Reviews in Endocrine and Metabolic Disorders

, Volume 12, Issue 3, pp 127–140 | Cite as

Hypothalamic AMP-activated protein kinase as a mediator of whole body energy balance

  • Pablo Blanco Martínez de Morentin
  • Carmen R. González
  • Asisk K. Saha
  • Luís Martins
  • Carlos Diéguez
  • Antonio Vidal-Puig
  • Manuel Tena-Sempere
  • Miguel López
Article

Abstract

The AMP-activated protein kinase (AMPK) is the downstream constituent of a kinase cascade that acts as a sensor of cellular energy levels. Current data unequivocally indicate that hypothalamic AMPK plays a key role in the control of the whole body energy balance, by integrating peripheral signals, such as hormones and metabolites, with central signals, such as neuropeptides, and eliciting allostatic changes in energy homeostasis. Although the molecular details of these interactions are not fully understood, recent evidence has suggested that the interaction between AMPK with hypothalamic lipid metabolism and other metabolic sensors, such as the uncoupling protein 2 (UCP-2), the mammalian target of rapamycin (mTOR) and the deacetylase sirtuin 1 (SIRT1), may play a main role in the hypothalamic control of feeding and energy expenditure. Here, we summarize the role of hypothalamic AMPK as whole body energy gauge. Understanding this key molecule and especially its functions at central level may provide new therapeutic targets for the treatment of metabolic alterations and obesity.

Keywords

AMPK Hypothalamus Metabolism Obesity 

Notes

Acknowledgements

The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreements n° 245009 (CD and ML) and nº 018734 (AVP), Xunta de Galicia (ML: 10PXIB208164PR), Fondo Investigaciones Sanitarias (ML: PS09/01880), Ministerio de Educacion y Ciencia (CD: BFU2008; ML: RyC-2007-00211), Medical Research Council (AVP), Wellcome Trust (AVP) and United States Public Health Service (AKS: DK-19514 and DK-67509). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII.

References

  1. 1.
    Friedman JM. A war on obesity, not the obese. Science. 2003;299:856–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004;116:337–50.PubMedCrossRefGoogle Scholar
  3. 3.
    Farooqi IS, O’Rahilly S. Monogenic obesity in humans. Annu Rev Med. 2005;56:443–58.PubMedCrossRefGoogle Scholar
  4. 4.
    Medina-Gomez G, Vidal-Puig A. Gateway to the metabolic syndrome. Nat Med. 2005;11:602–3.PubMedCrossRefGoogle Scholar
  5. 5.
    Ruderman NB, Saha AK, Kraegen EW. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology. 2003;144:5166–71.PubMedCrossRefGoogle Scholar
  6. 6.
    Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Carling D, Sanders MJ, Woods A. The regulation of AMP-activated protein kinase by upstream kinases. Int J Obes (Lond). 2008;32 Suppl 4:S55–9.CrossRefGoogle Scholar
  8. 8.
    Lage R, Diéguez C, Vidal-Puig A, López M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med. 2008;14:539–49.PubMedCrossRefGoogle Scholar
  9. 9.
    Carling D. The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem Sci. 2004;29:18–24.PubMedCrossRefGoogle Scholar
  10. 10.
    Kola B, Boscaro M, Rutter GA, Grossman AB, Korbonits M. Expanding role of AMPK in endocrinology. Trends Endocrinol Metab. 2006;17:205–15.PubMedCrossRefGoogle Scholar
  11. 11.
    Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8:774–85.PubMedCrossRefGoogle Scholar
  12. 12.
    Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, et al. Ca(2+)/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005;2:21–33.PubMedCrossRefGoogle Scholar
  13. 13.
    Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, et al. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005;2:9–19.PubMedCrossRefGoogle Scholar
  14. 14.
    Xie M, Zhang D, Dyck JR, Li Y, Zhang H, Morishima M, et al. A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc Natl Acad Sci U S A. 2006;103:17378–83.PubMedCrossRefGoogle Scholar
  15. 15.
    Costanzo-Garvey DL, Pfluger PT, Dougherty MK, Stock JL, Boehm M, Chaika O, et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab. 2009;10:366–78.PubMedCrossRefGoogle Scholar
  16. 16.
    Steinberg GR, Michell BJ, van Denderen BJ, Watt MJ, Carey AL, Fam BC, et al. Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab. 2006;4:465–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13:2004–8.PubMedCrossRefGoogle Scholar
  18. 18.
    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;281:32207–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J. 2007;403:139–48.PubMedCrossRefGoogle Scholar
  20. 20.
    Qi J, Gong J, Zhao T, Zhao J, Lam P, Ye J, et al. Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue. EMBO J. 2008;27:1537–48.PubMedCrossRefGoogle Scholar
  21. 21.
    Dowell P, Hu Z, Lane MD. Monitoring energy balance: metabolites of fatty acid synthesis as hypothalamic sensors. Annu Rev Biochem. 2005;74:515–34.PubMedCrossRefGoogle Scholar
  22. 22.
    López M, Lelliott CJ, Vidal-Puig A. Hypothalamic fatty acid metabolism: a housekeeping pathway that regulates food intake. Bioessays. 2007;29:248–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74.PubMedGoogle Scholar
  24. 24.
    López M, Lage R, Saha AK, Pérez-Tilve D, Vázquez MJ, Varela L, et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 2008;7:389–99.PubMedCrossRefGoogle Scholar
  25. 25.
    Saha AK, Schwarsin AJ, Roduit R, Masse F, Kaushik V, Tornheim K, et al. Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-beta -D-ribofuranoside. J Biol Chem. 2000;275:24279–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Park H, Kaushik VK, Constant S, Prentki M, Przybytkowski E, Ruderman NB, et al. Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J Biol Chem. 2002;277:32571–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Bungard D, Fuerth BJ, Zeng PY, Faubert B, Maas NL, Viollet B, et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science. 2010;329:1201–5.PubMedCrossRefGoogle Scholar
  28. 28.
    López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 2010;16:1001–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol. 2005;493:63–71.PubMedCrossRefGoogle Scholar
  30. 30.
    Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006;443:289–95.PubMedCrossRefGoogle Scholar
  31. 31.
    Gao Q, Horvath TL. Neurobiology of feeding and energy expenditure. Annu Rev Neurosci. 2007;30:367–98.PubMedCrossRefGoogle Scholar
  32. 32.
    López M, Tovar S, Vázquez MJ, Williams LM, Diéguez C. Peripheral tissue-brain interactions in the regulation of food intake. Proc Nutr Soc. 2007;66:131–55.PubMedCrossRefGoogle Scholar
  33. 33.
    López M, Tena-Sempere M, Diéguez C. Cross-talk between orexins (hypocretins) and the neuroendocrine axes (hypothalamic-pituitary axes). Front Neuroendocrinol. 2009;31:113–27.PubMedCrossRefGoogle Scholar
  34. 34.
    Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428:569–74.PubMedCrossRefGoogle Scholar
  35. 35.
    McCrimmon RJ, Fan X, Cheng H, McNay E, Chan O, Shaw M, et al. Activation of amp-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes. 2006;55:1755–60.PubMedCrossRefGoogle Scholar
  36. 36.
    López M, Lelliott CJ, Tovar S, Kimber W, Gallego R, Virtue S, et al. Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes. 2006;55:1327–36.PubMedCrossRefGoogle Scholar
  37. 37.
    Lage R, Vázquez MJ, Varela L, Saha AK, Vidal-Puig A, Nogueiras R, et al. Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J. 2010;24:2670–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, et al. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004;279:12005–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Namkoong C, Kim MS, Jang PG, Han SM, Park HS, Koh EH, et al. Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes. 2005;54:63–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Steinberg GR, Watt MJ, Fam BC, Proietto J, Andrikopoulos S, Allen AM, et al. Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase signaling in leptin-resistant obese mice. Endocrinology. 2006;147:3906–14.PubMedCrossRefGoogle Scholar
  41. 41.
    Wolfgang MJ, Cha SH, Sidhaye A, Chohnan S, Cline G, Shulman GI, et al. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc Natl Acad Sci U S A. 2007;104:19285–90.PubMedCrossRefGoogle Scholar
  42. 42.
    Gao S, Kinzig KP, Aja S, Scott KA, Keung W, Kelly S, et al. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc Natl Acad Sci U S A. 2007;104:17358–63.PubMedCrossRefGoogle Scholar
  43. 43.
    Seo S, Ju S, Chung H, Lee D, Park S. Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. Endocr J. 2008;55:867–74.PubMedCrossRefGoogle Scholar
  44. 44.
    Tsai YC, Lee YM, Lam KK, Wu YC, Yen MH, Cheng PY. The role of hypothalamic AMP-activated protein kinase in ovariectomy-induced obesity in rats. Menopause. 2010;17:1194–200.PubMedCrossRefGoogle Scholar
  45. 45.
    Vázquez MJ, González CR, Varela L, Lage R, Tovar S, Sangiao-Alvarellos S, et al. Central resistin regulates hypothalamic and peripheral lipid metabolism in a nutritional-dependent fashion. Endocrinology. 2008;149:4534–43.PubMedCrossRefGoogle Scholar
  46. 46.
    Brown RE, Wilkinson PM, Imran SA, Wilkinson M. Resistin differentially modulates neuropeptide gene expression and AMP-activated protein kinase activity in N-1 hypothalamic neurons. Brain Res. 2009;1294:52–60.PubMedCrossRefGoogle Scholar
  47. 47.
    Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, et al. The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007;408:297–315.PubMedCrossRefGoogle Scholar
  48. 48.
    Emerling BM, Weinberg F, Snyder C, Burgess Z, Mutlu GM, Viollet B, et al. Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free Radic Biol Med. 2009;46:1386–91.PubMedCrossRefGoogle Scholar
  49. 49.
    Mandard S, Zandbergen F, van Straten E, Wahli W, Kuipers F, Muller M, et al. The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J Biol Chem. 2006;281:934–44.PubMedCrossRefGoogle Scholar
  50. 50.
    Kim HK, Youn BS, Shin MS, Namkoong C, Park KH, Baik JH, et al. Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight. Diabetes. 2010;59:2772–80.PubMedCrossRefGoogle Scholar
  51. 51.
    Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005;280:25196–201.PubMedCrossRefGoogle Scholar
  52. 52.
    Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 2007;6:55–68.PubMedCrossRefGoogle Scholar
  53. 53.
    Shimizu H, Arima H, Watanabe M, Goto M, Banno R, Sato I, et al. Glucocorticoids increase neuropeptide y and agouti-related peptide gene expression via amp-activated protein kinase signaling in the arcuate nucleus of rats. Endocrinology. 2008;149:4544–53.PubMedCrossRefGoogle Scholar
  54. 54.
    López M, Saha AK, Diéguez C, Vidal-Puig A. The AMPK-malonyl-CoA-CPT1 axis in the control of hypothalamic neuronal function-Reply. Cell Metab. 2008;8:176.CrossRefGoogle Scholar
  55. 55.
    Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature. 2008;454:846–51.PubMedCrossRefGoogle Scholar
  56. 56.
    Guillod-Maximin E, Roy AF, Vacher CM, Aubourg A, Bailleux V, Lorsignol A, et al. Adiponectin receptors are expressed in hypothalamus and colocalized with proopiomelanocortin and neuropeptide Y in rodent arcuate neurons. J Endocrinol. 2009;200:93–105.PubMedCrossRefGoogle Scholar
  57. 57.
    Wen JP, Liu CE, Hu YT, Chen G, Lin LX. Globular adiponectin regulates energy homeostasis through AMP-activated protein kinase-acetyl-CoA carboxylase (AMPK/ACC) pathway in the hypothalamus. Mol Cell Biochem. 2010;344:109–15.PubMedCrossRefGoogle Scholar
  58. 58.
    McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ, Sherwin RS. Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes. 2004;53:1953–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Han SM, Namkoong C, Jang PG, Park IS, Hong SW, Katakami H, et al. Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats. Diabetologia. 2005;48:2170–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Yang CS, Lam CK, Chari M, Cheung GW, Kokorovic A, Gao S, et al. Hypothalamic AMP-activated protein kinase regulates glucose production. Diabetes. 2010;59:2435–43.PubMedCrossRefGoogle Scholar
  61. 61.
    Lam CK, Chari M, Rutter GA, Lam TK: Hypothalamic nutrient sensing activates a forebrain-hindbrain neuronal circuit to regulate glucose production in vivo. Diabetes. 2011;60:107–13Google Scholar
  62. 62.
    Cha SH, Wolfgang M, Tokutake Y, Chohnan S, Lane MD. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake. Proc Natl Acad Sci U S A. 2008;105:16871–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Cha SH, Lane MD. Central lactate metabolism suppresses food intake via the hypothalamic AMP kinase/malonyl-CoA signaling pathway. Biochem Biophys Res Commun. 2009;386:212–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Lane MD, Cha SH. Effect of glucose and fructose on food intake via malonyl-CoA signaling in the brain. Biochem Biophys Res Commun. 2009;382:1–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004;10:727–33.PubMedCrossRefGoogle Scholar
  66. 66.
    Ropelle ER, Fernandes MF, Flores MB, Ueno M, Rocco S, Marin R, et al. Central exercise action increases the AMPK and mTOR response to leptin. PLoS ONE. 2008;3:e3856.PubMedCrossRefGoogle Scholar
  67. 67.
    Stoppa GR, Cesquini M, Roman EA, Prada PO, Torsoni AS, Romanatto T, et al. Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling. J Endocrinol. 2008;198:157–68.PubMedCrossRefGoogle Scholar
  68. 68.
    Cesquini M, Stoppa GR, Prada PO, Torsoni AS, Romanatto T, Souza A, et al. Citrate diminishes hypothalamic acetyl-CoA carboxylase phosphorylation and modulates satiety signals and hepatic mechanisms involved in glucose homeostasis in rats. Life Sci. 2008;82:1262–71.PubMedCrossRefGoogle Scholar
  69. 69.
    Ropelle ER, Pauli JR, Fernandes MF, Rocco SA, Marin RM, Morari J, et al. A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high-protein diet-induced weight loss. Diabetes. 2008;57:594–605.PubMedCrossRefGoogle Scholar
  70. 70.
    Kim EK, Miller I, Aja S, Landree LE, Pinn M, McFadden J, et al. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem. 2004;279:19970–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Lee K, Li B, Xi X, Suh Y, Martin RJ. Role of neuronal energy status in the regulation of adenosine 5'-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior. Endocrinology. 2005;146:3–10.PubMedCrossRefGoogle Scholar
  72. 72.
    Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LG, et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest. 2007;117:2325–36.PubMedCrossRefGoogle Scholar
  73. 73.
    Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M, Landgraf R, et al. Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest. 2001;24:RC19–21.PubMedGoogle Scholar
  74. 74.
    Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86:5992.PubMedCrossRefGoogle Scholar
  75. 75.
    Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50:1714–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Drazen DL, Vahl TP, D'Alessio DA, Seeley RJ, Woods SC. Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. Endocrinology. 2006;147:23–30.PubMedCrossRefGoogle Scholar
  77. 77.
    Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes. 2001;50:2438–43.PubMedCrossRefGoogle Scholar
  79. 79.
    Seoane LM, López M, Tovar S, Casanueva F, Señarís R, Diéguez C. Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology. 2003;144:544–51.PubMedCrossRefGoogle Scholar
  80. 80.
    Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407:908–13.PubMedCrossRefGoogle Scholar
  81. 81.
    Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest. 2006;116:1983–93.PubMedCrossRefGoogle Scholar
  82. 82.
    Sangiao-Alvarellos S, Vázquez MJ, Varela L, Nogueiras R, Saha AK, Cordido F, et al. Central ghrelin regulates peripheral lipid metabolism in a growth hormone-independent fashion. Endocrinology. 2009;150:4562–74.PubMedCrossRefGoogle Scholar
  83. 83.
    Sangiao-Alvarellos S, Varela L, Vázquez MJ, Boit KD, Saha AK, Cordido F, et al. Influence of ghrelin and GH deficiency on AMPK and hypothalamic lipid metabolism. J Neuroendocrinol. 2010;22:543–56.PubMedCrossRefGoogle Scholar
  84. 84.
    Andrews ZB, Erion DM, Beiler R, Choi CS, Shulman GI, Horvath TL. Uncoupling protein-2 decreases the lipogenic actions of ghrelin. Endocrinology. 2010;151:2078–86.PubMedCrossRefGoogle Scholar
  85. 85.
    Wortley KE, Del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, et al. Absence of ghrelin protects against early-onset obesity. J Clin Invest. 2005;115:3573–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest. 2005;115:3564–72.PubMedCrossRefGoogle Scholar
  87. 87.
    Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–60.PubMedCrossRefGoogle Scholar
  88. 88.
    Nogueiras R, Tovar S, Mitchell SE, Rayner DV, Archer ZA, Dieguez C, et al. Regulation of growth hormone secretagogue receptor gene expression in the arcuate nuclei of the rat by leptin and ghrelin. Diabetes. 2004;53:2552–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Kola B, Farkas I, Christ-Crain M, Wittmann G, Lolli F, Amin F, et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS ONE. 2008;3:e1797.PubMedCrossRefGoogle Scholar
  90. 90.
    Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun. 2000;276:905–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab. 2000;85:4908–11.PubMedCrossRefGoogle Scholar
  92. 92.
    Peino R, Baldelli R, Rodriguez-Garcia J, Rodriguez-Segade S, Kojima M, Kangawa K, et al. Ghrelin-induced growth hormone secretion in humans. Eur J Endocrinol. 2000;143:R11–4.PubMedCrossRefGoogle Scholar
  93. 93.
    Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology. 2000;141:4325–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal L, Cohen MA, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes. 2001;50:2540–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Egecioglu E, Bjursell M, Ljungberg A, Dickson SL, Kopchick JJ, Bergstrom G, et al. Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice. Am J Physiol Endocrinol Metab. 2006;290:E317–25.PubMedCrossRefGoogle Scholar
  96. 96.
    Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 2008;7:377–88.PubMedCrossRefGoogle Scholar
  97. 97.
    Martin TL, Alquier T, Asakura K, Furukawa N, Preitner F, Kahn BB. Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. J Biol Chem. 2006;281:18933–41.PubMedCrossRefGoogle Scholar
  98. 98.
    Xue B, Pulinilkunnil T, Murano I, Bence KK, He H, Minokoshi Y, et al. Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. Mol Cell Biol. 2009;29:4563–73.PubMedCrossRefGoogle Scholar
  99. 99.
    Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest. 2006;116:1776–83.PubMedCrossRefGoogle Scholar
  100. 100.
    Viollet B, Andreelli F, Jorgensen SB, Perrin C, Geloen A, Flamez D, et al. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J Clin Invest. 2003;111:91–8.PubMedGoogle Scholar
  101. 101.
    Dzamko N, van Denderen BJ, Hevener AL, Jorgensen SB, Honeyman J, Galic S, et al. AMPK beta1 deletion reduces appetite, preventing obesity and hepatic insulin resistance. J Biol Chem. 2010;285:115–22.PubMedCrossRefGoogle Scholar
  102. 102.
    McCrimmon RJ, Shaw M, Fan X, Cheng H, Ding Y, Vella MC, et al. Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes. 2008;57:444–50.PubMedCrossRefGoogle Scholar
  103. 103.
    Fan X, Ding Y, Brown S, Zhou L, Shaw M, Vella MC, et al. Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes. Am J Physiol Regul Integr Comp Physiol. 2009;296:R1702–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415:339–43.PubMedCrossRefGoogle Scholar
  105. 105.
    Tanaka T, Masuzaki H, Yasue S, Ebihara K, Shiuchi T, Ishii T, et al. Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet. Cell Metab. 2007;5:395–402.PubMedCrossRefGoogle Scholar
  106. 106.
    Barazzoni R, Bosutti A, Stebel M, Cattin MR, Roder E, Visintin L, et al. Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am J Physiol Endocrinol Metab. 2005;288:E228–35.PubMedCrossRefGoogle Scholar
  107. 107.
    Muse ED, Obici S, Bhanot S, Monia BP, McKay RA, Rajala MW, et al. Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest. 2004;114:232–9.PubMedGoogle Scholar
  108. 108.
    Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity. Nature. 2009;458:1056–60.PubMedCrossRefGoogle Scholar
  109. 109.
    Ramadori G, Lee CE, Bookout AL, Lee S, Williams KW, Anderson J, et al. Brain SIRT1: anatomical distribution and regulation by energy availability. J Neurosci. 2008;28:9989–96.PubMedCrossRefGoogle Scholar
  110. 110.
    Cakir I, Perello M, Lansari O, Messier NJ, Vaslet CA, Nillni EA. Hypothalamic Sirt1 regulates food intake in a rodent model system. PLoS ONE. 2009;4:e8322.PubMedCrossRefGoogle Scholar
  111. 111.
    Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312:927–30.PubMedCrossRefGoogle Scholar
  112. 112.
    Cota D, Matter EK, Woods SC, Seeley RJ. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. J Neurosci. 2008;28:7202–8.PubMedCrossRefGoogle Scholar
  113. 113.
    Proulx K, Cota D, Woods SC, Seeley RJ. Fatty acid synthase inhibitors modulate energy balance via mammalian target of rapamycin complex 1 signaling in the central nervous system. Diabetes. 2008;57:3231–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Woods SC, Seeley RJ, Cota D. Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr. 2008;28:295–311.PubMedCrossRefGoogle Scholar
  115. 115.
    Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293:E444–52.PubMedCrossRefGoogle Scholar
  116. 116.
    Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360:1500–8.PubMedCrossRefGoogle Scholar
  117. 117.
    Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509–17.PubMedCrossRefGoogle Scholar
  118. 118.
    Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360:1518–25.PubMedCrossRefGoogle Scholar
  119. 119.
    Skarulis MC, Celi FS, Mueller E, Zemskova M, Malek R, Hugendubler L, et al. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab. 2010;95:256–62.PubMedCrossRefGoogle Scholar
  120. 120.
    Fryer LG, 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;277:25226–32.PubMedCrossRefGoogle Scholar
  121. 121.
    Ouyang J, Parakhia RA, Ochs RS: Metformin activates AMP-kinase through inhibition of AMP deaminase. J Biol Chem, doi: 10.1074/jbc.M110.121806, 2010
  122. 122.
    Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120:2355–69.PubMedCrossRefGoogle Scholar
  123. 123.
    Landree LE, Hanlon AL, Strong DW, Rumbaugh G, Miller IM, Thupari JN, et al. C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism. J Biol Chem. 2004;279:3817–27.PubMedCrossRefGoogle Scholar
  124. 124.
    Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 2006;3:403–16.PubMedCrossRefGoogle Scholar
  125. 125.
    Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, Carling D. Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J Biol Chem. 2007;282:32539–48.PubMedCrossRefGoogle Scholar
  126. 126.
    Goldberg JL. How does an axon grow? Genes Dev. 2003;17:941–58.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Pablo Blanco Martínez de Morentin
    • 1
    • 2
  • Carmen R. González
    • 1
    • 2
  • Asisk K. Saha
    • 3
  • Luís Martins
    • 1
    • 2
  • Carlos Diéguez
    • 1
    • 2
  • Antonio Vidal-Puig
    • 4
  • Manuel Tena-Sempere
    • 2
    • 5
  • Miguel López
    • 1
    • 2
  1. 1.Department of Physiology, School of MedicineUniversity of Santiago de Compostela—Instituto de Investigación SanitariaSantiago de CompostelaSpain
  2. 2.CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de CompostelaSpain
  3. 3.Diabetes Research Unit, EBRC-827Boston Medical CenterBostonUSA
  4. 4.Institute of Metabolic Science, Metabolic Research Laboratories, Addenbrooke’s HospitalUniversity of CambridgeCambridgeUK
  5. 5.Department of Cell Biology, Physiology and ImmunologyUniversity of CórdobaCórdobaSpain

Personalised recommendations