11. Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1: 15–25. 12. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, et al. (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428: 569–574. 13. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, et al. (2006) Hypothalamic mTOR signaling regulates food intake. Science 312: 927–930. 14. Brunn GJ, Hudson CC, Sekulic A, Williams JM, Hosoi H, et al. (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277: 99–101. 15. Ropelle ER, Pauli JR, Fernandes MF, Rocco SA, Marin RM, et al. (2008) A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high-protein diet-induced weight loss. Diabetes 57: 594–605. 16. Shamji AF, Nghiem P, Schreiber SL (2003) Integration of growth factor and nutrient signaling: implications for cancer biology. Mol Cell 12: 271–280. 17. Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, et al. (2001) Mammalian TOR: a homeostatic ATP sensor. Science 294: 1102–1105. 18. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4: 648–657. 19. Kimura N, Tokunaga C, Dalal S, Richardson C, Yoshino K, et al. (2003) A possible linkage between AMP-activated protein kinase (AMPK) and mamma- lian target of rapamycin (mTOR) signalling pathway. Genes Cells 8: 65–79. 20. Gleason CE, Lu D, Witters LA, Newgard CB, Birnbaum MJ (2007) The role of AMPK and mTOR in nutrient sensing in pancreatic beta-cells. J Biol Chem 282: 10341–10351. 21. Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, et al. (2003) Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 24: 113–119. 22. Penkowa M, Keller C, Keller P, Jauffred S, Pedersen BK (2003) Immunohis- tochemical detection of interleukin-6 in human skeletal muscle fibers following exercise. Faseb J 17: 2166–2168. 23. Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B, et al. (2000) Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol 529 Pt 1: 237–242. 24. Keller C, Keller P, Marshal S, Pedersen BK (2003) IL-6 gene expression in human adipose tissue in response to exercise–effect of carbohydrate ingestion. J Physiol 550: 927–931. 25. Lyngso D, Simonsen L, Bulow J (2002) Metabolic effects of interleukin-6 in human splanchnic and adipose tissue. J Physiol 543: 379–386. 26. Ruderman NB, Keller C, Richard AM, Saha AK, Luo Z, et al. (2006) Interleukin-6 Regulation of AMP-Activated Protein Kinase: Potential Role in the Systemic Response to Exercise and Prevention of the Metabolic Syndrome. Diabetes 55 Suppl 2: S48–54. 27. Kelly M, Keller C, Avilucea PR, Keller P, Luo Z, et al. (2004) AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun 320: 449–454. 28. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, et al. (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8: 75–79. 29. Lutticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, et al. (1994) Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science 263: 89–92. 30. Murakami M, Hibi M, Nakagawa N, Nakagawa T, Yasukawa K, et al. (1993) IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science 260: 1808–1810. 31. Narazaki M, Witthuhn BA, Yoshida K, Silvennoinen O, Yasukawa K, et al. (1994) Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc Natl Acad Sci U S A 91: 2285–2289. 32. Sadowski HB, Shuai K, Darnell JE Jr, Gilman MZ (1993) A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science 261: 1739–1744. 33. Chen RH, Chang MC, Su YH, Tsai YT, Kuo ML (1999) Interleukin-6 inhibits transforming growth factor-beta-induced apoptosis through the phosphatidyli- nositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J Biol Chem 274: 23013–23019. 34. Kim EK, Miller I, Aja S, Landree LE, Pinn M, et al. (2004) C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 279: 19970–19976. 35. Bi S, Scott KA, Hyun J, Ladenheim EE, Moran TH (2005) Running wheel activity prevents hyperphagia and obesity in Otsuka long-evans Tokushima Fatty rats: role of hypothalamic signaling. Endocrinology 146: 1676–1685. 36. Bruce CR, Lee JS, Kiens B, Hawley JA (2004) Postexercise muscle triacylglycerol and glycogen metabolism in obese insulin-resistant zucker rats. Obes Res 12: 1158–1165. 37. Martins C, Robertson MD, Morgan LM (2008) Effects of exercise and restrained eating behaviour on appetite control. Proc Nutr Soc 67: 28–41. 38. Martins C, Truby H, Morgan LM (2007) Short-term appetite control in response to a 6-week exercise programme in sedentary volunteers. Br J Nutr 98: 834–842. 39. Santti E, Huupponen R, Rouru J, Hanninen V, Pesonen U, et al. (1994) Potentiation of the anti-obesity effect of the selective beta 3-adrenoceptor agonist BRL 35135 in obese Zucker rats by exercise. Br J Pharmacol 113: 1231–1236. Exercise and Leptin Action 40. Daval M, Foufelle F, Ferre P (2006) Functions of AMP-activated protein kinase in adipose tissue. J Physiol 574: 55–62. 41. Long YC, Zierath JR (2006) AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 116: 1776–1783. 42. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, et al. (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415: 339–343. 43. Andersson U, Treebak JT, Nielsen JN, Smith KL, Abbott CR, et al. (2005) Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity. Biochem Biophys Res Commun 329: 719–725. 44. Carling D (2004) The AMP-activated protein kinase cascade–a unifying system for energy control. Trends Biochem Sci 29: 18–24. 45. Hardie DG, Scott JW, Pan DA, Hudson ER (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546: 113–120. 46. Wallenius K, Wallenius V, Sunter D, Dickson SL, Jansson JO (2002) Intracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem Biophys Res Commun 293: 560–565. 47. Boulton TG, Stahl N, Yancopoulos GD (1994) Ciliary neurotrophic factor/ leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. J Biol Chem 269: 11648–11655. 48. Al-Khalili L, Bouzakri K, Glund S, Lonnqvist F, Koistinen HA, et al. (2006) Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle. Mol Endocrinol 20: 3364–3375. 49. Weigert C, Brodbeck K, Staiger H, Kausch C, Machicao F, et al. (2004) Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor- kappaB. J Biol Chem 279: 23942–23952. 50. Weigert C, Hennige AM, Brodbeck K, Haring HU, Schleicher ED (2005) Interleukin-6 acts as insulin sensitizer on glycogen synthesis in human skeletal muscle cells by phosphorylation of Ser473 of Akt. Am J Physiol Endocrinol Metab 289: E251–257. 51. Weigert C, Hennige AM, Lehmann R, Brodbeck K, Baumgartner F, et al. (2006) Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells. J Biol Chem 281: 7060–7067. 52. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, et al. (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55: 2688–2697. 53. Reznick RM, Zong H, Li J, Morino K, Moore IK, et al. (2007) Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 5: 151–156. 54. Stouthard JM, Romijn JA, Van der Poll T, Endert E, Klein S, et al. (1995) Endocrinologic and metabolic effects of interleukin-6 in humans. Am J Physiol 268: E813–819. 55. Rothwell NJ, Busbridge NJ, Lefeuvre RA, Hardwick AJ, Gauldie J, et al. (1991) Interleukin-6 is a centrally acting endogenous pyrogen in the rat. Can J Physiol Pharmacol 69: 1465–1469. 56. Tsigos C, Papanicolaou DA, Defensor R, Mitsiadis CS, Kyrou I, et al. (1997) Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology 66: 54–62. 57. Li G, Klein RL, Matheny M, King MA, Meyer EM, et al. (2002) Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats. Neuroscience 115: 879–889. 58. Nybo L, Nielsen B, Pedersen BK, Moller K, Secher NH (2002) Interleukin-6 release from the human brain during prolonged exercise. J Physiol 542: 991–995. 59. Febbraio MA, Pedersen BK (2002) Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. Faseb J 16: 1335–1347. 60. Pedersen BK, Hoffman-Goetz L (2000) Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev 80: 1055–1081. 61. Martin TL, Alquier T, Asakura K, Furukawa N, Preitner F, et al. (2006) Diet- induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. J Biol Chem 281: 18933–18941. 62. Scott AM, Atwater I, Rojas E (1981) A method for the simultaneous measurement of insulin release and B cell membrane potential in single mouse islets of Langerhans. Diabetologia 21: 470–475. 63. Pauli JR, Ropelle ER, Cintra DE, Carvalho-Filho MA, Moraes JC, et al. (2008) Acute physical exercise reverses S-nitrosation of the insulin receptor, insulin receptor substrate 1 and protein kinase B/Akt in diet-induced obese Wistar rats. J Physiol 586: 659–671. 64. Carvalheira JB, Siloto RM, Ignacchitti I, Brenelli SL, Carvalho CR, et al. (2001) Insulin modulates leptin-induced STAT3 activation in rat hypothalamus. FEBS Lett 500: 119–124. 65. Ropelle ER, Pauli JR, Prada PO, de Souza CT, Picardi PK, et al. (2006) Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. J Physiol 577: 997–1007. 66. Carvalheira JB, Ribeiro EB, Araujo EP, Guimaraes RB, Telles MM, et al. (2003) Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats. Diabetologia 46: 1629–1640. PLoS ONE | www.plosone.org 16 December 2008 | Volume 3 | Issue 12 | e3856