PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth (2001)

peroxisome proliferator-activated receptor retinoid X receptor, PPRE, peroxisome proliferator-activated receptor response element nuclear hormone receptor thiazolidinedione phosphoenolpyruvate carboxykinase embryonic stem cells 15-hydroxyeicosatetraenoic acid 13-hydroxyoctadecadienoic acid CCAAT/enhancer-binding protein CREB-binding protein histone acetyltransferase tumor necrosis factor-α interleukin-6 liver X receptor The peroxisome proliferator-activated receptors (PPARs)1 comprise an important subfamily of the nuclear hormone receptor (NHR) superfamily. These ligand-activated transcription factors have been intensively studied for more than a decade and have been implicated in such diverse pathways as lipid and glucose homeostasis, control of cellular proliferation, and differentiation. The name PPAR derives from the initial cloning of one isoform as a target of various xenobiotic compounds that were observed to induce proliferation of peroxisomes in the liver (1Issemann I. Green S. Nature. 1990; 347: 645-650Crossref PubMed Scopus (3022) Google Scholar). This protein was called the peroxisome proliferator-activated receptor, now known as PPARα. Within a few years, the group of PPARs was expanded to include PPARγ and PPARδ (also referred to as PPARβ, NUC1, and FAAR) (2Dreyer C. Krey G. Keller H. Givel F. Helftenbein G. Wahli W. Cell. 1992; 68: 879-887Abstract Full Text PDF PubMed Scopus (1195) Google Scholar, 3Desvergne B. Wahli W. Endocr. Rev. 1999; 20: 649-688Crossref PubMed Scopus (2708) Google Scholar, 4Kliewer S.A. Forman B.M. Blumberg B. Ong E.S. Borgmeyer U. Mangelsdorf D.J. Umesono K. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7355-7359Crossref PubMed Scopus (1269) Google Scholar, 5Zhu Y. Alvares K. Huang Q. Rao M.S. Reddy J.K. J. Biol. Chem. 1993; 268: 26817-26820Abstract Full Text PDF PubMed Google Scholar, 6Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (1983) Google Scholar). This review will focus on PPARγ.How Do PPARs Work at the Molecular Level?PPARs possess the canonical domain structure of other NHR superfamily members (see Fig. 1). This includes a poorly characterized N-terminal region that contains a potential trans-activation function known as AF-1, followed by a DNA binding domain that includes two zinc fingers. At the carboxyl terminus is a dimerization and ligand binding domain that molecular modeling reveals to be a large hydrophobic pocket and which contains a key, ligand-dependent trans-activation function called AF-2 (7Nolte R.T. Wisely G.B. Westin S. Cobb J.E. Lambert M.H. Kurokawa R. Rosenfeld M.G. Willson T.M. Glass C.K. Milburn M.V. Nature. 1998; 395: 137-143Crossref PubMed Scopus (1661) Google Scholar,8Xu H.E. Lambert M.H. Montana V.G. Parks D.J. Blanchard S.G. Brown P.J. Sternbach D.D. Lehmann J.M. Wisely G.B. Willson T.M. Kliewer S.A. Milburn M.V. Mol Cell. 1999; 3: 397-403Abstract Full Text Full Text PDF PubMed Scopus (956) Google Scholar). PPARs bind to cognate DNA elements called PPAR response elements (PPREs) in the 5′-flanking region of target genes. Like many other NHRs, they bind DNA as obligate heterodimers by partnering with one of the retinoid X receptors (RXRs). Known PPREs are direct repeats of an AGGNCA half-site separated by a 1-base pair spacer. A short sequence located immediately upstream of the first half-site confers polarity on the PPRE, with the PPAR moiety binding 5′ to the RXR half of the heterodimer (9Juge-Aubry C. Pernin A. Favez T. Burger A.G. Wahli W. Meier C.A. Desvergne B. J. Biol. Chem. 1997; 272: 25252-25259Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 10DiRenzo J. Soderstrom M. Kurokawa R. Ogliastro M.H. Ricote M. Ingrey S. Horlein A. Rosenfeld M.G. Glass C.K. Mol. Cell. Biol. 1997; 17: 2166-2176Crossref PubMed Scopus (251) Google Scholar). Many cell types express more than one PPAR isoform, which begs the question of how isoform-specific targets are regulated. Most likely this occurs through a combination of subtle cis sequence differences flanking the core response element, the presence of specific or selective coactivator proteins, and regulation of endogenous ligands.PPARs, like other NHRs, form protein-protein interactions with a variety of nuclear proteins known as coactivators and corepressors, which mediate contact between the PPAR-RXR heterodimer, chromatin, and the basal transcriptional machinery and which promote activation and repression of gene expression, respectively. Coactivator proteins, which include members of the p160/CBP/p300 and DRIP/TRAP families, are general coactivators for NHRs and indeed many non-NHR transcription factors. There are no known receptor-specific coactivators or corepressors, although selectivity for one or another NHR has been illustrated in certain cases (11Castillo G. Brun R.P. Rosenfield J.K. Hauser S. Park C.W. Troy A.E. Wright M.E. Spiegelman B.M. EMBO J. 1999; 18: 3676-3687Crossref PubMed Scopus (106) Google Scholar, 12Yeh S. Chang C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5517-5521Crossref PubMed Scopus (529) Google Scholar). Coactivator proteins either possess or recruit histone acetyltransferase (HAT) activity to the transcription start site. Acetylation of histone proteins is believed to relieve the tightly packed structure of the chromatin, allowing the RNA polymerase II complex to bind and initiate transcription. Coactivators also recruit the chromatin remodeling SWI·SNF complex to target promoters (13Leo C. Chen J.D. Gene (Amst.). 2000; 245: 1-11Crossref PubMed Scopus (436) Google Scholar, 14Freedman L.P. Cell. 1999; 97: 5-8Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar).What Are the Physiological Roles Played by PPARγ?PPARγ is the most intensively studied PPAR isoform. Studies have shown that this receptor participates in biological pathways of intense basic and clinical interest, such as differentiation, insulin sensitivity, type 2 diabetes, atherosclerosis, and cancer. PPARγ exists in two protein isoforms that are created by alternative promoter usage and alternative splicing at the 5′ end of the gene; PPARγ2 contains 30 additional amino acids at the N terminus compared with PPARγ1 (6Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (1983) Google Scholar). Whereas many tissues express a low level of PPARγ1, PPARγ2 is fat-selective and is expressed at very high levels in that tissue.PPARγ LigandsBecause of its involvement in so many critical physiologic and pathologic functions (see below), great effort has been spent in trying to identify an endogenous, high affinity ligand for PPARγ. A variety of fatty acids and their derivatives have been found to bind to PPARγ with relatively low affinity, but most investigators believe that their relevant concentrations in the nuclei of target cells are likely to be too low for them to be bona fide ligands. Certain eicosanoids have been shown to bind and activate PPARγ with higher affinity (15Reginato M.J. Krakow S.L. Bailey S.T. Lazar M.A. J. Biol. Chem. 1998; 273: 1855-1858Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 16Yu K. Bayona W. Kallen C.B. Harding H.P. Ravera C.P. McMahon G. Brown M. Lazar M.A. J. Biol. Chem. 1995; 270: 23975-23983Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar). 15-Deoxy-Δ12,14-prostaglandin J2, for example, binds to PPARγ with a kD in the low micromolar range and can activate PPARγ target genes at concentrations at or near thekD (17Forman B.M. Tontonoz P. Chen J. Brun R.P. Spiegelman B.M. Evans R.M. Cell. 1995; 83: 803-812Abstract Full Text PDF PubMed Scopus (2715) Google Scholar, 18Kliewer S.A. Lenhard J.M. Willson T.M. Patel I. Morris D.C. Lehmann J.M. Cell. 1995; 83: 813-819Abstract Full Text PDF PubMed Scopus (1859) Google Scholar). 15-Deoxy-Δ12,14-prostaglandin J2, however, has never been definitively proven to existin vivo, nor are its effects specific to PPARγ. Many actions of this compound, which have been ascribed to PPARγ activation, have actually been shown to be mediated through inhibition of the NF-κB pathway (19Straus D.S. Pascual G. Li M. Welch J.S. Ricote M. Hsiang C.H. Sengchanthalangsy L.L. Ghosh G. Glass C.K. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4844-4849Crossref PubMed Scopus (940) Google Scholar, 20Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar). Other eicosanoids, such as 13-HODE and 15-HETE, have been suggested to act as PPARγ ligands (21Nagy L. Tontonoz P. Alvarez J.G. Chen H. Evans R.M. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1575) Google Scholar), a notion supported by the requirement for 12/15-lipoxygenase in some PPARγ responses in vitro (22Huang J.T. Welch J.S. Ricote M. Binder C.J. Willson T.M. Kelly C. Witztum J.L. Funk C.D. Conrad D. Glass C.K. Nature. 1999; 400: 378-382Crossref PubMed Scopus (766) Google Scholar).Despite the paucity of information on true endogenous ligands, several high affinity synthetic PPARγ ligands have been generated. These include the thiazolidinedione (TZD) class of drugs, which are used clinically as insulin sensitizers in patients with type 2 diabetes (23Kletzien R.F. Clarke S.D. Ulrich R.G. Mol. Pharmacol. 1992; 41: 393-398PubMed Google Scholar) and were developed without knowledge of their molecular target. Other novel agents, including aryl-tyrosine derivatives, have been developed and are likely to show promise in both the laboratory and the clinic (24Brown K.K. Henke B.R. Blanchard S.G. Cobb J.E. Mook R. Kaldor I. Kliewer S.A. Lehmann J.M. Lenhard J.M. Harrington W.W. Novak P.J. Faison W. Binz J.G. Hashim M.A. Oliver W.O. Brown H.R. Parks D.J. Plunket K.D. Tong W.Q. Menius J.A. Adkison K. Noble S.A. Willson T.M. Diabetes. 1999; 48: 1415-1424Crossref PubMed Scopus (164) Google Scholar).PPARγ and AdipogenesisPPARγ was cloned as a transcription factor important in fat cell differentiation; it was also isolated in screens seeking new members of the PPAR family. In the former case, PPARγ was identified as a protein that bound to an enhancer in the 5′-flanking region of the aP2 gene, which encodes a fat cell-selective fatty acid-binding protein (6Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (1983) Google Scholar). This discovery was rapidly followed up by experiments showing that ectopic expression of PPARγ could dramatically promote adipogenesis in nonadipogenic, fibroblastic cells such as NIH-3T3 cells (25Tontonoz P. Hu E. Spiegelman B.M. Cell. 1994; 79: 1147-1156Abstract Full Text PDF PubMed Scopus (3093) Google Scholar). When combined with an appropriate agonist and the pro-adipogenic protein C/EBPα, even myoblasts could be "trans-differentiated" to adipocytes (26Hu E. Tontonoz P. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9856-9860Crossref PubMed Scopus (578) Google Scholar). PPARγ plays a crucial role in the function of many, and perhaps most, fat cell-specific genes. PPARγ binding is absolutely required for the function of the fat-selective enhancers for the aP2 and PEPCK genes in cultured fat cells (27Tontonoz P. Hu E. Devine J. Beale E.G. Spiegelman B.M. Mol. Cell. Biol. 1995; 15: 351-357Crossref PubMed Google Scholar). This analysis of the PEPCK gene has recently been extended in vivo, where activation of this promoter in fat was shown to be dependent on a PPARγ binding site, whereas expression in other tissues was not (28Devine J.H. Eubank D.W. Clouthier D.E. Tontonoz P. Spiegelman B.M. Hammer R.E. Beale E.G. J. Biol. Chem. 1999; 274: 13604-13612Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). The role of PPARγ in adipogenesis is also illustrated in studies that have deleted this gene in mice. The homozygous null mutation is lethal relatively early in gestation (embryonic days 10–10.5) secondary to a defect in placental development (29Kubota N. Terauchi Y. Miki H. Tamemoto H. Yamauchi T. Komeda K. Satoh S. Nakano R. Ishii C. Sugiyama T. Eto K. Tsubamoto Y. Okuno A. Murakami K. Sekihara H. Hasegawa G. Naito M. Toyoshima Y. Tanaka S. Shiota K. Kitamura T. Fujita T. Ezaki O. Aizawa S. Kadowaki T. et al.Mol. Cell. 1999; 4: 597-609Abstract Full Text Full Text PDF PubMed Scopus (1214) Google Scholar, 30Barak Y. Nelson M.C. Ong E.S. Jones Y.Z. Ruiz-Lozano P. Chien K.R. Koder A. Evans R.M. Mol. Cell. 1999; 4: 585-595Abstract Full Text Full Text PDF PubMed Scopus (1630) Google Scholar), forcing investigators to use alternative means to investigate whether PPARγ is required for fat cell differentiation. Chimeric mice derived from both wild-type ES cells and cells with a homozygous deletion of PPARγ showed exclusion of null cells from white adipose tissue, but not several other tissues (31Rosen E.D. Sarraf P. Troy A.E. Bradwin G. Moore K. Milstone D.S. Spiegelman B.M. Mortensen R.M. Mol. Cell. 1999; 4: 611-617Abstract Full Text Full Text PDF PubMed Scopus (1627) Google Scholar). Another group succeeded in bringing a single PPARγ −/− mouse to term by making tetraploid chimeric placentas; although the animal died shortly after birth it was found to lack brown adipose stores (30Barak Y. Nelson M.C. Ong E.S. Jones Y.Z. Ruiz-Lozano P. Chien K.R. Koder A. Evans R.M. Mol. Cell. 1999; 4: 585-595Abstract Full Text Full Text PDF PubMed Scopus (1630) Google Scholar).In vitro, it has also been shown that PPARγ is required for the differentiation of adipose cells from ES cells and from embryonic fibroblasts (29Kubota N. Terauchi Y. Miki H. Tamemoto H. Yamauchi T. Komeda K. Satoh S. Nakano R. Ishii C. Sugiyama T. Eto K. Tsubamoto Y. Okuno A. Murakami K. Sekihara H. Hasegawa G. Naito M. Toyoshima Y. Tanaka S. Shiota K. Kitamura T. Fujita T. Ezaki O. Aizawa S. Kadowaki T. et al.Mol. Cell. 1999; 4: 597-609Abstract Full Text Full Text PDF PubMed Scopus (1214) Google Scholar, 31Rosen E.D. Sarraf P. Troy A.E. Bradwin G. Moore K. Milstone D.S. Spiegelman B.M. Mortensen R.M. Mol. Cell. 1999; 4: 611-617Abstract Full Text Full Text PDF PubMed Scopus (1627) Google Scholar). The results of these genetic studies have been complemented by experiments using pharmacological inhibitors and dominant negative alleles of PPARγ (32Oberfield J.L. Collins J.L. Holmes C.P. Goreham D.M. Cooper J.P. Cobb J.E. Lenhard J.M. Hull-Ryde E.A. Mohr C.P. Blanchard S.G. Parks D.J. Moore L.B. Lehmann J.M. Plunket K. Miller A.B. Milburn M.V. Kliewer S.A. Willson T.M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6102-6106Crossref PubMed Scopus (314) Google Scholar, 33Gurnell M. Wentworth J.M. Agostini M. Adams M. Collingwood T.N. Provenzano C. Browne P.O. Rajanayagam O. Burris T.P. Schwabe J.W. Lazar M.A. Chatterjee V.K. J. Biol. Chem. 2000; 275: 5754-5759Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar). These approaches have primarily been used to demonstrate a loss of PPARγ agonist-induced adipogenesis in vitro, although one study has shown a reduction in differentiation induced by the usual hormonal stimulants (34Wright H.M. Clish C.B. Mikami T. Hauser S. Yanagi K. Hiramatsu R. Serhan C.N. Spiegelman B.M. J. Biol. Chem. 2000; 275: 1873-1877Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar).The CCAAT/enhancer binding proteins C/EBPα, -β, and -δ have also been shown to be important in adipogenic differentiation. A transcriptional cascade exists in which C/EBPβ and -δ induce the formation of PPARγ and C/EBPα almost simultaneously (reviewed in Ref. 35Rosen E.D. Walkey C.J. Puigserver P. Spiegelman B.M. Genes Dev. 2000; 14: 1293-1307PubMed Google Scholar). These latter two proteins then go on to promote the fully differentiated phenotype. In a manner analogous to the situation with PPARγ, ectopic expression of C/EBPα in pre-adipocytes is able to drive adipogenesis to completion. Studies on fibroblasts engineered to lack C/EBPα show that they are deficient in PPARγ but can still become adipocytes (albeit without full insulin sensitivity) if PPARγ is added back (36Wu Z. Rosen E.D. Brun R. Hauser S. Adelmant G. Troy A.E. McKeon C. Darlington G.J. Spiegelman B.M. Mol. Cell. 1999; 3: 151-158Abstract Full Text Full Text PDF PubMed Scopus (813) Google Scholar). Conversely, ES cells or fibroblasts that lack PPARγ are deficient in C/EBPα (29Kubota N. Terauchi Y. Miki H. Tamemoto H. Yamauchi T. Komeda K. Satoh S. Nakano R. Ishii C. Sugiyama T. Eto K. Tsubamoto Y. Okuno A. Murakami K. Sekihara H. Hasegawa G. Naito M. Toyoshima Y. Tanaka S. Shiota K. Kitamura T. Fujita T. Ezaki O. Aizawa S. Kadowaki T. et al.Mol. Cell. 1999; 4: 597-609Abstract Full Text Full Text PDF PubMed Scopus (1214) Google Scholar, 31Rosen E.D. Sarraf P. Troy A.E. Bradwin G. Moore K. Milstone D.S. Spiegelman B.M. Mortensen R.M. Mol. Cell. 1999; 4: 611-617Abstract Full Text Full Text PDF PubMed Scopus (1627) Google Scholar). This raises the possibility that induction of PPARγ and C/EBPα represent redundant pathways for fat cell development. We have recently obtained data, however, that this is not the case, as fibroblasts that lack PPARγ are incompetent to undergo adipogenesis even when functional C/EBPα is added back at high levels. 2E. D. Rosen and B. M. Spiegelman, unpublished data. The role of C/EBPα in adipogenesis, therefore, is ancillary to the role of PPARγ (see Fig. 2).Figure 2PPARγ plays a critical role in the adipogenic transcriptional cascade. As preadipocytes begin to differentiate they express C/EBPβ and C/EBPδ, which in turn activate both PPARγ and C/EBPα. These two proteins potently induce each other's expression. PPARγ is required for differentiation, whereas C/EBPα plays a more ancillary role by promoting full insulin sensitivity and specific gene expression (see text).View Large Image Figure ViewerDownload Hi-res image Download (PPT)PPARγ and Type 2 DiabetesA role for PPARγ in type 2 diabetes is clearly suggested by the efficacy of TZD ligands in ameliorating insulin resistance, an effect used by over a million patients currently taking these drugs (37Mudaliar S. Henry R.R. Annu. Rev. Med. 2001; 52: 239-257Crossref PubMed Scopus (202) Google Scholar). Several lines of evidence converge to prove that PPARγ is the relevant target of these drugs, including the finding that novel ligands designed to bind the PPARγ ligand binding domain with high affinity are very potent insulin sensitizers in vivo (24Brown K.K. Henke B.R. Blanchard S.G. Cobb J.E. Mook R. Kaldor I. Kliewer S.A. Lehmann J.M. Lenhard J.M. Harrington W.W. Novak P.J. Faison W. Binz J.G. Hashim M.A. Oliver W.O. Brown H.R. Parks D.J. Plunket K.D. Tong W.Q. Menius J.A. Adkison K. Noble S.A. Willson T.M. Diabetes. 1999; 48: 1415-1424Crossref PubMed Scopus (164) Google Scholar).Additionally, mutations have been discovered in a few patients with severe insulin resistance (38Barroso I. Gurnell M. Crowley V.E. Agostini M. Schwabe J.W. Soos M.A. Maslen H. Chatterjee V.K. S. Nature. 1999; PubMed Scopus Google Scholar). The protein of these alleles in a dominant negative in vitro, a role for PPARγ in the of basal insulin for PPARγ insulin sensitivity to wild-type and also show resistance to (29Kubota N. Terauchi Y. Miki H. Tamemoto H. Yamauchi T. Komeda K. Satoh S. Nakano R. Ishii C. Sugiyama T. Eto K. Tsubamoto Y. Okuno A. Murakami K. Sekihara H. Hasegawa G. Naito M. Toyoshima Y. Tanaka S. Shiota K. Kitamura T. Fujita T. Ezaki O. Aizawa S. Kadowaki T. et al.Mol. Cell. 1999; 4: 597-609Abstract Full Text Full Text PDF PubMed Scopus (1214) Google Scholar, Y. W. Evans R.M. J.M. J. 2000; PubMed Scopus Google Scholar). This from levels and in these mice (29Kubota N. Terauchi Y. Miki H. Tamemoto H. Yamauchi T. Komeda K. Satoh S. Nakano R. Ishii C. Sugiyama T. Eto K. Tsubamoto Y. Okuno A. Murakami K. Sekihara H. Hasegawa G. Naito M. Toyoshima Y. Tanaka S. Shiota K. Kitamura T. Fujita T. Ezaki O. Aizawa S. Kadowaki T. et al.Mol. Cell. 1999; 4: 597-609Abstract Full Text Full Text PDF PubMed Scopus (1214) Google Scholar). exists a between the and that more a in the PPARγ gene has been with from type 2 diabetes, the that this a PPARγ in transcription D. M. M.C. J. S. C. T. D. M. L. E.S. 2000; PubMed Scopus Google Scholar, L. M. J. L. J. M. W. J. 1998; 20: PubMed Scopus Google Scholar).Despite and of clinical use of still the by which PPARγ insulin example, the specific target of is one likely and a study has shown that mice a dominant negative not show in insulin sensitivity when with L. B. J. C. E. O. J. 2000; PubMed Scopus Google Scholar). S. K. J. J. S. Graves R.A. 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Li C. L. G. J. 2001; PubMed Google Scholar). a protein called was discovered to be by fat cells and to promote insulin resistance, and is evidence that expression of this factor as Bailey S.T. S. Brown R.R. Wright Patel H.R. Lazar M.A. Nature. 2001; PubMed Scopus Google Scholar), although this question J.M. Tong Q. T. Brown K.K. Harrington W.W. Oliver Willson T.M. Kliewer S.A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). a recently discovered protein by known as and has been found to be both a TZD target as as a of insulin sensitivity T.P. M. Med. 2001; PubMed Scopus Google Scholar, T. J. H. Terauchi Y. N. K. Y. T. Murakami K. N. Ezaki O. Y. O. C. H. K. M. Nakano Y. K. R. S. M. P. Kadowaki T. Med. 2001; PubMed Scopus Google insulin of the by which PPARγ activation by TZD drugs insulin resistance are In act on PPARγ in adipose to the glucose and to levels of that induce insulin resistance in liver and act on tissues to fatty acids from and liver and in glucose in the Large Image Figure ViewerDownload Hi-res image Download (PPT)PPARγ and discovery that PPARγ was expressed at relatively high levels in and to studies showing that PPARγ could promote differentiation and induce the receptor P. L. Alvarez J.G. Evans R.M. Cell. 1998; 93: Full Text Full Text PDF PubMed Scopus Google Scholar). These with the of PPARγ in N. G. C. P. J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Huang J. L. Li A. Welch J. J. Witztum J.L. J. W. Glass C.K. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar), to that could be promoting in taking these ligands of PPARγ were identified in low in and it was shown that these could induce expression of PPARγ (21Nagy L. Tontonoz P. Alvarez J.G. Chen H. Evans R.M. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1575) Google Scholar). A was in which these induced their through activation of PPARγ and expression of to cell however, suggested that PPARγ be in (reviewed in Ref. E.D. Spiegelman B.M. J. 2000; PubMed Scopus Google Scholar). for example, have been shown to in several Other pathways are also by including proliferation and of cells and of in the such as and receptor A C. B. Nature. 1998; PubMed Scopus Google Scholar, M. Li Willson T.M. Kelly C.J. Glass C.K. Nature. 1998; PubMed Scopus Google Scholar). PPARγ also the expression of proteins in to a reduction of in These and are actually induced by the NHR which is a target of PPARγ A. C.H. Y. D. L. Evans R.M. Tontonoz P. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, D.C. H.R. Mangelsdorf D.J. Tontonoz P. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, A. D.C. Tontonoz P. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar). to receptor mice and in and no effect in Brown K.K. M.J. Willson T.M. W. Glass C.K. J. 2000; PubMed Scopus Google genetic studies show that PPARγ is not required for the formation of from although PPAR