011**, *81*, 534-543, doi:10.1016/j.bcp.2010.12.004.

518. Gong, K.; Qu, B.; Wang, C.; Zhou, J.; Liao, D.; Zheng, W.; Pan, X. Peroxisome Proliferator-Activated Receptor alpha Facilitates Osteogenic Differentiation in MC3T3-E1 Cells via the Sirtuin 1-Dependent Signaling Pathway. *Mol. Cells* **2017**, *40*, 393-400, doi:10.14348/molcells.2017.0018.

519. Gong, K.; Qu, B.; Liao, D.; Liu, D.; Wang, C.; Zhou, J.; Pan, X. MiR-132 regulates osteogenic differentiation via downregulating Sirtuin1 in a peroxisome proliferator-activated receptor beta/delta-dependent manner. *Biochem. Biophys. Res. Commun.* **2016**, *478*, 260-267, doi:10.1016/j.bbrc.2016.07.057.

520. Qu, B.; Ma, Y.; Yan, M.; Gong, K.; Liang, F.; Deng, S.; Jiang, K.; Ma, Z.; Pan, X. Sirtuin1 promotes osteogenic differentiation through downregulation of peroxisome proliferator-activated receptor gamma in MC3T3-E1 cells. *Biochem. Biophys. Res. Commun.* **2016**, *478*, 439-445, doi:10.1016/j.bbrc.2016.06.154.

521. Kim, M.Y.; Kang, E.S.; Ham, S.A.; Hwang, J.S.; Yoo, T.S.; Lee, H.; Paek, K.S.; Park, C.; Lee, H.T.; Kim, J.H.; et al. The PPARdelta-mediated inhibition of angiotensin II-induced premature senescence in human endothelial cells is SIRT1-dependent. *Biochem. Pharmacol.* **2012**, *84*, 1627-1634, doi:10.1016/j.bcp.2012.09.008.

522. Han, L.; Zhou, R.; Niu, J.; McNutt, M.A.; Wang, P.; Tong, T. SIRT1 is regulated by a PPAR{gamma}-SIRT1 negative feedback loop associated with senescence. *Nucleic Acids Res.* **2010**, *38*, 7458-7471, doi:10.1093/nar/gkq609.

523. Zhang, J.; Zhang, Y.; Xiao, F.; Liu, Y.; Wang, J.; Gao, H.; Rong, S.; Yao, Y.; Li, J.; Xu, G. The peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents NF-kappaB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway. *Biochem. Pharmacol.* **2016**, *101*, 100-111, doi:10.1016/j.bcp.2015.11.027.

524. Picard, F.; Kurtev, M.; Chung, N.; Topark-Ngarm, A.; Senawong, T.; Machado De Oliveira, R.; Leid, M.; McBurney, M.W.; Guarente, L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. *Nature* **2004**, *429*, 771-776, doi:10.1038/nature02583.

525. Floyd, Z.E.; Wang, Z.Q.; Kilroy, G.; Cefalu, W.T. Modulation of peroxisome proliferator-activated receptor gamma stability and transcriptional activity in adipocytes by resveratrol. *Metabolism* **2008**, *57*, S32-S38, doi:10.1016/j.metabol.2008.04.006.

526. Hagen, T.M. Oxidative stress, redox imbalance, and the aging process. *Antioxid. Redox Signal.* **2003**, *5*, 503-506, doi:10.1089/152308603770310149.

527. Navarro, A.; Boveris, A. The mitochondrial energy transduction system and the aging process. *Am. J. Physiol. Cell Physiol.* **2007**, *292*, C670-C686, doi:10.1152/ajpcell.00213.2006.

528. Harman, D. Aging: A theory based on free radical and radiation chemistry. *J. Gerontol.* **1956**, *11*, 298-300, doi:10.1093/geronj/11.3.298.

529. Merry, B.J. Molecular mechanisms linking calorie restriction and longevity. *Int. J. Biochem. Cell Biol.* **2002**, *34*, 1340-1354.

530. Sanz, A.; Caro, P.; Ibanez, J.; Gomez, J.; Gredilla, R.; Barja, G. Dietary restriction at old age lowers mitochondrial oxygen radical production and leak at complex I and oxidative DNA damage in rat brain. *J. Bioenerg. Biomembr.* **2005**, *37*, 83-90, doi:10.1007/s10863-005-4131-0.

531. Yu, B.P. Aging and oxidative stress: Modulation by dietary restriction. *Free Radic. Biol. Med.* **1996**, *21*, 651-668, doi:10.1016/0891-5849(96)00162-1.

532. Barja, G. Aging in vertebrates, and the effect of caloric restriction: A mitochondrial free radical production-DNA damage mechanism? *Biol. Rev. Cambr. Philos. Soc.* **2004**, *79*, 235-251.

533. Barja, G. Free radicals and aging. *Trends Neurosci.* **2004**, *27*, 595-600, doi:10.1016/j.tins.2004.07.005.

534. Forster, M.J.; Sohal, B.H.; Sohal, R.S. Reversible effects of long-term caloric restriction on protein oxidative damage. *J. Gerontol. Ser. A Biol. Sci. Med. Sci.* **2000**, *55*, B522-B529.
535. Lambert, A.J.; Merry, B.J. Lack of effect of caloric restriction on bioenergetics and reactive oxygen species production in intact rat hepatocytes. *J. Gerontol. Ser. A Biol. Sci. Med. Sci.* **2005**, *60*, 175-180.

536. Lambert, A.J.; Portero-Otin, M.; Pamplona, R.; Merry, B.J. Effect of ageing and caloric restriction on specific markers of protein oxidative damage and membrane peroxidizability in rat liver mitochondria. *Mech. Ageing Dev.* **2004**, *125*, 529-538, doi:10.1016/j.mad.2004.06.002.

537. Bagi, Z.; Koller, A.; Kaley, G. PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. *Am. J. Physiol. Heart Circ. Physiol.* **2004**, *286*, H742-H748, doi:10.1152/ajpheart.00718.2003.

538. Meerarani, P.; Reiterer, G.; Toborek, M.; Hennig, B. Zinc modulates PPARgamma signaling and activation of porcine endothelial cells. *J. Nutr.* **2003**, *133*, 3058-3064, doi:10.1093/jn/133.10.3058.

539. Iemitsu, M.; Miyauchi, T.; Maeda, S.; Tanabe, T.; Takanashi, M.; Irukayama-Tomobe, Y.; Sakai, S.; Ohmori, H.; Matsuda, M.; Yamaguchi, I. Aging-induced decrease in the PPAR-alpha level in hearts is improved by exercise training. *Am. J. Physiol. Heart Circ. Physiol.* **2002**, *283*, H1750-H1760, doi:10.1152/ajpheart.01051.2001.

540. Patterson, A.D.; Shah, Y.M.; Matsubara, T.; Krausz, K.W.; Gonzalez, F.J. Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity. *Hepatology* **2012**, *56*, 281-290, doi:10.1002/hep.25645.

541. Sekulic-Jablanovic, M.; Petkovic, V.; Wright, M.B.; Kucharava, K.; Huerzeler, N.; Levano, S.; Brand, Y.; Leitmeyer, K.; Glutz, A.; Bausch, A.; et al. Effects of peroxisome proliferator activated receptors (PPAR)-gamma and -alpha agonists on cochlear protection from oxidative stress. *PLoS ONE* **2017**, *12*, e0188596, doi:10.1371/journal.pone.0188596.

542. Girnun, G.D.; Domann, F.E.; Moore, S.A.; Robbins, M.E. Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter. *Mol. Endocrinol.* **2002**, *16*, 2793-2801, doi:10.1210/me.2002-0020.

543. Okuno, Y.; Matsuda, M.; Miyata, Y.; Fukuhara, A.; Komuro, R.; Shimabukuro, M.; Shimomura, I. Human catalase gene is regulated by peroxisome proliferator activated receptor-gamma through a response element distinct from that of mouse. *Endocr. J.* **2010**, *57*, 303-309, doi:10.1507/endocrj.k09e-113.

544. Ding, G.; Fu, M.; Qin, Q.; Lewis, W.; Kim, H.W.; Fukai, T.; Bacanamwo, M.; Chen, Y.E.; Schneider, M.D.; Mangelsdorf, D.J.; et al. Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage. *Cardiovasc. Res.* **2007**, *76*, 269-279, doi:10.1016/j.cardiores.2007.06.027.

545. Chung, S.S.; Kim, M.; Youn, B.S.; Lee, N.S.; Park, J.W.; Lee, I.K.; Lee, Y.S.; Kim, J.B.; Cho, Y.M.; Lee, H.K.; et al. Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells. *Mol. Cell Biol.* **2009**, *29*, 20-30, doi:10.1128/MCB.00544-08.

546. Zhang, F.; Liu, F.; Yan, M.; Ji, H.; Hu, L.; Li, X.; Qian, J.; He, X.; Zhang, L.; Shen, A.; et al. Peroxisome proliferator-activated receptor-gamma agonists suppress iNOS expression induced by LPS in rat primary Schwann cells. *J. Neuroimmunol.* **2010**, *218*, 36-47, doi:10.1016/j.jneuroim.2009.10.016.

547. Vandewalle, B.; Moerman, E.; Lefebvre, B.; Defrance, F.; Gmyr, V.; Lukowiak, B.; Kerr Conte, J.; Pattou, F. PPARgamma-dependent and -independent effects of rosiglitazone on lipotoxic human pancreatic islets. *Biochem. Biophys. Res. Commun.* **2008**, *366*, 1096-1101, doi:10.1016/j.bbrc.2007.12.088.

548. Kleinhenz, J.M.; Kleinhenz, D.J.; You, S.; Ritzenthaler, J.D.; Hansen, J.M.; Archer, D.R.; Sutliff, R.L.; Hart, C.M. Disruption of endothelial peroxisome proliferator-activated receptor-gamma reduces vascular nitric oxide production. *Am. J. Physiol. Heart Circ. Physiol.* **2009**, *297*, H1647-H1654, doi:10.1152/ajpheart.00148.2009.

549. Ricote, M.; Li, A.C.; Willson, T.M.; Kelly, C.J.; Glass, C.K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. *Nature* **1998**, *391*, 79-82, doi:10.1038/34178.

550. Li, M.; Pascual, G.; Glass, C.K. Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. *Mol. Cell Biol.* **2000**, *20*, 4699-4707, doi:10.1128/mcb.20.13.4699-4707.2000.

551. Ghosh, N.; Chaki, R.; Mandal, V.; Mandal, S.C. COX-2 as a target for cancer chemotherapy. *Pharmacol. Rep.* **2010**, *62*, 233-244.

552. Morgan, M.J.; Liu, Z.G. Crosstalk of reactive oxygen species and NF-kappaB signaling. *Cell Res.* **2011**, *21*, 103-115, doi:10.1038/cr.2010.178.
553. Wang, X.; Wang, Z.; Liu, J.Z.; Hu, J.X.; Chen, H.L.; Li, W.L.; Hai, C.X. Double antioxidant activities of rosiglitazone against high glucose-induced oxidative stress in hepatocyte. *Toxicol. In Vitro* **2011**, *25*, 839–847, doi:10.1016/j.tiv.2011.02.004.

554. Aleshin, S.; Grabeklis, S.; Hanck, T.; Sergeeva, M.; Reiser, G. Peroxisome proliferator-activated receptor (PPAR)-gamma positively controls and PPARalpha negatively controls cyclooxygenase-2 expression in rat brain astrocytes through a convergence on PPARbeta/delta via mutual control of PPAR expression levels. *Mol. Pharmacol.* **2009**, *76*, 414–424, doi:10.1124/mol.109.056010.

555. Collino, M.; Aragno, M.; Mastrocola, R.; Gallicchio, M.; Rosa, A.C.; Dianzani, C.; Danni, O.; Thiemermann, C.; Fantozzi, R. Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. *Eur. J. Pharmacol.* **2006**, *530*, 70–80, doi:10.1016/j.ejphar.2005.11.049.

556. Zhao, Y.; Patzer, A.; Herdegen, T.; Gohlke, P.; Culman, J. Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats. *FASEB J.* **2006**, *20*, 1162–1175, doi:10.1096/fj.05-5007com.

557. Chan, S.H.; Wu, K.L.; Kung, P.S.; Chan, J.Y. Oral intake of rosiglitazone promotes a central antihypertensive effect via upregulation of peroxisome proliferator-activated receptor-gamma and alleviation of oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats. *Hypertension* **2010**, *55*, 1444–1453, doi:10.1161/HYPERTENSIONAHA.109.149146.

558. Paradis, E.; Clavel, S.; Bouillaud, F.; Ricquier, D.; Richard, D. Uncoupling protein 2: A novel player in neuroprotection. *Trends Mol. Med.* **2003**, *9*, 522–525.

559. Nagy, L.; Tontonoz, P.; Alvarez, J.G.; Chen, H.; Evans, R.M. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. *Cell* **1998**, *93*, 229–240, doi:10.1016/s0092-8674(00)81574-3.

560. Ishii, T.; Itoh, K.; Ruiz, E.; Leake, D.S.; Unoki, H.; Yamamoto, M.; Mann, G.E. Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: Activation by oxidatively modified LDL and 4-hydroxynonenal. *Circ. Res.* **2004**, *94*, 609–616, doi:10.1161/01.RES.0000119171.44657.45.

561. Febbraio, M.; Hajjar, D.P.; Silverstein, R.L. CD36: A class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. *J. Clin. Investig.* **2001**, *108*, 785–791, doi:10.1172/JCI14006.

562. Fuenzalida, K.; Quintanilla, R.; Ramos, P.; Piderit, D.; Fuentealba, R.A.; Martinez, G.; Inestrosa, N.C.; Bronfman, M. Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis. *J. Biol. Chem.* **2007**, *282*, 37006–37015, doi:10.1074/jbc.M700447200.

563. Ren, Y.; Sun, C.; Sun, Y.; Tan, H.; Wu, Y.; Cui, B.; Wu, Z. PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation. *Vasc. Pharmacol.* **2009**, *51*, 169–174, doi:10.1016/j.vph.2009.06.004.

564. Chung, S.W.; Kang, B.Y.; Kim, S.H.; Pak, Y.K.; Cho, D.; Trinchieri, G.; Kim, T.S. Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. *J. Biol. Chem.* **2000**, *275*, 32681–32687, doi:10.1074/jbc.M002577200.

565. Liu, J.; Xia, Q.; Zhang, Q.; Li, H.; Zhang, J.; Li, A.; Xiu, R. Peroxisome proliferator-activated receptor-gamma ligands 15-deoxy-delta(12,14)-prostaglandin J2 and pioglitazone inhibit hydroxyl peroxide-induced TNF-alpha and lipopolysaccharide-induced CXC chemokine expression in neonatal rat cardiac myocytes. *Shock* **2009**, *32*, 317–324, doi:10.1097/SHK.0b013e31819c374c.

566. Goto, M.; Katayama, K.I.; Shirakawa, F.; Tanaka, I. Involvement of NF-kappaB p50/p65 heterodimer in activation of the human pro-interleukin-1beta gene at two subregions of the upstream enhancer element. *Cytokine* **1999**, *11*, 16–28, doi:10.1006/cyto.1998.0390.

567. Kim, H.J.; Kim, K.W.; Yu, B.P.; Chung, H.Y. The effect of age on cyclooxygenase-2 gene expression: NF-kappaB activation and IkappaBalpha degradation. *Free Radic. Biol. Med.* **2000**, *28*, 683–692, doi:10.1016/s0891-5849(99)00274-9.

568. Libermann, T.A.; Baltimore, D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. *Mol. Cell Biol.* **1990**, *10*, 2327–2334, doi:10.1128/mcb.10.5.2327.
569. Yao, J.; Mackman, N.; Edgington, T.S.; Fan, S.T. Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors. *J. Biol. Chem.* **1997**, *272*, 17795-17801, doi:10.1074/jbc.272.28.17795.

570. Taylor, B.S.; de Vera, M.E.; Ganster, R.W.; Wang, Q.; Shapiro, R.A.; Morris, S.M., Jr.; Billiar, T.R.; Geller, D.A. Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. *J. Biol. Chem.* **1998**, *273*, 15148-15156, doi:10.1074/jbc.273.24.15148.

571. Oliveira-Marques, V.; Marinho, H.S.; Cyrne, L.; Antunes, F. Role of hydrogen peroxide in NF-kappaB activation: From inducer to modulator. *Antioxid. Redox Signal.* **2009**, *11*, 2223-2243, doi:10.1089/ARS.2009.2601.

572. Ye, J. Regulation of PPARgamma function by TNF-alpha. *Biochem. Biophys. Res. Commun.* **2008**, *374*, 405-408, doi:10.1016/j.bbrc.2008.07.068.

573. Napolitano, M.; Costa, L.; Palermo, R.; Giovenco, A.; Vacca, A.; Gulino, A. Protective effect of pioglitazone, a PPARgamma ligand, in a 3 nitropropionic acid model of Huntington's disease. *Brain Res. Bull.* **2011**, *85*, 231-237, doi:10.1016/j.brainresbull.2011.03.011.

574. Osburn, W.O.; Kensler, T.W. Nrf2 signaling: An adaptive response pathway for protection against environmental toxic insults. *Mutat. Res.* **2008**, *659*, 31-39, doi:10.1016/j.mrrev.2007.11.006.

575. Lee, J.M.; Calkins, M.J.; Chan, K.; Kan, Y.W.; Johnson, J.A. Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. *J. Biol. Chem.* **2003**, *278*, 12029-12038, doi:10.1074/jbc.M211558200.

576. Park, E.Y.; Cho, I.J.; Kim, S.G. Transactivation of the PPAR-responsive enhancer module in chemopreventive glutathione S-transferase gene by the peroxisome proliferator-activated receptor-gamma and retinoid X receptor heterodimer. *Cancer Res.* **2004**, *64*, 3701-3713, doi:10.1158/0008-5472.CAN-03-3924.

577. D'Archivio, M.; Scazzocchio, B.; Filesi, C.; Vari, R.; Maggiorella, M.T.; Sernicola, L.; Santangelo, C.; Giovannini, C.; Masella, R. Oxidised LDL up-regulate CD36 expression by the Nrf2 pathway in 3T3-L1 preadipocytes. *FEBS Lett.* **2008**, *582*, 2291-2298, doi:10.1016/j.febslet.2008.05.029.

578. Gong, P.; Stewart, D.; Hu, B.; Li, N.; Cook, J.; Nel, A.; Alam, J. Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2. *Antioxid. Redox Signal.* **2002**, *4*, 249-257, doi:10.1089/152308602753666307.

579. Nakaso, K.; Yano, H.; Fukuhara, Y.; Takeshima, T.; Wada-Isoe, K.; Nakashima, K. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. *FEBS Lett.* **2003**, *546*, 181-184, doi:10.1016/s0014-5793(03)00517-9.

580. Huang, J.; Tabbi-Anneni, I.; Gunda, V.; Wang, L. Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism. *Am. J. Physiol. Gastrointest. Liver Physiol.* **2010**, *299*, G1211-G1221, doi:10.1152/ajpgi.00322.2010.

581. Cho, H.Y.; Gladwell, W.; Wang, X.; Chorley, B.; Bell, D.; Reddy, S.P.; Kleeberger, S.R. Nrf2-regulated PPAR{gamma} expression is critical to protection against acute lung injury in mice. *Am. J. Respir. Crit. Care Med.* **2010**, *182*, 170-182, doi:10.1164/rccm.200907-1047OC.

582. Chan, D.C. Mitochondria: Dynamic organelles in disease, aging, and development. *Cell* **2006**, *125*, 1241-1252, doi:10.1016/j.cell.2006.06.010.

583. Kregel, K.C.; Zhang, H.J. An integrated view of oxidative stress in aging: Basic mechanisms, functional effects, and pathological considerations. *Am. J. Physiol. Regul. Integr. Comp. Physiol.* **2007**, *292*, R18-R36, doi:10.1152/ajpregu.00327.2006.

584. Short, K.R.; Bigelow, M.L.; Kahl, J.; Singh, R.; Coenen-Schimke, J.; Raghavakaimal, S.; Nair, K.S. Decline in skeletal muscle mitochondrial function with aging in humans. *Proc. Natl. Acad. Sci. USA* **2005**, *102*, 5618-5623, doi:10.1073/pnas.0501559102.

585. Chen, J.C.; Warshaw, J.B.; Sanadi, D.R. Regulation of mitochondrial respiration in senescence. *J. Cell Physiol.* **1972**, *80*, 141-148, doi:10.1002/jcp.1040800115.

586. Hansford, R.G. Lipid oxidation by heart mitochondria from young adult and senescent rats. *Biochem. J.* **1978**, *170*, 285-295, doi:10.1042/bj1700285.

587. Trounce, I.; Byrne, E.; Marzuki, S. Decline in skeletal muscle mitochondrial respiratory chain function: Possible factor in ageing. *Lancet* **1989**, *1*, 637-639.

588. Cooper, J.M.; Mann, V.M.; Schapira, A.H. Analyses of mitochondrial respiratory chain function and mitochondrial DNA deletion in human skeletal muscle: Effect of ageing. *J. Neurol. Sci.* **1992**, *113*, 91-98.
589. Boffoli, D.; Scacco, S.C.; Vergari, R.; Solarino, G.; Santacroce, G.; Papa, S. Decline with age of the respiratory chain activity in human skeletal muscle. *Biochim. Biophys. Acta* **1994**, *1226*, 73-82.

590. Linnane, A.W.; Marzuki, S.; Ozawa, T.; Tanaka, M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. *Lancet* **1989**, *1*, 642-645.

591. Hancock, C.R.; Han, D.H.; Higashida, K.; Kim, S.H.; Holloszy, J.O. Does calorie restriction induce mitochondrial biogenesis? A reevaluation. *FASEB J.* **2011**, *25*, 785-791, doi:10.1096/fj.10-170415.

592. Zhu, M.; de Cabo, R.; Lane, M.A.; Ingram, D.K. Caloric restriction modulates early events in insulin signaling in liver and skeletal muscle of rat. *Ann. N. Y. Acad. Sci.* **2004**, *1019*, 448-452, doi:10.1196/annals.1297.082.

593. Ranhotra, H.S. Long-term caloric restriction up-regulates PPAR gamma co-activator 1 alpha (PGC-1alpha) expression in mice. *Indian J. Biochem. Biophys.* **2010**, *47*, 272-277.

594. Puigserver, P.; Wu, Z.; Park, C.W.; Graves, R.; Wright, M.; Spiegelman, B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. *Cell* **1998**, *92*, 829-839.

595. Handschin, C.; Spiegelman, B.M. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. *Endocr. Rev.* **2006**, *27*, 728-735, doi:10.1210/er.2006-0037.

596. Wu, Z.; Puigserver, P.; Andersson, U.; Zhang, C.; Adelmant, G.; Mootha, V.; Troy, A.; Cinti, S.; Lowell, B.; Scarpulla, R.C.; et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. *Cell* **1999**, *98*, 115-124, doi:10.1016/S0092-8674(00)80611-X.

597. St-Pierre, J.; Drori, S.; Uldry, M.; Silvaggi, J.M.; Rhee, J.; Jager, S.; Handschin, C.; Zheng, K.; Lin, J.; Yang, W.; et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. *Cell* **2006**, *127*, 397-408, doi:10.1016/j.cell.2006.09.024.

598. Lanza, I.R.; Zabielski, P.; Klaus, K.A.; Morse, D.M.; Heppelmann, C.J.; Bergen, H.R., 3rd; Dasari, S.; Walrand, S.; Short, K.R.; Johnson, M.L.; et al. Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis. *Cell Metab.* **2012**, *16*, 777-788, doi:10.1016/j.cmet.2012.11.003.

599. Hepple, R.T.; Baker, D.J.; McConkey, M.; Murynka, T.; Norris, R. Caloric restriction protects mitochondrial function with aging in skeletal and cardiac muscles. *Rejuvenation Res.* **2006**, *9*, 219-222, doi:10.1089/rej.2006.9.219.

600. Miller, B.F.; Robinson, M.M.; Bruss, M.D.; Hellerstein, M.; Hamilton, K.L. A comprehensive assessment of mitochondrial protein synthesis and cellular proliferation with age and caloric restriction. *Aging Cell* **2012**, *11*, 150-161, doi:10.1111/j.1474-9726.2011.00769.x.

601. Lopez-Lluch, G.; Hunt, N.; Jones, B.; Zhu, M.; Jamieson, H.; Hilmer, S.; Cascajo, M.V.; Allard, J.; Ingram, D.K.; Navas, P.; et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. *Proc. Natl. Acad. Sci. USA* **2006**, *103*, 1768-1773, doi:10.1073/pnas.0510452103.

602. Gudiksen, A.; Pilegaard, H. PGC-1alpha and fasting-induced PDH regulation in mouse skeletal muscle. *Physiol. Rep.* **2017**, *5*, doi:10.14814/phy2.13222.

603. Geng, T.; Li, P.; Okutsu, M.; Yin, X.; Kwek, J.; Zhang, M.; Yan, Z. PGC-1alpha plays a functional role in exercise-induced mitochondrial biogenesis and angiogenesis but not fiber-type transformation in mouse skeletal muscle. *Am. J. Physiol. Cell Physiol.* **2010**, *298*, C572-C579, doi:10.1152/ajpcell.00481.2009.

604. Leick, L.; Wojtaszewski, J.F.; Johansen, S.T.; Kiilerich, K.; Comes, G.; Hellsten, Y.; Hidalgo, J.; Pilegaard, H. PGC-1alpha is not mandatory for exercise- and training-induced adaptive gene responses in mouse skeletal muscle. *Am. J. Physiol. Endocrinol. Metab.* **2008**, *294*, E463-E474, doi:10.1152/ajpendo.00666.2007.

605. Vega, R.B.; Huss, J.M.; Kelly, D.P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. *Mol. Cell Biol.* **2000**, *20*, 1868-1876, doi:10.1128/mcb.20.5.1868-1876.2000.

606. Perez-Schindler, J.; Summermatter, S.; Salatino, S.; Zorzato, F.; Beer, M.; Balwierz, P.J.; van Nimwegen, E.; Feige, J.N.; Auwerx, J.; Handschin, C. The corepressor NCoR1 antagonizes PGC-1alpha and estrogen-related receptor alpha in the regulation of skeletal muscle function and oxidative metabolism. *Mol. Cell Biol.* **2012**, *32*, 4913-4924, doi:10.1128/MCB.00877-12.

607. Zolezzi, J.M.; Silva-Alvarez, C.; Ordenes, D.; Godoy, J.A.; Carvajal, F.J.; Santos, M.J.; Inestrosa, N.C. Peroxisome proliferator-activated receptor (PPAR) gamma and PPARalpha agonists modulate mitochondrial fusion-fission dynamics: Relevance to reactive oxygen species (ROS)-related neurodegenerative disorders? *PLoS ONE* **2013**, *8*, e64019, doi:10.1371/journal.pone.0064019.
608. Watanabe, K.; Fujii, H.; Takahashi, T.; Kodama, M.; Aizawa, Y.; Ohta, Y.; Ono, T.; Hasegawa, G.; Naito, M.; Nakajima, T.; et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity. *J. Biol. Chem.* **2000**, *275*, 22293-22299, doi:10.1074/jbc.M000248200.

609. Minnich, A.; Tian, N.; Byan, L.; Bilder, G. A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle. *Am. J. Physiol. Endocrinol. Metab.* **2001**, *280*, E270-E279, doi:10.1152/ajpendo.2001.280.2.E270.

610. Iershov, A.; Nemazanyy, I.; Alkhoury, C.; Girard, M.; Barth, E.; Cagnard, N.; Montagner, A.; Chretien, D.; Rugarli, E.I.; Guillou, H.; et al. The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARalpha. *Nat. Commun.* **2019**, *10*, 1566, doi:10.1038/s41467-019-09598-9.

611. Cree, M.G.; Zwetsloot, J.J.; Herndon, D.N.; Qian, T.; Morio, B.; Fram, R.; Sanford, A.P.; Aarsland, A.; Wolfe, R.R. Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate. *Ann. Surg.* **2007**, *245*, 214-221, doi:10.1097/01.sla.0000250409.51289.ca.

612. Hong, M.; Song, K.D.; Lee, H.K.; Yi, S.; Lee, Y.S.; Heo, T.H.; Jun, H.S.; Kim, S.J. Fibrates inhibit the apoptosis of Batten disease lymphoblast cells via autophagy recovery and regulation of mitochondrial membrane potential. *In Vitro Cell Dev. Biol. Anim.* **2016**, *52*, 349-355, doi:10.1007/s11626-015-9979-7.

613. Mohagheghi, F.; Ahmadiani, A.; Rahmani, B.; Moradi, F.; Romond, N.; Khalaj, L. Gemfibrozil pretreatment resulted in a sexually dimorphic outcome in the rat models of global cerebral ischemia-reperfusion via modulation of mitochondrial pro-survival and apoptotic cell death factors as well as MAPKs. *J. Mol. Neurosci.* **2013**, *50*, 379-393, doi:10.1007/s12031-012-9932-0.

614. Brunmair, B.; Lest, A.; Staniek, K.; Gras, F.; Scharf, N.; Roden, M.; Nohl, H.; Waldhausl, W.; Furnsinn, C. Fenofibrate impairs rat mitochondrial function by inhibition of respiratory complex I. *J. Pharmacol. Exp. Ther.* **2004**, *311*, 109-114, doi:10.1124/jpet.104.068312.

615. Zhou, S.; Wallace, K.B. The effect of peroxisome proliferators on mitochondrial bioenergetics. *Toxicol. Sci.* **1999**, *48*, 82-89, doi:10.1093/toxsci/48.1.82.

616. Zungu, M.; Young, M.E.; Stanley, W.C.; Essop, M.F. Chronic treatment with the peroxisome proliferator-activated receptor alpha agonist Wy-14,643 attenuates myocardial respiratory capacity and contractile function. *Mol. Cell Biochem.* **2009**, *330*, 55-62, doi:10.1007/s11010-009-0100-y.

617. Koh, J.H.; Hancock, C.R.; Terada, S.; Higashida, K.; Holloszy, J.O.; Han, D.H. PPARbeta Is Essential for Maintaining Normal Levels of PGC-1alpha and Mitochondria and for the Increase in Muscle Mitochondria Induced by Exercise. *Cell Metab.* **2017**, *25*, 1176-1185 e1175, doi:10.1016/j.cmet.2017.04.029.

618. Dressel, U.; Allen, T.L.; Pippal, J.B.; Rohde, P.R.; Lau, P.; Muscat, G.E. The peroxisome proliferator-activated receptor beta/delta agonist GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. *Mol. Endocrinol.* **2003**, *17*, 2477-2493, doi:10.1210/me.2003-0151.

619. Dulloo, A.G.; Samec, S. Uncoupling proteins: Their roles in adaptive thermogenesis and substrate metabolism reconsidered. *Br. J. Nutr.* **2001**, *86*, 123-139, doi:10.1079/bjn2001412.

620. Luquet, S.; Lopez-Soriano, J.; Holst, D.; Fredenrich, A.; Melki, J.; Rassoulzadegan, M.; Grimaldi, P.A. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. *FASEB J.* **2003**, *17*, 2299-2301, doi:10.1096/fj.03-0269fje.

621. Lin, J.; Wu, H.; Tarr, P.T.; Zhang, C.Y.; Wu, Z.; Boss, O.; Michael, L.F.; Puigserver, P.; Isotani, E.; Olson, E.N.; et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. *Nature* **2002**, *418*, 797-801, doi:10.1038/nature00904.

622. Kleiner, S.; Nguyen-Tran, V.; Bare, O.; Huang, X.; Spiegelman, B.; Wu, Z. PPAR{delta} agonism activates fatty acid oxidation via PGC-1{alpha} but does not increase mitochondrial gene expression and function. *J. Biol. Chem.* **2009**, *284*, 18624-18633, doi:10.1074/jbc.M109.008797.

623. Fan, W.; Waizenegger, W.; Lin, C.S.; Sorrentino, V.; He, M.X.; Wall, C.E.; Li, H.; Liddle, C.; Yu, R.T.; Atkins, A.R.; et al. PPARdelta Promotes Running Endurance by Preserving Glucose. *Cell Metab.* **2017**, *25*, 1186-1193 e1184, doi:10.1016/j.cmet.2017.04.006.

624. Zhou, Y.; Yang, J.; Huang, J.; Li, T.; Xu, D.; Zuo, B.; Hou, L.; Wu, W.; Zhang, L.; Xia, X.; et al. The formation of brown adipose tissue induced by transgenic over-expression of PPARgamma2. *Biochem. Biophys. Res. Commun.* **2014**, *446*, 959-964, doi:10.1016/j.bbrc.2014.03.033.
625. Son, N.H.; Park, T.S.; Yamashita, H.; Yokoyama, M.; Huggins, L.A.; Okajima, K.; Homma, S.; Szabolcs, M.J.; Huang, L.S.; Goldberg, I.J. Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice. *J. Clin. Investig.* **2007**, *117*, 2791–2801, doi:10.1172/JCI30335.

626. Wilson-Fritch, L.; Nicoloro, S.; Chouinard, M.; Lazar, M.A.; Chui, P.C.; Leszyk, J.; Straubhaar, J.; Czech, M.P.; Corvera, S. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. *J. Clin. Investig.* **2004**, *114*, 1281–1289, doi:10.1172/JCI21752.

627. Hakansson, J.; Eliasson, B.; Smith, U.; Enerback, S. Adipocyte mitochondrial genes and the forkhead factor FOXC2 are decreased in type 2 diabetes patients and normalized in response to rosiglitazone. *Diabetol. Metab. Syndr.* **2011**, *3*, 32, doi:10.1186/1758-5996-3-32.

628. Bogacka, I.; Xie, H.; Bray, G.A.; Smith, S.R. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. *Diabetes* **2005**, *54*, 1392–1399, doi:10.2337/diabetes.54.5.1392.

629. Rong, J.X.; Klein, J.L.; Qiu, Y.; Xie, M.; Johnson, J.H.; Waters, K.M.; Zhang, V.; Kashatus, J.A.; Remlinger, K.S.; Bing, N.; et al. Rosiglitazone Induces Mitochondrial Biogenesis in Differentiated Murine 3T3-L1 and C3H/10T1/2 Adipocytes. *PPAR Res.* **2011**, *2011*, 179454, doi:10.1155/2011/179454.

630. Wang, Y.L.; Frauwirth, K.A.; Rangwala, S.M.; Lazar, M.A.; Thompson, C.B. Thiazolidinedione activation of peroxisome proliferator-activated receptor gamma can enhance mitochondrial potential and promote cell survival. *J. Biol. Chem.* **2002**, *277*, 31781–31788, doi:10.1074/jbc.M204279200.

631. Chiang, M.C.; Chern, Y.; Huang, R.N. PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease. *Neurobiol. Dis.* **2012**, *45*, 322–328, doi:10.1016/j.nbd.2011.08.016.

632. Dello Russo, C.; Gavrilyuk, V.; Weinberg, G.; Almeida, A.; Bolanos, J.P.; Palmer, J.; Pelligrino, D.; Galea, E.; Feinstein, D.L. Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists increase glucose metabolism in astrocytes. *J. Biol. Chem.* **2003**, *278*, 5828–5836, doi:10.1074/jbc.M208132200.

633. Miglio, G.; Rosa, A.C.; Rattazzi, L.; Collino, M.; Lombardi, G.; Fantozzi, R. PPARgamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss. *Neurochem. Int.* **2009**, *55*, 496–504, doi:10.1016/j.neuint.2009.05.001.

634. Ghosh, S.; Patel, N.; Rahn, D.; McAllister, J.; Sadeghi, S.; Horwitz, G.; Berry, D.; Wang, K.X.; Swerdlow, R.H. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. *Mol. Pharmacol.* **2007**, *71*, 1695–1702, doi:10.1124/mol.106.033845.

635. Feinstein, D.L.; Spagnolo, A.; Akar, C.; Weinberg, G.; Murphy, P.; Gavrilyuk, V.; Dello Russo, C. Receptor-independent actions of PPAR thiazolidinedione agonists: Is mitochondrial function the key? *Biochem. Pharmacol.* **2005**, *70*, 177–188, doi:10.1016/j.bcp.2005.03.033.

636. Colca, J.R.; Tanis, S.P.; McDonald, W.G.; Kletzien, R.F. Insulin sensitizers in 2013: New insights for the development of novel therapeutic agents to treat metabolic diseases. *Expert Opin. Investig. Drugs* **2014**, *23*, 1–7, doi:10.1517/13543784.2013.839659.

637. Hobbs, M.V.; Weigle, W.O.; Noonan, D.J.; Torbett, B.E.; McEvilly, R.J.; Koch, R.J.; Cardenas, G.J.; Ernst, D.N. Patterns of cytokine gene expression by CD4+ T cells from young and old mice. *J. Immunol.* **1993**, *150*, 3602–3614.

638. Riancho, J.A.; Zarrabeitia, M.T.; Amado, J.A.; Olmos, J.M.; Gonzalez-Macias, J. Age-related differences in cytokine secretion. *Gerontology* **1994**, *40*, 8–12, doi:10.1159/000213568.

639. Miller, R.A. Aging and immune function. *Int. Rev. Cytol.* **1991**, *124*, 187–215, doi:10.1016/s0074-7696(08)61527-2.

640. Kubo, M.; Cinader, B. Polymorphism of age-related changes in interleukin (IL) production: Differential changes of T helper subpopulations, synthesizing IL 2, IL 3 and IL 4. *Eur. J. Immunol.* **1990**, *20*, 1289–1296, doi:10.1002/eji.1830200614.

641. Hayek, M.G.; Mura, C.; Wu, D.; Beharka, A.A.; Han, S.N.; Paulson, K.E.; Hwang, D.; Meydani, S.N. Enhanced expression of inducible cyclooxygenase with age in murine macrophages. *J. Immunol.* **1997**, *159*, 2445–2451.

642. Erol, A. Interleukin-6 (IL-6) is still the leading biomarker of the metabolic and aging related disorders. *Med. Hypotheses* **2007**, *69*, 708, doi:10.1016/j.mehy.2007.01.021.

643. Ricote, M.; Huang, J.; Fajas, L.; Li, A.; Welch, J.; Najib, J.; Witztum, J.L.; Auwerx, J.; Palinski, W.; Glass, C.K. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. *Proc. Natl. Acad. Sci. USA* **1998**, *95*, 7614–7619.
644. Jiang, C.; Ting, A.T.; Seed, B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. *Nature* **1998**, *391*, 82–86, doi:10.1038/34184.

645. Okada, M.; Yan, S.F.; Pinsky, D.J. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets. *FASEB J.* **2002**, *16*, 1861–1868, doi:10.1096/fj.02-0503com.

646. Barbier, O.; Torra, I.P.; Duguay, Y.; Blanquart, C.; Fruchart, J.C.; Glineur, C.; Staels, B. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. *Arterioscler. Thromb. Vasc. Biol.* **2002**, *22*, 717–726.

647. Narala, V.R.; Adapala, R.K.; Suresh, M.V.; Brock, T.G.; Peters-Golden, M.; Reddy, R.C. Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor-alpha agonist. *J. Biol. Chem.* **2010**, *285*, 22067–22074, doi:10.1074/jbc.M109.085118.

648. Delerive, P.; De Bosscher, K.; Besnard, S.; Vanden Berghe, W.; Peters, J.M.; Gonzalez, F.J.; Fruchart, J.C.; Tedgui, A.; Haegeman, G.; Staels, B. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. *J. Biol. Chem.* **1999**, *274*, 32048–32054.

649. Crisafulli, C.; Cuzzocrea, S. The role of endogenous and exogenous ligands for the peroxisome proliferator-activated receptor alpha (PPAR-alpha) in the regulation of inflammation in macrophages. *Shock* **2009**, *32*, 62–73, doi:10.1097/shk.0b013e31818bbad6.

650. Peters, J.M.; Hollingshead, H.E.; Gonzalez, F.J. Role of peroxisome-proliferator-activated receptor beta/delta (PPARbeta/delta) in gastrointestinal tract function and disease. *Clin. Sci. (Lond.)* **2008**, *115*, 107–127, doi:10.1042/CS20080022.

651. Ding, G.; Cheng, L.; Qin, Q.; Frontin, S.; Yang, Q. PPARdelta modulates lipopolysaccharide-induced TNFalpha inflammation signaling in cultured cardiomyocytes. *J. Mol. Cell Cardiol.* **2006**, *40*, 821–828, doi:10.1016/j.yjmcc.2006.03.422.

652. Iwashita, A.; Muramatsu, Y.; Yamazaki, T.; Muramoto, M.; Kita, Y.; Yamazaki, S.; Mihara, K.; Moriguchi, A.; Matsuoka, N. Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo. *J. Pharmacol. Exp. Ther.* **2007**, *320*, 1087–1096, doi:10.1124/jpet.106.115758.

653. Benetti, E.; Mastrocola, R.; Rogazzo, M.; Chiazza, F.; Aragno, M.; Fantozzi, R.; Collino, M.; Minetto, M.A. High sugar intake and development of skeletal muscle insulin resistance and inflammation in mice: A protective role for PPAR- delta agonism. *Mediat. Inflamm.* **2013**, *2013*, 509502, doi:10.1155/2013/509502.

654. Lewis, J.D.; Lichtenstein, G.R.; Deren, J.J.; Sands, B.E.; Hanauer, S.B.; Katz, J.A.; Lashner, B.; Present, D.H.; Chuai, S.; Ellenberg, J.H.; et al. Rosiglitazone for active ulcerative colitis: A randomized placebo-controlled trial. *Gastroenterology* **2008**, *134*, 688–695, doi:10.1053/j.gastro.2007.12.012.

655. Lewis, J.D.; Lichtenstein, G.R.; Stein, R.B.; Deren, J.J.; Judge, T.A.; Fogt, F.; Furth, E.E.; Demissie, E.J.; Hurd, L.B.; Su, C.G.; et al. An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis. *Am. J. Gastroenterol.* **2001**, *96*, 3323–3328, doi:10.1111/j.1572-0241.2001.05333.x.

656. Liang, H.L.; Ouyang, Q. A clinical trial of combined use of rosiglitazone and 5-aminosalicylate for ulcerative colitis. *World J. Gastroenterol.* **WJG** **2008**, *14*, 114–119.

657. Bassaganya-Riera, J.; Hontecillas, R. CLA and n-3 PUFA differentially modulate clinical activity and colonic PPAR-responsive gene expression in a pig model of experimental IBD. *Clin. Nutr.* **2006**, *25*, 454–465, doi:10.1016/j.clnu.2005.12.008.

658. Hontecillas, R.; Wannemeulher, M.J.; Zimmerman, D.R.; Hutto, D.L.; Wilson, J.H.; Ahn, D.U.; Bassaganya-Riera, J. Nutritional regulation of porcine bacterial-induced colitis by conjugated linoleic acid. *J. Nutr.* **2002**, *132*, 2019–2027.

659. Sanchez-Hidalgo, M.; Martin, A.R.; Villegas, I.; de la Lastra, C.A. Rosiglitazone, a PPARgamma ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats. *Eur. J. Pharmacol.* **2007**, *562*, 247–258, doi:10.1016/j.ejphar.2007.01.047.

660. Sato, N.; Kozar, R.A.; Zou, L.; Weatherall, J.M.; Attuwaybi, B.; Moore-Olufemi, S.D.; Weisbrodt, N.W.; Moore, F.A. Peroxisome proliferator-activated receptor gamma mediates protection against cyclooxygenase-2-induced gut dysfunction in a rodent model of mesenteric ischemia/reperfusion. *Shock* **2005**, *24*, 462–469.

661. Saubermann, L.J.; Nakajima, A.; Wada, K.; Zhao, S.; Terauchi, Y.; Kadowaki, T.; Aburatani, H.; Matsuhashi, N.; Nagai, R.; Blumberg, R.S. Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis. *Inflamm. Bowel Dis.* **2002**, *8*, 330–339.
662. Su, C.G.; Wen, X.; Bailey, S.T.; Jiang, W.; Rangwala, S.M.; Keilbaugh, S.A.; Flanigan, A.; Murthy, S.; Lazar, M.A.; Wu, G.D. A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. *J. Clin. Investig.* **1999**, *104*, 383–389, doi:10.1172/JCI7145.

663. Kundu, P.; Ling, T.W.; Korecka, A.; Li, Y.; D'Arienzo, R.; Bunte, R.M.; Berger, T.; Arulampalam, V.; Chambon, P.; Mak, T.W.; et al. Absence of intestinal PPARgamma aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway. *PLoS Pathog* **2014**, *10*, e1003887, doi:10.1371/journal.ppat.1003887.

664. Michalik, L.; Wahli, W. PPARs Mediate Lipid Signaling in Inflammation and Cancer. *PPAR Res.* **2008**, *2008*, 134059, doi:10.1155/2008/134059.

665. Shah, Y.M.; Morimura, K.; Gonzalez, F.J. Expression of peroxisome proliferator-activated receptor-gamma in macrophage suppresses experimentally induced colitis. *Am. J. Physiol. Gastrointest. Liver Physiol.* **2007**, *292*, G657–G666, doi:10.1152/ajpgi.00381.2006.

666. Leung, E.; Hong, J.; Fraser, A.; Merriman, T.; Krissansen, G. PPAR-gamma and Crohn's disease in New Zealand. *Gastroenterology* **2006**, *130*, 2249–2250; author reply 2250, doi:10.1053/j.gastro.2006.04.053.

667. Wada, K.; Nakajima, A.; Blumberg, R.S. PPARgamma and inflammatory bowel disease: A new therapeutic target for ulcerative colitis and Crohn's disease. *Trends Mol. Med.* **2001**, *7*, 329–331.

668. Pascual, G.; Fong, A.L.; Ogawa, S.; Gamliel, A.; Li, A.C.; Perissi, V.; Rose, D.W.; Willson, T.M.; Rosenfeld, M.G.; Glass, C.K. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. *Nature* **2005**, *437*, 759–763, doi:10.1038/nature03988.

669. Chawla, A.; Barak, Y.; Nagy, L.; Liao, D.; Tontonoz, P.; Evans, R.M. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. *Nat. Med.* **2001**, *7*, 48–52, doi:10.1038/83336.

670. Gosset, P.; Charbonnier, A.S.; Delerive, P.; Fontaine, J.; Staels, B.; Pestel, J.; Tonnel, A.B.; Trottein, F. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. *Eur. J. Immunol.* **2001**, *31*, 2857–2865.

671. Faveeuw, C.; Fougeray, S.; Angeli, V.; Fontaine, J.; Chinetti, G.; Gosset, P.; Delerive, P.; Maliszewski, C.; Capron, M.; Staels, B.; et al. Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. *FEBS Lett.* **2000**, *486*, 261–266.

672. Odegaard, J.I.; Ricardo-Gonzalez, R.R.; Goforth, M.H.; Morel, C.R.; Subramanian, V.; Mukundan, L.; Red Eagle, A.; Vats, D.; Brombacher, F.; Ferrante, A.W.; et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. *Nature* **2007**, *447*, 1116–1120, doi:10.1038/nature05894.

673. Klotz, L.; Schmidt, S.; Heun, R.; Klockgether, T.; Kolsch, H. Association of the PPARgamma gene polymorphism Pro12Ala with delayed onset of multiple sclerosis. *Neurosci. Lett.* **2009**, *449*, 81–83, doi:10.1016/j.neulet.2008.10.066.

674. Regieli, J.J.; Jukema, J.W.; Doevendans, P.A.; Zwinderman, A.H.; van der Graaf, Y.; Kastelein, J.J.; Grobbee, D.E. PPAR gamma variant influences angiographic outcome and 10-year cardiovascular risk in male symptomatic coronary artery disease patients. *Diabetes Care* **2009**, *32*, 839–844, doi:10.2337/dc08-1819.

675. Jiang, J.; Xie, Z.; Guo, J.; Wang, Y.; Liu, C.; Zhang, S.; Tang, W.; Chen, Y. Association of PPARG rs 1801282 C>G polymorphism with risk of colorectal cancer: From a case-control study to a meta-analysis. *Oncotarget* **2017**, *8*, 100558–100569, doi:10.18632/oncotarget.20138.

676. Lin, J.; Chen, Y.; Tang, W.F.; Liu, C.; Zhang, S.; Guo, Z.Q.; Chen, G.; Zheng, X.W. PPARG rs3856806 C>T Polymorphism Increased the Risk of Colorectal Cancer: A Case-Control Study in Eastern Chinese Han Population. *Front. Oncol.* **2019**, *9*, 63, doi:10.3389/fonc.2019.00063.

677. Bassaganya-Riera, J.; Reynolds, K.; Martino-Catt, S.; Cui, Y.; Hennighausen, L.; Gonzalez, F.; Rohrer, J.; Benninghoff, A.U.; Hontecillas, R. Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease. *Gastroenterology* **2004**, *127*, 777–791.

678. Yasui, Y.; Hosokawa, M.; Sahara, T.; Suzuki, R.; Ohgiya, S.; Kohno, H.; Tanaka, T.; Miyashita, K. Bitter gourd seed fatty acid rich in 9c,11t,13t-conjugated linolenic acid induces apoptosis and up-regulates the GADD45, p53 and PPARgamma in human colon cancer Caco-2 cells. *Prostaglandins Leukot. Essent. Fatty Acids* **2005**, *73*, 113–119, doi:10.1016/j.plefa.2005.04.013.

679. Akinyeke, T.O.; Stewart, L.V. Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARgamma-independent mechanism. *Cancer Biol. Ther.* **2011**, *11*, 1046–1058.
680. Yang, W.L.; Frucht, H. Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells. *Carcinogenesis* **2001**, *22*, 1379-1383.

681. Subbaramaiah, K.; Lin, D.T.; Hart, J.C.; Dannenberg, A.J. Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300. *J. Biol. Chem.* **2001**, *276*, 12440-12448, doi:10.1074/jbc.M007237200.

682. Vandoros, G.P.; Konstantinopoulos, P.A.; Sotipropoulou-Bonikou, G.; Kominea, A.; Papachristou, G.I.; Karamouzis, M.V.; Gkermpesi, M.; Varakis, I.; Papavassiliou, A.G. PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas. *J. Cancer Res. Clin. Oncol.* **2006**, *132*, 76-84, doi:10.1007/s00432-005-0042-z.

683. Heneka, M.T.; Klockgether, T.; Feinstein, D.L. Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. *J. Neurosci.* **2000**, *20*, 6862-6867.

684. Girnun, G.D.; Smith, W.M.; Drori, S.; Sarraf, P.; Mueller, E.; Eng, C.; Nambiar, P.; Rosenberg, D.W.; Bronson, R.T.; Edelmann, W.; et al. APC-dependent suppression of colon carcinogenesis by PPARgamma. *Proc. Natl. Acad. Sci. USA* **2002**, *99*, 13771-13776, doi:10.1073/pnas.162480299.

685. Fujisawa, T.; Nakajima, A.; Fujisawa, N.; Takahashi, H.; Ikeda, I.; Tomimoto, A.; Yonemitsu, K.; Nakajima, N.; Kudo, C.; Wada, K.; et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) suppresses colonic epithelial cell turnover and colon carcinogenesis through inhibition of the beta-catenin/T cell factor (TCF) pathway. *J. Pharmacol. Sci.* **2008**, *106*, 627-638.

686. Peeters, A.; Baes, M. Role of PPAR in Hepatic Carbohydrate Metabolism. *PPAR Res.* **2010**, *2010*, doi:http://dx.doi.org/10.1155/2010/572405.

687. Xu, J.; Xiao, G.; Trujillo, C.; Chang, V.; Blanco, L.; Joseph, S.B.; Bassilian, S.; Saad, M.F.; Tontonoz, P.; Lee, W.N.; et al. Peroxisome proliferator-activated receptor alpha (PPARalpha) influences substrate utilization for hepatic glucose production. *J. Biol. Chem.* **2002**, *277*, 50237-50244, doi:10.1074/jbc.M201208200.

688. Mandard, S.; Stienstra, R.; Escher, P.; Tan, N.S.; Kim, I.; Gonzalez, F.J.; Wahli, W.; Desvergne, B.; Muller, M.; Kersten, S. Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors. *Cell Mol. Life Sci.* **2007**, *64*, 1145-1157, doi:10.1007/s00018-007-7006-1.

689. Finck, B.N.; Lehman, J.J.; Leone, T.C.; Welch, M.J.; Bennett, M.J.; Kovacs, A.; Han, X.; Gross, R.W.; Kozak, R.; Lopaschuk, G.D.; et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. *J. Clin. Investig.* **2002**, *109*, 121-130, doi:10.1172/JCI14080.

690. Philp, A.; MacKenzie, M.G.; Belew, M.Y.; Towler, M.C.; Corstorphine, A.; Papalamprou, A.; Hardie, D.G.; Baar, K. Glycogen content regulates peroxisome proliferator activated receptor- partial differential (PPAR-partial differential) activity in rat skeletal muscle. *PLoS ONE* **2013**, *8*, e77200, doi:10.1371/journal.pone.0077200.

691. Rodriguez, J.C.; Gil-Gomez, G.; Hegardt, F.G.; Haro, D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. *J. Biol. Chem.* **1994**, *269*, 18767-18772.

692. Rakhshandehroo, M.; Hooiveld, G.; Muller, M.; Kersten, S. Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human. *PLoS ONE* **2009**, *4*, e6796, doi:10.1371/journal.pone.0006796.

693. Louet, J.F.; Chatelain, F.; Decaux, J.F.; Park, E.A.; Kohl, C.; Pineau, T.; Girard, J.; Pegorier, J.P. Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway. *Biochem. J.* **2001**, *354*, 189-197, doi:10.1042/0264-6021:3540189.

694. Mascaro, C.; Acosta, E.; Ortiz, J.A.; Marrero, P.F.; Hegardt, F.G.; Haro, D. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. *J. Biol. Chem.* **1998**, *273*, 8560-8563, doi:10.1074/jbc.273.15.8560.

695. Barrero, M.J.; Camarero, N.; Marrero, P.F.; Haro, D. Control of human carnitine palmitoyltransferase II gene transcription by peroxisome proliferator-activated receptor through a partially conserved peroxisome proliferator-responsive element. *Biochem. J.* **2003**, *369*, 721-729, doi:10.1042/BJ20020851.

696. Gulick, T.; Cresci, S.; Cairia, T.; Moore, D.D.; Kelly, D.P. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. *Proc. Natl. Acad. Sci. USA* **1994**, *91*, 11012-11016, doi:10.1073/pnas.91.23.11012.
697. Aoyama, T.; Peters, J.M.; Iritani, N.; Nakajima, T.; Furihata, K.; Hashimoto, T.; Gonzalez, F.J. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). *J. Biol. Chem.* **1998**, *273*, 5678–5684, doi:10.1074/jbc.273.10.5678.

698. Badman, M.K.; Pissios, P.; Kennedy, A.R.; Koukos, G.; Flier, J.S.; Maratos-Flier, E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. *Cell Metab.* **2007**, *5*, 426–437, doi:10.1016/j.cmet.2007.05.002.

699. Galman, C.; Lundasen, T.; Kharitonenkov, A.; Bina, H.A.; Eriksson, M.; Hafstrom, I.; Dahlin, M.; Amark, P.; Angelin, B.; Rudling, M. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. *Cell Metab.* **2008**, *8*, 169–174, doi:10.1016/j.cmet.2008.06.014.

700. Iroz, A.; Montagner, A.; Benhamed, F.; Levavasseur, F.; Polizzi, A.; Anthony, E.; Regnier, M.; Fouche, E.; Lukowicz, C.; Cauzac, M.; et al. A Specific ChREBP and PPARalpha Cross-Talk Is Required for the Glucose-Mediated FGF21 Response. *Cell Rep.* **2017**, *21*, 403–416, doi:10.1016/j.celrep.2017.09.065.

701. Li, G.; Brocker, C.N.; Yan, T.; Xie, C.; Krausz, K.W.; Xiang, R.; Gonzalez, F.J. Corrigendum to "Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha" [Mol Metab 7 (2018) 80-89]. *Mol. Metab.* **2018**, *9*, 217-219, doi:10.1016/j.molmet.2018.01.008.

702. Chaix, A.; Lin, T.; Le, H.D.; Chang, M.W.; Panda, S. Time-Restricted Feeding Prevents Obesity and Metabolic Syndrome in Mice Lacking a Circadian Clock. *Cell Metab.* **2019**, *29*, 303–319.e4, doi:10.1016/j.cmet.2018.08.004.

703. Adamo, K.B.; Dent, R.; Langefeld, C.D.; Cox, M.; Williams, K.; Carrick, K.M.; Stuart, J.S.; Sundseth, S.S.; Harper, M.E.; McPherson, R.; et al. Peroxisome proliferator-activated receptor gamma 2 and acyl-CoA synthetase 5 polymorphisms influence diet response. *Obesity (Silver Spring)* **2007**, *15*, 1068–1075, doi:10.1038/oby.2007.630.

704. Matsuo, T.; Nakata, Y.; Katayama, Y.; Iemitsu, M.; Maeda, S.; Okura, T.; Kim, M.K.; Ohkubo, H.; Hotta, K.; Tanaka, K. PPARG genotype accounts for part of individual variation in body weight reduction in response to calorie restriction. *Obesity (Silver Spring)* **2009**, *17*, 1924–1931, doi:10.1038/oby.2009.199.

705. Stryjecki, C.; Peralta-Romero, J.; Alyass, A.; Karam-Araujo, R.; Suarez, F.; Gomez-Zamudio, J.; Burguete-Garcia, A.; Cruz, M.; Meyre, D. Association between PPAR-gamma2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children. *Sci. Rep.* **2016**, *6*, 24472, doi:10.1038/srep24472.

706. Masugi, J.; Tamori, Y.; Mori, H.; Koike, T.; Kasuga, M. Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis. *Biochem. Biophys. Res. Commun.* **2000**, *268*, 178–182, doi:10.1006/bbrc.2000.2096.

707. Memisoglu, A.; Hu, F.B.; Hankinson, S.E.; Manson, J.E.; De Vivo, I.; Willett, W.C.; Hunter, D.J. Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. *Hum. Mol. Genet.* **2003**, *12*, 2923–2929, doi:10.1093/hmg/ddg318.

708. Robitaille, J.; Despres, J.P.; Perusse, L.; Vohl, M.C. The PPAR-gamma P12A polymorphism modulates the relationship between dietary fat intake and components of the metabolic syndrome: Results from the Quebec Family Study. *Clin. Genet.* **2003**, *63*, 109–116, doi:10.1034/j.1399-0004.2003.00026.x.

709. Luan, J.; Browne, P.O.; Harding, A.H.; Halsall, D.J.; O'Rahilly, S.; Chatterjee, V.K.; Wareham, N.J. Evidence for gene-nutrient interaction at the PPARgamma locus. *Diabetes* **2001**, *50*, 686–689, doi:10.2337/diabetes.50.3.686.

710. Lindi, V.; Schwab, U.; Louheranta, A.; Laakso, M.; Vessby, B.; Hermansen, K.; Storlien, L.; Riccardi, G.; Matti IJ Uusitupa for the KANWU Study Group. Impact of the Pro12Ala polymorphism of the PPAR-gamma2 gene on serum triacylglycerol response to n-3 fatty acid supplementation. *Mol. Genet. Metab.* **2003**, *79*, 52–60, doi:10.1016/s1096-7192(03)00065-9.

711. Nicklas, B.J.; van Rossum, E.F.; Berman, D.M.; Ryan, A.S.; Dennis, K.E.; Shuldiner, A.R. Genetic variation in the peroxisome proliferator-activated receptor-gamma2 gene (Pro12Ala) affects metabolic responses to weight loss and subsequent weight regain. *Diabetes* **2001**, *50*, 2172–2176, doi:10.2337/diabetes.50.9.2172.

712. Ballor, D.L.; Poehlman, E.T. Exercise intensity does not affect depression of resting metabolic rate during severe diet restriction in male Sprague-Dawley rats. *J. Nutr.* **1993**, *123*, 1270–1276.

713. Koizumi, A.; Wada, Y.; Tuskada, M.; Kayo, T.; Naruse, M.; Horiuchi, K.; Mogi, T.; Yoshioka, M.; Sasaki, M.; Miyamaura, Y.; et al. A tumor preventive effect of dietary restriction is antagonized by a high housing temperature through deprivation of torpor. *Mech. Ageing Dev.* **1996**, *92*, 67–82.
714. Tabarean, I.; Morrison, B.; Marcondes, M.C.; Bartfai, T.; Conti, B. Hypothalamic and dietary control of temperature-mediated longevity. *Ageing Res. Rev.* **2010**, *9*, 41–50, doi:10.1016/j.arr.2009.07.004.

715. Rachid, T.L.; Penna-de-Carvalho, A.; Bringhenti, I.; Aguila, M.B.; Mandarim-de-Lacerda, C.A.; Souza-Mello, V. Fenofibrate (PPARalpha agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice. *Mol. Cell Endocrinol.* **2015**, *402*, 86–94, doi:10.1016/j.mce.2014.12.027.

716. Rachid, T.L.; Silva-Veiga, F.M.; Graus-Nunes, F.; Bringhenti, I.; Mandarim-de-Lacerda, C.A.; Souza-Mello, V. Differential actions of PPAR-alpha and PPAR-beta/delta on beige adipocyte formation: A study in the subcutaneous white adipose tissue of obese male mice. *PLoS ONE* **2018**, *13*, e0191365, doi:10.1371/journal.pone.0191365.

717. Lu, C.; Cheng, S.Y. Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors. *J. Mol. Endocrinol.* **2010**, *44*, 143–154, doi:10.1677/JME-09-0107.

718. Liu, Y.Y.; Brent, G.A. Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation. *Trends Endocrinol. Metab.* **2010**, *21*, 166–173, doi:10.1016/j.tem.2009.11.004.

719. Colbert, L.H.; Mai, V.; Tooze, J.A.; Perkins, S.N.; Berrigan, D.; Hursting, S.D. Negative energy balance induced by voluntary wheel running inhibits polyp development in APCMin mice. *Carcinogenesis* **2006**, *27*, 2103–2107, doi:10.1093/carcin/bgl056.

720. Holloszy, J.O. Mortality rate and longevity of food-restricted exercising male rats: A reevaluation. *J. Appl. Physiol.* (1985) **1997**, *82*, 399–403, doi:10.1152/jappl.1997.82.2.399.

721. Manini, T.M.; Everhart, J.E.; Patel, K.V.; Schoeller, D.A.; Colbert, L.H.; Visser, M.; Tylavsky, F.; Bauer, D.C.; Goodpaster, B.H.; Harris, T.B. Daily activity energy expenditure and mortality among older adults. *JAMA* **2006**, *296*, 171–179, doi:10.1001/jama.296.2.171.

722. Warburton, D.E.; Nicol, C.W.; Bredin, S.S. Health benefits of physical activity: The evidence. *CMAJ* **2006**, *174*, 801–809, doi:10.1503/cmaj.051351.

723. Laaksonen, D.E.; Lindstrom, J.; Lakka, T.A.; Eriksson, J.G.; Niskanen, L.; Wikstrom, K.; Aunola, S.; Keinanen-Kiukaanniemi, S.; Laakso, M.; Valle, T.T.; et al. Physical activity in the prevention of type 2 diabetes: The Finnish diabetes prevention study. *Diabetes* **2005**, *54*, 158–165, doi:10.2337/diabetes.54.1.158.

724. Holloszy, J.O. Exercise and longevity: Studies on rats. *J. Gerontol.* **1988**, *43*, B149–B151, doi:10.1093/geronj/43.6.b149.

725. Samorajski, T.; Delaney, C.; Durham, L.; Ordy, J.M.; Johnson, J.A.; Dunlap, W.P. Effect of exercise on longevity, body weight, locomotor performance, and passive-avoidance memory of C57BL/6J mice. *Neurobiol. Aging* **1985**, *6*, 17–24, doi:10.1016/0197-4580(85)90066-1.

726. Pekkanen, J.; Marti, B.; Nissinen, A.; Tuomilehto, J.; Punsar, S.; Karvonen, M.J. Reduction of premature mortality by high physical activity: A 20-year follow-up of middle-aged Finnish men. *Lancet* **1987**, *1*, 1473–1477, doi:10.1016/s0140-6736(87)92218-5.

727. Fontana, L.; Meyer, T.E.; Klein, S.; Holloszy, J.O. Long-term low-calorie low-protein vegan diet and endurance exercise are associated with low cardiometabolic risk. *Rejuvenation Res.* **2007**, *10*, 225–234, doi:10.1089/rej.2006.0529.

728. Fontana, L.; Klein, S.; Holloszy, J.O. Long-term low-protein, low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk. *Am. J. Clin. Nutr.* **2006**, *84*, 1456–1462, doi:10.1093/ajcn/84.6.1456.

729. Huffman, D.M.; Moellering, D.R.; Grizzle, W.E.; Stockard, C.R.; Johnson, M.S.; Nagy, T.R. Effect of exercise and calorie restriction on biomarkers of aging in mice. *Am. J. Physiol. Regul. Integr. Comp. Physiol.* **2008**, *294*, R1618–R1627, doi:10.1152/ajpregu.00890.2007.

730. Thomas, A.W.; Davies, N.A.; Moir, H.; Watkeys, L.; Ruffino, J.S.; Isa, S.A.; Butcher, L.R.; Hughes, M.G.; Morris, K.; Webb, R. Exercise-associated generation of PPARgamma ligands activates PPARgamma signaling events and upregulates genes related to lipid metabolism. *J. Appl. Physiol.* (1985) **2012**, *112*, 806–815, doi:10.1152/japplphysiol.00864.2011.

731. Zhang, S.; Liu, Y.; Li, Q.; Dong, X.; Hu, H.; Hu, R.; Ye, H.; Wu, Y.; Hu, R.; Li, Y. Exercise improved rat metabolism by raising PPAR-alpha. *Int. J. Sports Med.* **2011**, *32*, 568–573, doi:10.1055/s-0031-1271755.

732. Santos, M.H.; Higuchi Mde, L.; Tucci, P.J.; Garavelo, S.M.; Reis, M.M.; Antonio, E.L.; Serra, A.J.; Maranhao, R.C. Previous exercise training increases levels of PPAR-alpha in long-term post-myocardial infarction in
rats, which is correlated with better inflammatory response. *Clinics* (Sao Paulo) **2016**, *71*, 163-168,
doi:10.6061/clinics/2016(03)08.

733. Chen, W.; Gao, R.; Xie, X.; Zheng, Z.; Li, H.; Li, S.; Dong, F.; Wang, L. A metabolomic study of the PPARdelta agonist GW501516 for enhancing running endurance in Kunming mice. *Sci. Rep.* **2015**, *5*, 9884, doi:10.1038/srep09884.

734. Butcher, L.R.; Thomas, A.; Backx, K.; Roberts, A.; Webb, R.; Morris, K. Low-intensity exercise exerts beneficial effects on plasma lipids via PPARgamma. *Med. Sci. Sports Exerc.* **2008**, *40*, 1263-1270, doi:10.1249/MSS.0b013e31816c091d.

735. Ruschke, K.; Fishbein, L.; Dietrich, A.; Kloting, N.; Tonjes, A.; Oberbach, A.; Fasshauer, M.; Jenkner, J.; Schon, M.R.; Stumvoll, M.; et al. Gene expression of PPARgamma and PGC-1alpha in human omental and subcutaneous adipose tissues is related to insulin resistance markers and mediates beneficial effects of physical training. *Eur. J. Endocrinol.* **2010**, *162*, 515-523, doi:10.1530/EJE-09-0767.

736. Sasaki, T.; Nakata, R.; Inoue, H.; Shimizu, M.; Inoue, J.; Sato, R. Role of AMPK and PPARgamma1 in exercise-induced lipoprotein lipase in skeletal muscle. *Am. J. Physiol. Endocrinol. Metab.* **2014**, *306*, E1085-E1092, doi:10.1152/ajpendo.00691.2013.

737. Weiss, E.P.; Kulaputana, O.; Ghiu, I.A.; Brandauer, J.; Wohn, C.R.; Phares, D.A.; Shuldiner, A.R.; Hagberg, J.M. Endurance training-induced changes in the insulin response to oral glucose are associated with the peroxisome proliferator-activated receptor-gamma2 Pro12Ala genotype in men but not in women. *Metabolism* **2005**, *54*, 97-102, doi:10.1016/j.metabol.2004.08.006.

738. Kahara, T.; Takamura, T.; Hayakawa, T.; Nagai, Y.; Yamaguchi, H.; Katsuki, T.; Katsuki, K.; Katsuki, M.; Kobayashi, K. PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men. *Metabolism* **2003**, *52*, 209-212, doi:10.1053/meta.2003.50038.

739. Adamo, K.B.; Sigal, R.J.; Williams, K.; Kenny, G.; Prud'homme, D.; Tesson, F. Influence of Pro12Ala peroxisome proliferator-activated receptor gamma2 polymorphism on glucose response to exercise training in type 2 diabetes. *Diabetologia* **2005**, *48*, 1503-1509, doi:10.1007/s00125-005-1827-y.

740. Ostergard, T.; Ek, J.; Hamid, Y.; Saltin, B.; Pedersen, O.B.; Hansen, T.; Schmitz, O. Influence of the PPAR-gamma2 Pro12Ala and ACE I/D polymorphisms on insulin sensitivity and training effects in healthy offspring of type 2 diabetic subjects. *Horm. Metab. Res.* **2005**, *37*, 99-105, doi:10.1055/s-2005-861174.

741. Pan, W.; Liu, C.; Zhang, J.; Gao, X.; Yu, S.; Tan, H.; Yu, J.; Qian, D.; Li, J.; Bian, S.; et al. Association Between Single Nucleotide Polymorphisms in PPARA and EPAS1 Genes and High-Altitude Appetite Loss in Chinese Young Men. *Front. Physiol.* **2019**, *10*, doi:10.3389/fphys.2019.00059.

742. Fu, J.; Gaetani, S.; Oveisi, F.; Lo Verme, J.; Serrano, A.; Rodriguez De Fonseca, F.; Rosengarth, A.; Luecke, H.; Di Giacomo, B.; Tarzia, G.; et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. *Nature* **2003**, *425*, 90-93, doi:10.1038/nature01921.

743. Fu, J.; Dipatrizio, N.V.; Guijarro, A.; Schwartz, G.J.; Li, X.; Gaetani, S.; Astarita, G.; Piomelli, D. Sympathetic activity controls fat-induced oleylethanolamide signaling in small intestine. *J. Neurosci.* **2011**, *31*, 5730-5736, doi:10.1523/JNEUROSCI.5668-10.2011.

744. Magotti, P.; Bauer, I.; Igarashi, M.; Babagoli, M.; Marotta, R.; Piomelli, D.; Garau, G. Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: Regulation of fatty acid ethanolamide biosynthesis by bile acids. *Structure* **2015**, *23*, 598-604, doi:10.1016/j.str.2014.12.018.

745. Gaetani, S.; Oveisi, F.; Piomelli, D. Modulation of meal pattern in the rat by the anorexic lipid mediator oleylethanolamide. *Neuropsychopharmacology* **2003**, *28*, 1311-1316, doi:10.1038/sj.npp.1300166.

746. Fu, J.; Oveisi, F.; Gaetani, S.; Lin, E.; Piomelli, D. Oleylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. *Neuropharmacology* **2005**, *48*, 1147-1153, doi:10.1016/j.neuropharm.2005.02.013.

747. Caillon, A.; Duszka, K.; Wahli, W.; Rohner-Jeanrenaud, F.; Altirriba, J. The OEA effect on food intake is independent from the presence of PPARalpha in the intestine and the nodose ganglion, while the impact of OEA on energy expenditure requires the presence of PPARalpha in mice. *Metabolism* **2018**, *10.1016/j.metabol.2018.06.005*, doi:10.1016/j.metabol.2018.06.005.

748. Lo Verme, J.; Gaetani, S.; Fu, J.; Oveisi, F.; Burton, K.; Piomelli, D. Regulation of food intake by oleylethanolamide. *Cell Mol. Life Sci.* **2005**, *62*, 708-716, doi:10.1007/s00018-004-4494-0.

749. Piomelli, D. A fatty gut feeling. *Trends Endocrinol. Metab.* **2013**, *24*, 332-341, doi:10.1016/j.tem.2013.03.001.
750. Proulx, K.; Cota, D.; Castaneda, T.R.; Tschop, M.H.; D'Alessio, D.A.; Tso, P.; Woods, S.C.; Seeley, R.J. Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activity. *Am. J. Physiol. Regul. Integr. Comp. Physiol.* **2005**, *289*, R729–R737, doi:10.1152/ajpregu.00029.2005.

751. Rodriguez de Fonseca, F.; Navarro, M.; Gomez, R.; Escuredo, L.; Nava, F.; Fu, J.; Murillo-Rodriguez, E.; Giuffrida, A.; LoVerme, J.; Gaetani, S.; et al. An anorexic lipid mediator regulated by feeding. *Nature* **2001**, *414*, 209–212, doi:10.1038/35102582.

752. Gaetani, S.; Fu, J.; Cassano, T.; Dipasquale, P.; Romano, A.; Righetti, L.; Cianci, S.; Laconca, L.; Giannini, E.; Scaccianoce, S.; et al. The fat-induced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin. *J. Neurosci.* **2010**, *30*, 8096–8101, doi:10.1523/JNEUROSCI.0036-10.2010.

753. Koleva, D.I.; Orbetzova, M.M.; Atanassova, P.K. Adipose tissue hormones and appetite and body weight regulators in insulin resistance. *Folia Med. (Plovdiv)* **2013**, *55*, 25–32.

754. Gautron, L.; Laye, S. Neurobiology of inflammation-associated anorexia. *Front. Neurosci.* **2009**, *3*, 59, doi:10.3389/neuro.23.003.2009.

755. Shi, X.; Wang, X.; Li, Q.; Su, M.; Chew, E.; Wong, E.T.; Lacza, Z.; Radda, G.K.; Tergaonkar, V.; Han, W. Nuclear factor kappaB (NF-kappaB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter. *Diabetologia* **2013**, *56*, 925–936, doi:10.1007/s00125-013-2831-2.

756. Jang, P.G.; Namkoong, C.; Kang, G.M.; Hur, M.W.; Kim, S.W.; Kim, G.H.; Kang, Y.; Jeon, M.J.; Kim, E.H.; Lee, M.S.; et al. NF-kappaB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia. *J. Biol. Chem.* **2010**, *285*, 9706–9715, doi:10.1074/jbc.M109.070706.

757. Speakman, J.R. Body size, energy metabolism and lifespan. *J. Exp. Biol.* **2005**, *208*, 1717–1730, doi:10.1242/jeb.01556.

758. Pearl, R. *The Rate of Living*; University of London Press: London, UK, 1928.

759. Houthoofd, K.; Braeckman, B.P.; Lenaerts, I.; Brys, K.; De Vreese, A.; Van Eygen, S.; Vanfleteren, J.R. Axenic growth up-regulates mass-specific metabolic rate, stress resistance, and extends life span in Caenorhabditis elegans. *Exp. Gerontol.* **2002**, *37*, 1371–1378, doi:10.1016/s0531-5565(02)00173-0.

760. Metaxakis, A.; Partridge, L. Dietary restriction extends lifespan in wild-derived populations of Drosophila melanogaster. *PLoS ONE* **2013**, *8*, e74681, doi:10.1371/journal.pone.0074681.

761. Abalan, F.; Mayo, W.; Simon, H.; Le Moal, M. Paradoxical effect of severe dietary restriction on Long-Evans rat life span. *Int. J. Vitam. Nutr. Res.* **2010**, *80*, 386–393, doi:10.1024/0300-9831/a000027.

762. Pifferi, F.; Terrien, J.; Marchal, J.; Dal-Pan, A.; Djelti, F.; Hardy, I.; Chahory, S.; Cordonnier, N.; Desquilbet, L.; Hurion, M.; et al. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. *Commun. Biol.* **2018**, *1*, 1–8, doi:10.1038/s42003-018-0024-8.

763. Colman, R.J.; Beasley, T.M.; Kemnitz, J.W.; Johnson, S.C.; Weindruch, R.; Anderson, R.M. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. *Nat. Commun.* **2014**, *5*, 3557, doi:10.1038/ncomms4557.

764. Knight, J.A. The biochemistry of aging. *Adv. Clin. Chem.* **2000**, *35*, 1–62.

765. Park, S.Y.; Kim, Y.W.; Kim, J.E.; Kim, J.Y. Age-associated changes in fat metabolism in the rat and its relation to sympathetic activity. *Life Sci.* **2006**, *79*, 2228–2233, doi:10.1016/j.lfs.2006.07.014.

766. Petersen, K.F.; Befroy, D.; Dufour, S.; Dziura, J.; Ariyan, C.; Rothman, D.L.; DiPietro, L.; Cline, G.W.; Shulman, G.I. Mitochondrial dysfunction in the elderly: Possible role in insulin resistance. *Science* **2003**, *300*, 1140–1142, doi:10.1126/science.1082889.

767. Kenyon, C. The plasticity of aging: Insights from long-lived mutants. *Cell* **2005**, *120*, 449–460, doi:10.1016/j.cell.2005.02.002.

768. Siersbaek, R.; Nielsen, R.; Mandrup, S. PPARgamma in adipocyte differentiation and metabolism--novel insights from genome-wide studies. *FEBS Lett.* **2010**, *584*, 3242–3249, doi:10.1016/j.febslet.2010.06.010.

769. Tontonoz, P.; Hu, E.; Spiegelman, B.M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. *Cell* **1994**, *79*, 1147–1156, doi:10.1016/0092-8674(94)90006-x.

770. Cock, T.A.; Houten, S.M.; Auwerx, J. Peroxisome proliferator-activated receptor-gamma: Too much of a good thing causes harm. *EMBO Rep.* **2004**, *5*, 142–147, doi:10.1038/sj.embor.7400082.

771. Argmann, C.; Dobrin, R.; Heikkinen, S.; Auburtin, A.; Pouilly, L.; Cock, T.A.; Koutnikova, H.; Zhu, J.; Schadt, E.E.; Auwerx, J. Ppargamma2 is a key driver of longevity in the mouse. *PLoS Genet.* **2009**, *5*, e1000752, doi:10.1371/journal.pgen.1000752.
772. Viguerie, N.; Vidal, H.; Arner, P.; Holst, C.; Verdich, C.; Avizou, S.; Astrup, A.; Saris, W.H.; Macdonald, I.A.; Klimcakova, E.; et al. Adipose tissue gene expression in obese subjects during low-fat and high-fat hypocaloric diets. *Diabetologia* **2005**, *48*, 123–131, doi:10.1007/s00125-004-1618-x.

773. Karbowska, J.; Kochan, Z. Intermittent fasting up-regulates Fsp27/Cidec gene expression in white adipose tissue. *Nutrition* **2012**, *28*, 294–299, doi:10.1016/j.nut.2011.06.009.

774. Lee, C.K.; Allison, D.B.; Brand, J.; Weindruch, R.; Prolla, T.A. Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. *Proc. Natl. Acad. Sci. USA* **2002**, *99*, 14988–14993, doi:10.1073/pnas.232308999.

775. Chao, C.; Youssef, J.; Rezaiekhaleigh, M.; Birnbaum, L.S.; Badr, M. Senescence-associated decline in hepatic peroxisomal enzyme activities corresponds with diminished levels of retinoid X receptor alpha, but not peroxisome proliferator-activated receptor alpha. *Mech. Ageing Dev.* **2002**, *123*, 1469–1476, doi:10.1016/s0047-6374(02)00086-6.

776. Long, X.; Boluyt, M.O.; O'Neill, L.; Zheng, J.S.; Wu, G.; Nitta, Y.K.; Crow, M.T.; Lakatta, E.G. Myocardial retinoid X receptor, thyroid hormone receptor, and myosin heavy chain gene expression in the rat during adult aging. *J. Gerontol. A Biol. Sci. Med. Sci.* **1999**, *54*, B23–B27, doi:10.1093/gerona/54.1.b23.

777. Enderlin, V.; Pallet, V.; Alfos, S.; Dargelos, E.; Jaffard, R.; Garcin, H.; Higueret, P. Age-related decreases in mRNA for brain nuclear receptors and target genes are reversed by retinoic acid treatment. *Neurosci. Lett.* **1997**, *229*, 125–129, doi:10.1016/s0304-3940(97)00424-2.

778. Stauber, A.J.; Brown-Borg, H.; Liu, J.; Waalkes, M.P.; Laughter, A.; Staben, R.A.; Coley, J.C.; Swanson, C.; Voss, K.A.; Kopchick, J.J.; et al. Constitutive expression of peroxisome proliferator-activated receptor alpha-regulated genes in dwarf mice. *Mol. Pharmacol.* **2005**, *67*, 681–694, doi:10.1124/mol.104.007278.

779. Zhang, Y.; Xie, Y.; Berglund, E.D.; Coate, K.C.; He, T.T.; Katafuchi, T.; Xiao, G.; Potthoff, M.J.; Wei, W.; Wan, Y.; et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. *Elife* **2012**, *1*, e00065, doi:10.7554/eLife.00065.

780. Olsson, B.; Bohlooly, Y.M.; Brusehed, O.; Isaksson, O.G.; Ahren, B.; Olofsson, S.O.; Oscarsson, J.; Tornell, J. Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes. *Am. J. Physiol. Endocrinol. Metab.* **2003**, *285*, E504–E511, doi:10.1152/ajpendo.00444.2002.

781. Sugiyama, H.; Yamada, J.; Suga, T. Effects of testosterone, hypophysectomy and growth hormone treatment on clofibrate induction of peroxisomal beta-oxidation in female rat liver. *Biochem. Pharmacol.* **1994**, *47*, 918–921, doi:10.1016/0006-2952(94)90494-4.

782. Zhou, Y.C.; Waxman, D.J. Cross-talk between janus kinase-signal transducer and activator of transcription (JAK-STAT) and peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling pathways. Growth hormone inhibition of pparalpha transcriptional activity mediated by stat5b. *J. Biol. Chem.* **1999**, *274*, 2672–2681, doi:10.1074/jbc.274.5.2672.

783. Zhou, Y.C.; Waxman, D.J. STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 trans-activation domain. *J. Biol. Chem.* **1999**, *274*, 29874–29882, doi:10.1074/jbc.274.42.29874.

784. Shipley, J.M.; Waxman, D.J. Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma. *Mol. Pharmacol.* **2003**, *64*, 355–364, doi:10.1124/mol.64.2.355.

785. Zheng, X.; Wang, S.; Jia, W. Calorie restriction and its impact on gut microbial composition and global metabolism. *Front. Med.* **2018**, *12*, 634–644, doi:10.1007/s11684-018-0670-8.

786. Ruiz, A.; Cerdo, T.; Jauregui, R.; Pieper, D.H.; Marcos, A.; Clemente, A.; Garcia, F.; Margolles, A.; Ferrer, M.; Campoy, C.; et al. One-year calorie restriction impacts gut microbial composition but not its metabolic performance in obese adolescents. *Environ. Microbiol.* **2017**, *19*, 1536–1551, doi:10.1111/1462-2920.13713.

787. Tanca, A.; Abbondio, M.; Palomba, A.; Fraumene, C.; Marongiu, F.; Serra, M.; Pagnozzi, D.; Laconi, E.; Uzzau, S. Caloric restriction promotes functional changes involving short-chain fatty acid biosynthesis in the rat gut microbiota. *Sci. Rep.* **2018**, *8*, 14778, doi:10.1038/s41598-018-33100-y.

788. Zhang, C.; Li, S.; Yang, L.; Huang, P.; Li, W.; Wang, S.; Zhao, G.; Zhang, M.; Pang, X.; Yan, Z.; et al. Structural modulation of gut microbiota in life-long calorie-restricted mice. *Nat. Commun.* **2013**, *4*, 2163, doi:10.1038/ncomms3163.

789. Fraumene, C.; Manghina, V.; Cadoni, E.; Marongiu, F.; Abbondio, M.; Serra, M.; Palomba, A.; Tanca, A.; Laconi, E.; Uzzau, S. Caloric restriction promotes rapid expansion and long-lasting increase of Lactobacillus in the rat fecal microbiota. *Gut Microbes* **2018**, *9*, 104–114, doi:10.1080/19490976.2017.1371894.
790. Liu, T.; Wu, Y.; Wang, L.; Pang, X.; Zhao, L.; Yuan, H.; Zhang, C. A More Robust Gut Microbiota in Calorie-Restricted Mice Is Associated with Attenuated Intestinal Injury Caused by the Chemotherapy Drug Cyclophosphamide. *mBio* **2019**, *10*, doi:10.1128/mBio.02903-18.

791. Wang, S.; Huang, M.; You, X.; Zhao, J.; Chen, L.; Wang, L.; Luo, Y.; Chen, Y. Gut microbiota mediates the anti-obesity effect of calorie restriction in mice. *Sci. Rep.* **2018**, *8*, 13037, doi:10.1038/s41598-018-31353-1.

792. Crawford, P.A.; Crowley, J.R.; Sambandam, N.; Muegge, B.D.; Costello, E.K.; Hamady, M.; Knight, R.; Gordon, J.I. Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation. *Proc. Natl. Acad. Sci. USA* **2009**, *106*, 11276-11281, doi:10.1073/pnas.0902366106.

793. Montagner, A.; Korecka, A.; Polizzi, A.; Lippi, Y.; Blum, Y.; Canlet, C.; Tremblay-Franco, M.; Gautier-Stein, A.; Burcelin, R.; Yen, Y.C.; et al. Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals. *Sci. Rep.* **2016**, *6*, 20127, doi:10.1038/srep20127.

794. Mukherji, A.; Kobiita, A.; Ye, T.; Chambon, P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. *Cell* **2013**, *153*, 812-827, doi:10.1016/j.cell.2013.04.020.

795. Manoharan, I.; Suryawanshi, A.; Hong, Y.; Ranganathan, P.; Shanmugam, A.; Ahmad, S.; Swafford, D.; Manicassamy, B.; Ramesh, G.; Koni, P.A.; et al. Homeostatic PPARalpha Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine. *J. Immunol.* **2016**, *196*, 4739-4749, doi:10.4049/jimmunol.1501489.

796. Li, G.; Xie, C.; Lu, S.; Nichols, R.G.; Tian, Y.; Li, L.; Patel, D.; Ma, Y.; Brocker, C.N.; Yan, T.; et al. Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota. *Cell Metab.* **2017**, *26*, 801, doi:10.1016/j.cmet.2017.10.007.

797. Burdick, A.D.; Kim, D.J.; Peraza, M.A.; Gonzalez, F.J.; Peters, J.M. The role of peroxisome proliferator-activated receptor-beta/delta in epithelial cell growth and differentiation. *Cell. Signal.* **2006**, *18*, 9-20, doi:10.1016/j cellsig.2005.07.009.

798. Murakami, M.; Tognini, P.; Liu, Y.; Eckel-Mahan, K.L.; Baldi, P.; Sassone-Corsi, P. Gut microbiota directs PPARgamma-driven reprogramming of the liver circadian clock by nutritional challenge. *EMBO Rep.* **2016**, *17*, 1292-1303, doi:10.15252/embr.201642463.

799. Peyrin-Biroulet, L.; Beisner, J.; Wang, G.; Nuding, S.; Oommen, S.T.; Kelly, D.; Parmentier-Decrucq, E.; Dessein, R.; Merour, E.; Chavatte, P.; et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. *Proc. Natl. Acad. Sci. USA* **2010**, *107*, 8772-8777, doi:10.1073/pnas.0905745107.

800. Oh, H.Y.P.; Visvalingam, V.; Wahli, W. The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology. *FASEB J.* **2019**, *33*, 9706-9730, doi:10.1096/fj.201802681RR.

801. Fann, D.Y.; Ng, G.Y.; Poh, L.; Arumugam, T.V. Positive effects of intermittent fasting in ischemic stroke. *Exp. Gerontol.* **2017**, *89*, 93-102, doi:10.1016/j.exger.2017.01.014.

802. Razeghi Jahromi, S.; Ghaemi, A.; Alizadeh, A.; Sabetghadam, F.; Moradi Tabriz, H.; Togha, M. Effects of Intermittent Fasting on Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice. *Iran. J. Allergy Asthma Immunol.* **2016**, *15*, 212-219.

803. Okada, T.; Otsubo, T.; Hagiwara, T.; Inazuka, F.; Kobayashi, E.; Fukuda, S.; Inoue, T.; Higuchi, K.; Kawamura, Y.I.; Dohi, T. Intermittent fasting prompted recovery from dextran sulfate sodium-induced colitis in mice. *J. Clin. Biochem. Nutr.* **2017**, *61*, 100-107, doi:10.3164/jcbn.17-9.

804. Savendahl, L.; Underwood, L.E.; Haldeman, K.M.; Ulshen, M.H.; Lund, P.K. Fasting prevents experimental murine colitis produced by dextran sulfate sodium and decreases interleukin-1 beta and insulin-like growth factor I messenger ribonucleic acid. *Endocrinology* **1997**, *138*, 734-740, doi:10.1210/endo.138.2.4941.

805. Cheng, C.W.; Villani, V.; Buono, R.; Wei, M.; Kumar, S.; Yilmaz, O.H.; Cohen, P.; Sneddon, J.B.; Perin, L.; Longo, V.D. Fasting-Mimicking Diet Promotes Ngn3-Driven beta-Cell Regeneration to Reverse Diabetes. *Cell* **2017**, *168*, 775-788 e712, doi:10.1016/j.cell.2017.01.040.

806. Wei, M.; Brandhorst, S.; Shelehchi, M.; Mirzaei, H.; Cheng, C.W.; Budniak, J.; Groshen, S.; Mack, W.J.; Guen, E.; Di Biase, S.; et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. *Sci. Transl. Med.* **2017**, *9*, doi:10.1126/scitranslmed.aai8700.

807. Rangan, P.; Choi, I.; Wei, M.; Navarrete, G.; Guen, E.; Brandhorst, S.; Enyati, N.; Pasia, G.; Maesincee, D.; Ocon, V.; et al. Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology. *Cell Rep.* **2019**, *26*, 2704-2719.e6, doi:10.1016/j.celrep.2019.02.019.
808. Liu, K.; Liu, B.; Heilbronn, L.K. Intermittent fasting: What questions should we be asking? *Physiol. Behav.* **2020**, *218*, 112827, doi:10.1016/j.physbeh.2020.112827.
809. Horne, B.D.; Muhlestein, J.B.; Anderson, J.L. Health effects of intermittent fasting: Hormesis or harm? A systematic review. *Am. J. Clin. Nutr.* **2015**, *102*, 464–470, doi:10.3945/ajcn.115.109553.

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