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Role of hypothalamic 5′-AMP-activated protein kinase in the regulation of food intake and energy homeostasis

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Abstract

Although obesity is an epidemic threat to general health worldwide, an effective treatment has yet to be found. Insights into weight-regulatory pathways will accelerate the identification of new molecular targets for anti-obesity agents. 5′-AMP-activated protein kinase (AMPK) is an enzyme activated during low cellular energy charge. In peripheral tissues, the activation of AMPK influences various metabolic pathways, including glucose uptake, glycolysis, and fatty acid oxidation, all of which help to re-establish a normal cellular energy balance. AMPK is also present in the neurons of the hypothalamus, a critical center in the regulation of energy homeostasis. Recent studies from our group and others have shown that many factors (α-lipoic acid, leptin, insulin, ghrelin, glucose, 2-deoxyglucose, etc.) cause an alteration in hypothalamic AMPK activity that mediates effects on feeding behavior. Hypothalamic AMPK also appears to play a role in the central regulation of energy expenditure and peripheral glucose metabolism. These data indicate that hypothalamic AMPK is an important signaling molecule that integrates nutritional and hormonal signals and modulates feeding behavior and energy metabolism.

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References

  1. Flegal KM, Carroll MD, Kuczmarski RJ, et al (1998) Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord 22:39–47

    Google Scholar 

  2. Gordon T, Kannel WB (1976) Obesity and cardiovascular diseases: the Framingham study. Clin Endocrinol Metab 5:367–375

    Google Scholar 

  3. Schwartz MW, Woods SC, Porte D Jr, et al (2000) Central nervous system control of food intake. Nature 404:661–671

    CAS  PubMed  Google Scholar 

  4. Kemp BE, Stapleton D, Campbell DJ, et al (2003) AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans 31:162–168

    CAS  Google Scholar 

  5. Hardie DG, Salt IP, Hawley SA, et al (1999) AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge. Biochem J 338:717–722

    Google Scholar 

  6. Turnley AM, Stapleton D, Mann RJ, et al (1999) Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J Neurochem 72:1707–1716

    Google Scholar 

  7. Culmsee C, Monnig J, Kemp BE, et al (2001) AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci 17:45–58

    Google Scholar 

  8. Kim MS, Park JY, Namkoong C, et al (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 10:727–733

    Google Scholar 

  9. Minokoshi Y, Alquier T, Furukawa N, et al (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574

    Google Scholar 

  10. Andersson U, Filipsson K, Abbott CR, et al (2004) AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279:12005–12008

    Google Scholar 

  11. Beg ZH, Allmann DW, Gibson DM (1973) Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cAMP and with protein fractions of rat liver cytosol. Biochem Biophys Res Commun 54:1362–1369

    Google Scholar 

  12. Carlson CA, Kim KH (1973) Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation. J Biol Chem 248:378–380

    Google Scholar 

  13. Yeh LA, Lee KH, Kim KH (1980) Regulation of rat liver acetyl-CoA carboxylase. Regulation of phosphorylation and inactivation of acetyl-CoA carboxylase by the adenylate energy charge. J Biol Chem 255:2308–2314

    Google Scholar 

  14. Hardie DG, Guy PS (1980) Reversible phosphorylation and inactivation of acetyl-CoA carboxylase from lactating rat mammary gland by cyclic AMP-dependent protein kinase. Eur J Biochem 110:167–177

    Google Scholar 

  15. Stapleton D, Woollatt E, Mitchelhill KI, et al (1997) AMP-activated protein kinase isoenzyme family: subunit structure and chromosomal location. FEBS Lett 409:452–456

    Google Scholar 

  16. da Silva Xavier G, Leclerc I, Salt IP, et al (2000) Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression. Proc Natl Acad Sci USA 97:4023–4028

    Google Scholar 

  17. Woods A, Azzout-Marniche D, Foretz M, et al (2000) Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol Cell Biol 20:6704–6711

    Google Scholar 

  18. Chen Z, Heierhorst J, Mann RJ, et al (1999) Expression of the AMP-activated protein kinase beta1 and beta2 subunits in skeletal muscle. FEBS Lett 460:343–348

    Google Scholar 

  19. Hardie DG, Salt IP, Hawley SA, et al (1999) AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge. Biochem J 338:717–722

    Google Scholar 

  20. Vavvas D, Apazidis A, Saha AK, et al (1997) Contraction-induced changes in acetyl-CoA carboxylase and 5′-AMP-activated kinase in skeletal muscle. J Biol Chem 272:13255–13261

    Google Scholar 

  21. Christopher MJ, Chen ZP, Rantzau C, et al (2003) Skeletal muscle basal AMP-activated protein kinase activity is chronically elevated in alloxan-diabetic dogs: impact of exercise. J Appl Physiol 95:1523–1530

    Google Scholar 

  22. Marsin AS, Bouzin C, Bertrand L, et al (2002) 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 277:30778–30783

    Google Scholar 

  23. Choi SL, Kim SJ, Lee KT, et al (2001) The regulation of AMP-activated protein kinase by H2O2. Biochem Biophys Res Commun 287:92–97

    Google Scholar 

  24. Hardie DG (1999) Roles of the AMP-activated/SNF1 protein kinase family in the response to cellular stress. Biochem Soc Symp 64:13–27

    Google Scholar 

  25. Patel N, Khayat ZA, Ruderman NB, et al (2001) Dissociation of 5′ AMP-activated protein kinase activation and glucose uptake stimulation by mitochondrial uncoupling and hyperosmolar stress: differential sensitivities to intracellular Ca2+ and protein kinase C inhibition. Biochem Biophys Res Commun 285:1066–1070

    Google Scholar 

  26. Zhou G, Myers R, Li Y, et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174

    Article  CAS  PubMed  Google Scholar 

  27. Mu J, Brozinick JT Jr, Valladares O, et al (2001) A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 7:1085–1094

    Google Scholar 

  28. Goodyear LJ, Kahn BB (1998) Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49:235–261

    Article  CAS  PubMed  Google Scholar 

  29. Holmes BF, Lang DB, Birnbaum MJ, et al (2004) AMP kinase is not required for the GLUT4 response to exercise and denervation in skeletal muscle. Am J Physiol Endocrinol Metab 287:E739–E743

    Google Scholar 

  30. Ruderman NB, Saha AK, Kraegen EW (2003) Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 144:5166–5171

    Article  CAS  PubMed  Google Scholar 

  31. Minokoshi Y, Kim YB, Peroni OD, et al (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343

    Article  CAS  PubMed  Google Scholar 

  32. Tomas E, Tsao TS, Saha AK, et al (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99:16309–16313

    Google Scholar 

  33. Yamauchi T, Kamon J, Minokoshi Y, et al (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295

    Article  CAS  PubMed  Google Scholar 

  34. Zong H, Ren JM, Young LH, et al (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA 99:15983–15987

    Google Scholar 

  35. Fiedler M, Zierath JR, Selen G, et al (2001) 5-aminoimidazole-4-carboxy-amide-1-beta-D-ribofuranoside treatment ameliorates hyperglycaemia and hyperinsulinaemia but not dyslipidaemia in KKAy-CETP mice. Diabetologia 44:2180–2186

    Article  CAS  PubMed  Google Scholar 

  36. Leclerc I, Lenzner C, Gourdon L, et al (2001) Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase. Diabetes 50:1515–1521

    Google Scholar 

  37. Horman S, Browne G, Krause U, et al (2002) Activation of AMP-activated protein kinase leads to the phosphorylation of elongation factor 2 and an inhibition of protein synthesis. Curr Biol 12:1419–1423

    Google Scholar 

  38. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590

    Article  CAS  PubMed  Google Scholar 

  39. Salt IP, Connell JM, Gould GW (2000) 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes. Diabetes 49:1649–1656

    Google Scholar 

  40. Sullivan JE, Brocklehurst KJ, Marley AE, et al (1994) Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett 353:33–36

    Google Scholar 

  41. Yin W, Mu J, Birnbaum MJ (2001) Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis in 3T3-L1 adipocytes. J Biol Chem 278:43074–43080

    Google Scholar 

  42. da Silva Xavier G, Leclerc I, Salt IP, et al (2000) Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression. Proc Natl Acad Sci USA 97:4023–4028

    Google Scholar 

  43. da Silva Xavier G, Leclerc I, Varadi A, et al (2003) Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J 371:761–774

    Article  PubMed  Google Scholar 

  44. Kefas BA, Heimberg H, Vaulont S, et al (2003) AICA-riboside induces apoptosis of pancreatic beta cells through stimulation of AMP-activated protein kinase. Diabetologia 46:250–254

    Google Scholar 

  45. Unger RH, Zhou YT (2001) Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50[Suppl 1]:S118–S121

    Google Scholar 

  46. Diraison F, Parton L, Ferre P, et al (2004) Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Biochem J 378:769–778

    Article  CAS  PubMed  Google Scholar 

  47. Davis JD, Wirtshafter D, Asin KE, et al (1981) Sustained intracerebroventricular infusion of brain fuels reduces body weight and food intake in rats. Science 212:81–83

    Google Scholar 

  48. Obici S, Feng Z, Morgan K, et al (2002) Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51:271–275

    CAS  PubMed  Google Scholar 

  49. Thompson DA, Campbell RG (1977) Hunger in humans induced by 2-deoxy-D-glucose: glucoprivic control of taste preference and food intake. Science 198:1065–1068

    Google Scholar 

  50. Sergeyev V, Broberger C, Gorbatyuk O, et al (2000) Effect of 2-mercaptoacetate and 2-deoxy-D-glucose administration on the expression of NPY, AGRP, POMC, MCH and hypocretin/orexin in the rat hypothalamus. Neuroreport 11:117–121

    Google Scholar 

  51. Loftus TM, Jaworsky DE, Frehywot GL, et al (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288:2379–2381

    Article  CAS  PubMed  Google Scholar 

  52. Obici S, Feng Z, Arduini A, Conti R, et al (2003) Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9:756–761

    Google Scholar 

  53. Levin BE (2001) Glucosensing neurons do more than just sense glucose. Int J Obes Relat Metab Disord 25[Suppl 5]:S68–S72

    Google Scholar 

  54. Miki T, Liss B, Minami K, et al (2001) ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4:507–512

    Google Scholar 

  55. Spanswick D, Smith MA, Groppi VE, et al (1997) Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390:521–525

    Google Scholar 

  56. Spanswick D, Smith MA, Mirshamsi S, et al (2000) Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 3:757–758

    Google Scholar 

  57. Kim EK, Miller I, Aja S, et al (2004) C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 279:19970–19976

    Google Scholar 

  58. Landree LE, Hanlon AL, Strong DW, et al (2004) C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism. J Biol Chem 279:3817–3827

    Google Scholar 

  59. Namkoong C, Kim MS, Jang PG, et al (2005) Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes 54:63–68

    Google Scholar 

  60. Lee K, Li B, Xi X, Suh Y, et al (2005) Role of neuronal energy status in the regulation of adenosine 5′-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior. Endocrinology 146:3–10

    Google Scholar 

  61. Light PE, Wallace CH, Dyck JR (2003) Constitutively active adenosine monophosphate-activated protein kinase regulates voltage-gated sodium channels in ventricular myocytes. Circulation 107:1962–1965

    Google Scholar 

  62. Hallows KR, Raghuram V, Kemp BE, et al (2000) Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase. J Clin Invest 105:1711–1721

    Google Scholar 

  63. Minokoshi Y, Kim YB, Peroni OD, et al (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343

    Article  CAS  PubMed  Google Scholar 

  64. Viollet B, Andreelli F, Jorgensen SB, et al (2003) The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J Clin Invest 111:91–98

    Google Scholar 

  65. Penicaud L, Leloup C, Lorsignol A, et al (2002) Brain glucose sensing mechanism and glucose homeostasis. Curr Opin Clin Nutr Metab Care 5:539–543

    Google Scholar 

  66. Minokoshi Y, Haque MS, Shimazu T (1999) Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes 48:287–291

    Google Scholar 

  67. Obici S, Zhang BB, Karkanias G, et al (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382

    Google Scholar 

  68. Obici S, Feng Z, Tan J, et al (2001) Central melanocortin receptors regulate insulin action. J Clin Invest 108:1079–1085

    Google Scholar 

  69. Perrin C, Knauf C, Burcelin R (2004) Intracerebroventricular infusion of glucose, insulin, and the adenosine monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, controls muscle glycogen synthesis. Endocrinology 145:4025–4033

    Google Scholar 

  70. McCrimmon RJ, Fan X, Ding Y, et al (2004) Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes 53:1953–1958

    Google Scholar 

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Acknowledgements

This work was supported by grants from the Korean Ministry of Science and Technology (M1040000000804J000000810), Korean Ministry of Health and Welfare (03-PJ1-PG1-CH05-0005), and the Asan Institute of Life Sciences (04-326).

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  1. Department of Internal Medicine, University of Ulsan College of Medicine, Poongnap-dong, Songpa-gu, Seoul, 138-736, South Korea

    Min Seon Kim & Ki Up Lee

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  1. Min Seon Kim
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  2. Ki Up Lee
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Correspondence to Ki Up Lee.

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Kim, M.S., Lee, K.U. Role of hypothalamic 5′-AMP-activated protein kinase in the regulation of food intake and energy homeostasis. J Mol Med 83, 514–520 (2005). https://doi.org/10.1007/s00109-005-0659-z

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