Skip to main content

Advertisement

Log in

Hypothalamic control of energy and glucose metabolism

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

The central nervous system (CNS), generally accepted to regulate energy homeostasis, has been implicated in the metabolic perturbations that either cause or are associated with obesity. Normally, the CNS receives hormonal, metabolic, and neuronal input to assure adequate energy levels and maintain stable energy homeostasis. Recent evidence also supports that the CNS uses these same inputs to regulate glucose homeostasis and this aspect of CNS regulation also becomes impaired in the face of dietary-induced obesity. This review focuses on the literature surrounding hypothalamic regulation of energy and glucose homeostasis and discusses how dysregulation of this system may contribute to obesity and T2DM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Sandoval D, Cota D, Seeley RJ. The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol. 2008;70:513–35. doi:10.1146/annurev.physiol.70.120806.095256.

    Article  PubMed  CAS  Google Scholar 

  2. Langhans W, Geary N. Overview of the physiological control of eating. Forum Nutr. 2010;63:9–53.

    Article  PubMed  CAS  Google Scholar 

  3. Yanovski JA, Yanovski SZ, Sovik KN, Nguyen TT, O'Neil PM, Sebring NG. A prospective study of holiday weight gain. N Engl J Med. 2000;342(12):861–7. doi:10.1056/NEJM200003233421206.

    Article  PubMed  CAS  Google Scholar 

  4. Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988;81(2):442–8. doi:10.1172/JCI113339.

    Article  PubMed  CAS  Google Scholar 

  5. Schwartz MW, Sipols A, Kahn SE, Lattemann DF, Taborsky Jr GJ, Bergman RN, et al. Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am J Physiol. 1990;259(3 Pt 1):E378–83.

    PubMed  CAS  Google Scholar 

  6. Baskin DG, Woods SC, West DB, van Houten M, Posner BI, Dorsa DM, et al. Immunocytochemical detection of insulin in rat hypothalamus and its possible uptake from cerebrospinal fluid. Endocrinology. 1983;113(5):1818–25.

    Article  PubMed  CAS  Google Scholar 

  7. Baskin DG, Schwartz MW, Sipols AJ, D'Alessio DA, Goldstein BJ, White MF. Insulin receptor substrate-1 (IRS-1) expression in rat brain. Endocrinology. 1994;134(4):1952–5.

    Article  PubMed  CAS  Google Scholar 

  8. Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci. 2002;5(6):566–72. doi:10.1038/nn861.

    Article  PubMed  CAS  Google Scholar 

  9. Chavez M, Kaiyala K, Madden LJ, Schwartz MW, Woods SC. Intraventricular insulin and the level of maintained body weight in rats. Behav Neurosci. 1995;109(3):528–31.

    Article  PubMed  CAS  Google Scholar 

  10. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122–5.

    Article  PubMed  CAS  Google Scholar 

  11. Air EL, Benoit SC, Blake Smith KA, Clegg DJ, Woods SC. Acute third ventricular administration of insulin decreases food intake in two paradigms. Pharmacol Biochem Behav. 2002;72(1–2):423–9.

    Article  PubMed  CAS  Google Scholar 

  12. Woods SC, Lotter EC, McKay LD, Porte Jr D. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 1979;282(5738):503–5.

    Article  PubMed  CAS  Google Scholar 

  13. Figlewicz DP, Sipols AJ, Seeley RJ, Chavez M, Woods SC, Porte Jr D. Intraventricular insulin enhances the meal-suppressive efficacy of intraventricular cholecystokinin octapeptide in the baboon. Behav Neurosci. 1995;109(3):567–9.

    Article  PubMed  CAS  Google Scholar 

  14. Clegg DJ, Riedy CA, Smith KA, Benoit SC, Woods SC. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes. 2003;52(3):682–7.

    Article  PubMed  CAS  Google Scholar 

  15. Clegg DJ, Brown LM, Woods SC, Benoit SC. Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes. 2006;55(4):978–87.

    Article  PubMed  CAS  Google Scholar 

  16. Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers Jr MG, et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes. 2003;52(2):227–31.

    Article  PubMed  CAS  Google Scholar 

  17. Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Munzberg H, et al. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest. 2006;116(7):1886–901. doi:10.1172/JCI27123.

    Article  PubMed  CAS  Google Scholar 

  18. Schwartz MW, Sipols AJ, Marks JL, Sanacora G, White JD, Scheurink A, et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology. 1992;130(6):3608–16.

    Article  PubMed  CAS  Google Scholar 

  19. Clegg DJ, Gotoh K, Kemp C, Wortman MD, Benoit SC, Brown LM et al. Consumption of a high-fat diet induces central insulin resistance independent of adiposity. Physiol Behav. 2011.

  20. Clegg DJ, Benoit SC, Reed JA, Woods SC, Dunn-Meynell A, Levin BE. Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet. Am J Physiol Regul Integr Comp Physiol. 2005;288(4):R981–6.

    Article  PubMed  CAS  Google Scholar 

  21. Schwartz MW, Marks JL, Sipols AJ, Baskin DG, Woods SC, Kahn SE, et al. Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats. Endocrinology. 1991;128(5):2645–7.

    Article  PubMed  CAS  Google Scholar 

  22. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334(5):292–5.

    Article  PubMed  CAS  Google Scholar 

  23. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest. 1996;98(5):1101–6. doi:10.1172/JCI118891.

    Article  PubMed  CAS  Google Scholar 

  24. Cox JE, Powley TL. Development of obesity in diabetic mice pair-fed with lean siblings. J Comp Physiol Psychol. 1977;91(2):347–58.

    Article  PubMed  CAS  Google Scholar 

  25. Chan TM, Young KM, Hutson NJ, Brumley FT, Exton JH. Hepatic metabolism of genetically diabetic (db/db) mice. I. Carbohydrate metabolism. Am J Physiol. 1975;229(6):1702–12.

    PubMed  CAS  Google Scholar 

  26. Mayer J. Genetic factors in obesity. Bull N Y Acad Med. 1960;36(5):323–43.

    PubMed  CAS  Google Scholar 

  27. Morton GJ, Niswender KD, Rhodes CJ, Myers Jr MG, Blevins JE, Baskin DG, et al. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats. Endocrinology. 2003;144(5):2016–24.

    Article  PubMed  CAS  Google Scholar 

  28. Seeley RJ, van Dijk G, Campfield LA, Smith FJ, Burn P, Nelligan JA, et al. Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. Horm Metab Res. 1996;28(12):664–8. doi:10.1055/s-2007-979874.

    Article  PubMed  CAS  Google Scholar 

  29. al-Barazanji KA, Buckingham RE, Arch JR, Haynes A, Mossakowska DE, McBay DL, et al. Effects of intracerebroventricular infusion of leptin in obese Zucker rats. Obes Res. 1997;5(5):387–94.

    PubMed  CAS  Google Scholar 

  30. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661–71. doi:10.1038/35007534.

    PubMed  CAS  Google Scholar 

  31. Buettner C, Pocai A, Muse ED, Etgen AM, Myers Jr MG, Rossetti L. Critical role of STAT3 in leptin's metabolic actions. Cell Metab. 2006;4(1):49–60.

    Article  PubMed  CAS  Google Scholar 

  32. Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI, et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc Natl Acad Sci USA. 2004;101(13):4661–6. doi:10.1073/pnas.0303992101.

    Article  PubMed  CAS  Google Scholar 

  33. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers Jr MG, Schwartz MW. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature. 2001;413(6858):794–5. doi:10.1038/35101657.

    Article  PubMed  CAS  Google Scholar 

  34. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab. 2005;2(6):411–20.

    Article  PubMed  CAS  Google Scholar 

  35. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312(5775):927–30.

    Article  PubMed  CAS  Google Scholar 

  36. Cusin I, Zakrzewska KE, Boss O, Muzzin P, Giacobino JP, Ricquier D, et al. Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins. Diabetes. 1998;47(7):1014–9.

    Article  PubMed  CAS  Google Scholar 

  37. Widdowson PS, Upton R, Buckingham R, Arch J, Williams G. Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity. Diabetes. 1997;46(11):1782–5.

    Article  PubMed  CAS  Google Scholar 

  38. 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(28):7202–8.

    Article  PubMed  CAS  Google Scholar 

  39. Metlakunta AS, Sahu M, Sahu A. Hypothalamic phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice. Endocrinology. 2008;149(3):1121–8.

    Article  PubMed  CAS  Google Scholar 

  40. Munzberg H, Flier JS, Bjorbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology. 2004;145(11):4880–9. doi:10.1210/en.2004-0726.

    Article  PubMed  CAS  Google Scholar 

  41. Oomura Y, Ono T, Ooyama H, Wayner MJ. Glucose and osmosensitive neurones of the rat hypothalamus. Nature. 1969;222(5190):282–4.

    Article  PubMed  CAS  Google Scholar 

  42. Anand BK, Chhina GS, Sharma KN, Dua S, Singh B. Activity of single neurons in the hypothalamic feeding centers: effect of glucose. Am J Physiol. 1964;207:1146–54.

    PubMed  CAS  Google Scholar 

  43. Burdakov D, Luckman SM, Verkhratsky A. Glucose-sensing neurons of the hypothalamus. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2227–35.

    Article  PubMed  CAS  Google Scholar 

  44. Ibrahim N, Bosch MA, Smart JL, Qiu J, Rubinstein M, Ronnekleiv OK, et al. Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology. 2003;144(4):1331–40.

    Article  PubMed  CAS  Google Scholar 

  45. Muroya S, Yada T, Shioda S, Takigawa M. Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y. Neurosci Lett. 1999;264(1–3):113–6.

    Article  PubMed  CAS  Google Scholar 

  46. Mountjoy PD, Bailey SJ, Rutter GA. Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity. Diabetologia. 2007;50(1):168–77. doi:10.1007/s00125-006-0473-3.

    Article  PubMed  CAS  Google Scholar 

  47. Fioramonti X, Contie S, Song Z, Routh VH, Lorsignol A, Penicaud L. Characterization of glucosensing neuron subpopulations in the arcuate nucleus: integration in neuropeptide Y and pro-opio melanocortin networks? Diabetes. 2007;56(5):1219–27.

    Article  PubMed  CAS  Google Scholar 

  48. Davis JD, Wirtshafter D, Asin KE, Brief D. Sustained intracerebroventricular infusion of brain fuels reduces body weight and food intake in rats. Science. 1981;212(4490):81–3.

    Article  PubMed  CAS  Google Scholar 

  49. Panksepp J, Rossi 3rd J. D-glucose infusions into the basal ventromedial hypothalamus and feeding. Behav Brain Res. 1981;3(3):381–92.

    Article  PubMed  CAS  Google Scholar 

  50. Kurata K, Fujimoto K, Sakata T, Etou H, Fukagawa K. D-glucose suppression of eating after intra-third ventricle infusion in rat. Physiol Behav. 1986;37(4):615–20.

    Article  PubMed  CAS  Google Scholar 

  51. Levin BE, Routh VH, Kang L, Sanders NM, Dunn-Meynell AA. Neuronal glucosensing: what do we know after 50 years? Diabetes. 2004;53(10):2521–8.

    Article  PubMed  CAS  Google Scholar 

  52. Miselis RR, Epstein AN. Feeding induced by intracerebroventricular 2-deoxy-D-glucose in the rat. Am J Physiol. 1975;229(5):1438–47.

    PubMed  CAS  Google Scholar 

  53. Smith GP, Epstein AN. Increased feeding in response to decreased glucose utilization in the rat and monkey. Am J Physiol. 1969;217(4):1083–7.

    PubMed  CAS  Google Scholar 

  54. Berthoud HR, Mogenson GJ. Ingestive behavior after intracerebral and intracerebroventricular infusions of glucose and 2-deoxy-D-glucose. Am J Physiol. 1977;233(3):R127–33.

    PubMed  CAS  Google Scholar 

  55. Wan HZ, Hulsey MG, Martin RJ. Intracerebroventricular administration of antisense oligodeoxynucleotide against GLUT2 glucose transporter mRNA reduces food intake, body weight change and glucoprivic feeding response in rats. J Nutr. 1998;128(2):287–91.

    PubMed  CAS  Google Scholar 

  56. Bady I, Marty N, Dallaporta M, Emery M, Gyger J, Tarussio D, et al. Evidence from glut2-null mice that glucose is a critical physiological regulator of feeding. Diabetes. 2006;55(4):988–95.

    Article  PubMed  CAS  Google Scholar 

  57. Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y, et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci. 2001;4(5):507–12. doi:10.1038/87455.

    PubMed  CAS  Google Scholar 

  58. Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature. 2007;449(7159):228–32.

    Article  PubMed  CAS  Google Scholar 

  59. 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(8):2325–36. doi:10.1172/JCI31516.

    Article  PubMed  CAS  Google Scholar 

  60. Clegg DJ, Wortman MD, Benoit SC, McOsker CC, Seeley RJ. Comparison of central and peripheral administration of C75 on food intake, body weight, and conditioned taste aversion. Diabetes. 2002;51(11):3196–201.

    Article  PubMed  CAS  Google Scholar 

  61. Wortman MD, Clegg DJ, D'Alessio D, Woods SC, Seeley RJ. C75 inhibits food intake by increasing CNS glucose metabolism. Nat Med. 2003;9(5):483–5. doi:10.1038/nm0503-483.

    Article  PubMed  CAS  Google Scholar 

  62. Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005;11(3):320–7.

    Article  PubMed  CAS  Google Scholar 

  63. Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000;288(5475):2379–81.

    Article  PubMed  CAS  Google Scholar 

  64. Hu Z, Dai Y, Prentki M, Chohnan S, Lane MD. A role for hypothalamic malonyl-CoA in the control of food intake. J Biol Chem. 2005;280(48):39681–3.

    Article  PubMed  CAS  Google Scholar 

  65. Wang R, Cruciani-Guglielmacci C, Migrenne S, Magnan C, Cotero VE, Routh VH. Effects of oleic acid on distinct populations of neurons in the hypothalamic arcuate nucleus are dependent on extracellular glucose levels. J Neurophysiol. 2006;95(3):1491–8.

    Article  PubMed  CAS  Google Scholar 

  66. Le Foll C, Irani BG, Magnan C, Dunn-Meynell AA, Levin BE. Characteristics and mechanisms of hypothalamic neuronal fatty acid sensing. Am J Physiol Regul Integr Comp Physiol. 2009;297(3):R655–64.

    Article  PubMed  CAS  Google Scholar 

  67. Andrews ZB, Horvath B, Barnstable CJ, Elsworth J, Yang L, Beal MF, et al. Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J Neurosci. 2005;25(1):184–91.

    Article  PubMed  CAS  Google Scholar 

  68. Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002;51(2):271–5.

    Article  PubMed  CAS  Google Scholar 

  69. He W, Lam TK, Obici S, Rossetti L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci. 2006;9(2):227–33.

    Article  PubMed  CAS  Google Scholar 

  70. Morgan K, Obici S, Rossetti L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem. 2004;279(30):31139–48. doi:10.1074/jbc.M400458200.

    Article  PubMed  CAS  Google Scholar 

  71. Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J Clin Invest. 2006;116(4):1081–91. doi:10.1172/JCI26640.

    Article  PubMed  CAS  Google Scholar 

  72. Chakravarthy MV, Zhu Y, Yin L, Coleman T, Pappan KL, Marshall CA, et al. Inactivation of hypothalamic FAS protects mice from diet-induced obesity and inflammation. J Lipid Res. 2009;50(4):630–40.

    Article  PubMed  CAS  Google Scholar 

  73. Benoit SC, Kemp CJ, Elias CF, Abplanalp W, Herman JP, Migrenne S, et al. Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents. J Clin Invest. 2009;119(9):2577–89.

    Article  PubMed  CAS  Google Scholar 

  74. Lu M, Sarruf DA, Talukdar S, Sharma S, Li P, Bandyopadhyay G, et al. Brain PPAR-gamma promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med. 2011;17(5):618–22.

    Article  PubMed  CAS  Google Scholar 

  75. Ryan KK, Li B, Grayson BE, Matter EK, Woods SC, Seeley RJ. A role for central nervous system PPAR-gamma in the regulation of energy balance. Nat Med. 2011;17(5):623–6.

    Article  PubMed  CAS  Google Scholar 

  76. Strader AD, Woods SC. American Gastroenterological Association. Gastrointestinal hormones and food intake. Rev Gastroenterol Mex. 2005;70(4):439–57.

    PubMed  Google Scholar 

  77. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–13. doi:10.1038/35038090.

    Article  PubMed  CAS  Google Scholar 

  78. Rocca AS, Brubaker PL. Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology. 1999;140(4):1687–94.

    Article  PubMed  CAS  Google Scholar 

  79. Merchenthaler I, Lane M, Shughrue P. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol. 1999;403(2):261–80. doi:10.1002/(SICI)1096-9861(19990111)403:2<261::AID-CNE8>3.0.CO;2-5.

    Article  PubMed  CAS  Google Scholar 

  80. Han VK, Hynes MA, Jin C, Towle AC, Lauder JM, Lund PK. Cellular localization of proglucagon/glucagon-like peptide I messenger RNAs in rat brain. J Neurosci Res. 1986;16(1):97–107. doi:10.1002/jnr.490160110.

    Article  PubMed  CAS  Google Scholar 

  81. van Dijk G, Thiele TE. Glucagon-like peptide-1 (7–36) amide: a central regulator of satiety and interoceptive stress. Neuropeptides. 1999;33(5):406–14. doi:10.1054/npep.1999.0053.

    Article  PubMed  Google Scholar 

  82. Thiele TE, Seeley RJ, D'Alessio D, Eng J, Bernstein IL, Woods SC, et al. Central infusion of glucagon-like peptide-1-(7–36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem. Brain Res. 1998;801(1–2):164–70.

    Article  PubMed  CAS  Google Scholar 

  83. Yamamoto H, Lee CE, Marcus JN, Williams TD, Overton JM, Lopez ME, et al. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest. 2002;110(1):43–52. doi:10.1172/JCI15595.

    PubMed  CAS  Google Scholar 

  84. Osaka T, Endo M, Yamakawa M, Inoue S. Energy expenditure by intravenous administration of glucagon-like peptide-1 mediated by the lower brainstem and sympathoadrenal system. Peptides. 2005;26(9):1623–31.

    Article  PubMed  CAS  Google Scholar 

  85. Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379(6560):69–72. doi:10.1038/379069a0.

    Article  PubMed  CAS  Google Scholar 

  86. Tang-Christensen M, Havel PJ, Jacobs RR, Larsen PJ, Cameron JL. Central administration of leptin inhibits food intake and activates the sympathetic nervous system in rhesus macaques. J Clin Endocrinol Metab. 1999;84(2):711–7.

    Article  PubMed  CAS  Google Scholar 

  87. Van Dijk G, Thiele TE, Seeley RJ, Woods SC, Bernstein IL. Glucagon-like peptide-1 and satiety. Nature. 1997;385(6613):214. doi:10.1038/385214a0.

    Article  PubMed  Google Scholar 

  88. Naslund E, Gutniak M, Skogar S, Rossner S, Hellstrom PM. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998;68(3):525–30.

    PubMed  CAS  Google Scholar 

  89. Flint A, Raben A, Rehfeld JF, Holst JJ, Astrup A. The effect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans. Int J Obes Relat Metab Disord. 2000;24(3):288–98.

    Article  PubMed  CAS  Google Scholar 

  90. Grill HJ, Carmody JS, Amanda Sadacca L, Williams DL, Kaplan JM. Attenuation of lipopolysaccharide anorexia by antagonism of caudal brain stem but not forebrain GLP-1-R. Am J Physiol Regul Integr Comp Physiol. 2004;287(5):R1190–3. doi:10.1152/ajpregu.00163.2004.

    Article  PubMed  CAS  Google Scholar 

  91. McMahon LR, Wellman PJ. PVN infusion of GLP-1-(7–36) amide suppresses feeding but does not induce aversion or alter locomotion in rats. Am J Physiol. 1998;274(1 Pt 2):R23–9.

    PubMed  CAS  Google Scholar 

  92. Sandoval DA, Bagnol D, Woods SC, D'Alessio DA, Seeley RJ. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes. 2008;57(8):2046–54.

    Article  PubMed  CAS  Google Scholar 

  93. Schusdziarra V, Zimmermann JP, Schick RR. Importance of orexigenic counter-regulation for multiple targeted feeding inhibition. Obes Res. 2004;12(4):627–32.

    Article  PubMed  CAS  Google Scholar 

  94. Furuse M, Matsumoto M, Mori R, Sugahara K, Kano K, Hasegawa S. Influence of fasting and neuropeptide Y on the suppressive food intake induced by intracerebroventricular injection of glucagon-like peptide-1 in the neonatal chick. Brain Res. 1997;764(1–2):289–92.

    Article  PubMed  CAS  Google Scholar 

  95. Tritos NA, Vicent D, Gillette J, Ludwig DS, Flier ES, Maratos-Flier E. Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus. Diabetes. 1998;47:1687–92.

    Article  PubMed  CAS  Google Scholar 

  96. Edwards CM, Abbott CR, Sunter D, Kim M, Dakin CL, Murphy KG, et al. Cocaine- and amphetamine-regulated transcript, glucagon-like peptide-1 and corticotrophin releasing factor inhibit feeding via agouti-related protein independent pathways in the rat. Brain Res. 2000;866(1–2):128–34.

    Article  PubMed  CAS  Google Scholar 

  97. Donahey JC, van Dijk G, Woods SC, Seeley RJ. Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats. Brain Res. 1998;779(1–2):75–83.

    Article  PubMed  CAS  Google Scholar 

  98. D'Alessio DA, Vahl TP. Utilizing the GLP-1 signaling system to treat diabetes: sorting through the pharmacologic approaches. Curr Diab Rep. 2005;5(5):346–52.

    Article  PubMed  Google Scholar 

  99. Knop FK, Vilsboll T, Hojberg PV, Larsen S, Madsbad S, Volund A, et al. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes. 2007;56(8):1951–9.

    Article  PubMed  CAS  Google Scholar 

  100. Meeran K, O'Shea D, Edwards CM, Turton MD, Heath MM, Gunn I, et al. Repeated intracerebroventricular administration of glucagon-like peptide-1-(7–36) amide or exendin-(9–39) alters body weight in the rat. Endocrinology. 1999;140(1):244–50.

    Article  PubMed  CAS  Google Scholar 

  101. Scrocchi LA, Brown TJ, MaClusky N, Brubaker PL, Auerbach AB, Joyner AL, et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med. 1996;2(11):1254–8.

    Article  PubMed  CAS  Google Scholar 

  102. Scrocchi LA, Drucker DJ. Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor −/− mice. Endocrinology. 1998;139(7):3127–32.

    Article  PubMed  CAS  Google Scholar 

  103. Hansotia T, Maida A, Flock G, Yamada Y, Tsukiyama K, Seino Y, et al. Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007;117(1):143–52. doi:10.1172/JCI25483.

    Article  PubMed  CAS  Google Scholar 

  104. Knauf C, Cani PD, Kim DH, Iglesias MA, Chabo C, Waget A, et al. Role of central nervous system glucagon-like Peptide-1 receptors in enteric glucose sensing. Diabetes. 2008;57(10):2603–12.

    Article  PubMed  CAS  Google Scholar 

  105. Brown M, Bing C, King P, Pickavance L, Heal D, Wilding J. Sibutramine reduces feeding, body fat and improves insulin resistance in dietary-obese male Wistar rats independently of hypothalamic neuropeptide Y. Br J Pharmacol. 2001;132(8):1898–904. doi:10.1038/sj.bjp.0704030.

    Article  PubMed  CAS  Google Scholar 

  106. Luo S, Liang Y, Cincotta AH. Intracerebroventricular administration of bromocriptine ameliorates the insulin-resistant/glucose-intolerant state in hamsters. Neuroendocrinology. 1999;69(3):160–6.

    Article  PubMed  CAS  Google Scholar 

  107. Cincotta AH, Tozzo E, Scislowski PW. Bromocriptine/SKF38393 treatment ameliorates obesity and associated metabolic dysfunctions in obese (ob/ob) mice. Life Sci. 1997;61(10):951–6.

    Article  PubMed  CAS  Google Scholar 

  108. Oltmans GA. Norepinephrine and dopamine levels in hypothalamic nuclei of the genetically obese mouse (ob/ob). Brain Res. 1983;273(2):369–73.

    Article  PubMed  CAS  Google Scholar 

  109. Salamone JD, Mahan K, Rogers S. Ventrolateral striatal dopamine depletions impair feeding and food handling in rats. Pharmacol Biochem Behav. 1993;44(3):605–10.

    Article  PubMed  CAS  Google Scholar 

  110. Szczypka MS, Rainey MA, Kim DS, Alaynick WA, Marck BT, Matsumoto AM, et al. Feeding behavior in dopamine-deficient mice. Proc Natl Acad Sci USA. 1999;96(21):12138–43.

    Article  PubMed  CAS  Google Scholar 

  111. Patterson TA, Brot MD, Zavosh A, Schenk JO, Szot P, Figlewicz DP. Food deprivation decreases mRNA and activity of the rat dopamine transporter. Neuroendocrinology. 1998;68(1):11–20.

    Article  PubMed  CAS  Google Scholar 

  112. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–23.

    Article  PubMed  CAS  Google Scholar 

  113. Ader M, Kim SP, Catalano KJ, Ionut V, Hucking K, Richey JM, et al. Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs. Diabetes. 2005;54(3):862–71.

    Article  PubMed  CAS  Google Scholar 

  114. Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H. Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology. 2007;32(2):289–97.

    Article  PubMed  CAS  Google Scholar 

  115. Chintoh AF, Mann SW, Lam L, Lam C, Cohn TA, Fletcher PJ, et al. Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration. J Clin Psychopharmacol. 2008;28(5):494–9. doi:10.1097/JCP.0b013e318184b4c5.

    Article  PubMed  CAS  Google Scholar 

  116. Dasgupta A, Singh OP, Rout JK, Saha T, Mandal S. Insulin resistance and metabolic profile in antipsychotic naive schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(7):1202–7.

    Article  PubMed  CAS  Google Scholar 

  117. Melkersson KI, Gunes A, Dahl ML. Impact of serotonin receptor 2A gene haplotypes on C-peptide levels in clozapine- and olanzapine-treated patients. Hum Psychopharmacol. 2010;25(4):347–52. doi:10.1002/hup.1114.

    Article  PubMed  CAS  Google Scholar 

  118. Mulder H, Cohen D, Scheffer H, Gispen-de Wied C, Arends J, Wilmink FW, et al. HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. J Clin Psychopharmacol. 2009;29(1):16–20. doi:10.1097/JCP.0b013e3181934462.

    Article  PubMed  CAS  Google Scholar 

  119. Mancilla-Diaz JM, Escartin-Perez RE, Lopez-Alonso VE, Floran-Garduno B, Romano-Camacho JB. Role of 5-HT1A and 5-HT1B receptors in the hypophagic effect of 5-HT on the structure of feeding behavior. Med Sci Monit. 2005;11(3):BR74–9.

    PubMed  CAS  Google Scholar 

  120. Leibowitz SF, Alexander JT. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatry. 1998;44(9):851–64.

    Article  PubMed  CAS  Google Scholar 

  121. Choi S, Blake V, Cole S, Fernstrom JD. Effects of chronic fenfluramine administration on hypothalamic neuropeptide mRNA expression. Brain Res. 2006;1087(1):83–6.

    Article  PubMed  CAS  Google Scholar 

  122. Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med. 1998;4(10):1152–6. doi:10.1038/2647.

    Article  PubMed  CAS  Google Scholar 

  123. Xu Y, Jones JE, Kohno D, Williams KW, Lee CE, Choi MJ, et al. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron. 2008;60(4):582–9.

    Article  PubMed  CAS  Google Scholar 

  124. Yamauchi A, Shizuka F, Yamamoto T, Nikawa T, Kido Y, Rokutan K, et al. Amino acids and glucose differentially increased extracellular 5-hydroxyindoleacetic acid in the rat brain. J Nutr Sci Vitaminol (Tokyo). 1995;41(3):325–40.

    CAS  Google Scholar 

  125. Barzilay J, Freedland E. Inflammation and its association with glucose disorders and cardiovascular disease. Treat Endocrinol. 2003;2(2):85–94.

    Article  PubMed  Google Scholar 

  126. Guijarro A, Laviano A, Meguid MM. Hypothalamic integration of immune function and metabolism. Prog Brain Res. 2006;153:367–405.

    Article  PubMed  CAS  Google Scholar 

  127. Jansson JO, Wallenius K, Wernstedt I, Ohlsson C, Dickson SL, Wallenius V. On the site and mechanism of action of the anti-obesity effects of interleukin-6. Growth Horm IGF Res. 2003;13(Suppl A):S28–32.

    Article  PubMed  CAS  Google Scholar 

  128. Reid J, Lightbody TD. The insulin equivalence of salicylate. Br Med J. 1959;1(5126):897–900.

    Article  PubMed  CAS  Google Scholar 

  129. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293(5535):1673–7. doi:10.1126/science.1061620.

    Article  PubMed  CAS  Google Scholar 

  130. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998;396(6706):77–80. doi:10.1038/23948.

    Article  PubMed  CAS  Google Scholar 

  131. Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002;109(10):1321–6. doi:10.1172/JCI14955.

    PubMed  CAS  Google Scholar 

  132. Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J, Laflamme N. How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med. 2000;223(1):22–38.

    Article  PubMed  CAS  Google Scholar 

  133. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008;135(1):61–73.

    Article  PubMed  CAS  Google Scholar 

  134. Belgardt BF, Mauer J, Wunderlich FT, Ernst MB, Pal M, Spohn G, et al. Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism. Proc Natl Acad Sci USA. 2010;107(13):6028–33.

    Article  PubMed  CAS  Google Scholar 

  135. Cincotta AH, Luo S, Zhang Y, Liang Y, Bina KG, Jetton TL, et al. Chronic infusion of norepinephrine into the VMH of normal rats induces the obese glucose-intolerant state. Am J Physiol Regul Integr Comp Physiol. 2000;278(2):R435–44.

    PubMed  CAS  Google Scholar 

  136. Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab. 2009;296(5):E1003–12.

    Article  PubMed  CAS  Google Scholar 

  137. Unger EK, Piper ML, Olofsson LE, Xu AW. Functional role of c-Jun-N-terminal kinase in feeding regulation. Endocrinology. 2010;151(2):671–82.

    Article  PubMed  CAS  Google Scholar 

  138. de Backer MW, Brans MA, van Rozen AJ, van der Zwaal EM, Luijendijk MC, Garner KG, et al. Suppressor of cytokine signaling 3 knockdown in the mediobasal hypothalamus: counterintuitive effects on energy balance. J Mol Endocrinol. 2010;45(5):341–53.

    Article  PubMed  CAS  Google Scholar 

  139. Reed AS, Unger EK, Olofsson LE, Piper ML, Myers Jr MG, Xu AW. Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes. 2010;59(4):894–906.

    Article  PubMed  CAS  Google Scholar 

  140. Kleinridders A, Schenten D, Konner AC, Belgardt BF, Mauer J, Okamura T, et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 2009;10(4):249–59.

    Article  PubMed  CAS  Google Scholar 

  141. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci. 2009;29(2):359–70.

    Article  PubMed  CAS  Google Scholar 

  142. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9(1):35–51.

    Article  PubMed  CAS  Google Scholar 

  143. Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science. 2005;309(5736):943–7.

    Article  PubMed  CAS  Google Scholar 

  144. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature. 2005;434(7036):1026–31.

    Article  PubMed  CAS  Google Scholar 

  145. Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med. 2003;9(6):756–61. doi:10.1038/nm873.

    Article  PubMed  CAS  Google Scholar 

  146. Wang PY, Caspi L, Lam CK, Chari M, Li X, Light PE, et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature. 2008;452(7190):1012–6.

    Article  PubMed  CAS  Google Scholar 

  147. Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, et al. Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab. 2006;3(4):267–75.

    Article  PubMed  CAS  Google Scholar 

  148. Konner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 2007;5(6):438–49.

    Article  PubMed  CAS  Google Scholar 

  149. Ono H, Pocai A, Wang Y, Sakoda H, Asano T, Backer JM, et al. Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest. 2008;118(8):2959–68. doi:10.1172/JCI34277.

    PubMed  CAS  Google Scholar 

  150. Shi ZQ, Nelson A, Whitcomb L, Wang J, Cohen AM. Intracerebroventricular administration of leptin markedly enhances insulin sensitivity and systemic glucose utilization in conscious rats. Metabolism. 1998;47(10):1274–80.

    Article  PubMed  CAS  Google Scholar 

  151. Liu L, Karkanias GB, Morales JC, Hawkins M, Barzilai N, Wang J, et al. Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J Biol Chem. 1998;273(47):31160–7.

    Article  PubMed  CAS  Google Scholar 

  152. Lin CY, Higginbotham DA, Judd RL, White BD. Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab. 2002;282(5):E1084–91. doi:10.1152/ajpendo.00489.2001.

    PubMed  CAS  Google Scholar 

  153. Park S, Hong SM, Sung SR, Jung HK. Long-term effects of central leptin and resistin on body weight, insulin resistance, and beta-cell function and mass by the modulation of hypothalamic leptin and insulin signaling. Endocrinology. 2008;149(2):445–54.

    Article  PubMed  CAS  Google Scholar 

  154. Pocai A, Morgan K, Buettner C, Gutierrez-Juarez R, Obici S, Rossetti L. Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes. 2005;54(11):3182–9.

    Article  PubMed  CAS  Google Scholar 

  155. Robertson SA, Leinninger GM, Myers Jr MG. Molecular and neural mediators of leptin action. Physiol Behav. 2008;94(5):637–42.

    Article  PubMed  CAS  Google Scholar 

  156. Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, et al. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 2007;6(5):398–405.

    Article  PubMed  CAS  Google Scholar 

  157. Martins PJ, Haas M, Obici S. Central nervous system delivery of the antipsychotic olanzapine induces hepatic insulin resistance. Diabetes. 2010;59(10):2418–25.

    Article  PubMed  CAS  Google Scholar 

  158. Hakansson ML, Meister B. Transcription factor STAT3 in leptin target neurons of the rat hypothalamus. Neuroendocrinology. 1998;68(6):420–7.

    Article  PubMed  CAS  Google Scholar 

  159. Horvath TL, Naftolin F, Leranth C. Beta-endorphin innervation of dopamine neurons in the rat hypothalamus: a light and electron microscopic double immunostaining study. Endocrinology. 1992;131(3):1547–55.

    Article  PubMed  CAS  Google Scholar 

  160. Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron. 2006;51(6):801–10.

    Article  PubMed  CAS  Google Scholar 

  161. Garfield AS, Heisler LK. Pharmacological targeting of the serotonergic system for the treatment of obesity. J Physiol. 2009;587(Pt 1):49–60.

    Article  PubMed  CAS  Google Scholar 

  162. Buettner C, Camacho RC. Hypothalamic control of hepatic glucose production and its potential role in insulin resistance. Endocrinol Metab Clin North Am. 2008;37(4):825–40.

    Article  PubMed  CAS  Google Scholar 

  163. Perrin C, Knauf C, Burcelin R. 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. 2004;145(9):4025–33. doi:10.1210/en.2004-0270.

    Article  PubMed  CAS  Google Scholar 

  164. Minokoshi Y, Okano Y, Shimazu T. Regulatory mechanism of the ventromedial hypothalamus in enhancing glucose uptake in skeletal muscles. Brain Res. 1994;649(1–2):343–7.

    Article  PubMed  CAS  Google Scholar 

  165. Minokoshi Y, Haque MS, Shimazu T. Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes. 1999;48(2):287–91.

    Article  PubMed  CAS  Google Scholar 

  166. Chen M, Woods SC, Porte Jr D. Effect of cerebral intraventricular insulin on pancreatic insulin secretion in the dog. Diabetes. 1975;24(10):910–4.

    Article  PubMed  CAS  Google Scholar 

  167. Sako Y, Grill VE. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology. 1990;127(4):1580–9.

    Article  PubMed  CAS  Google Scholar 

  168. Zhou YP, Grill VE. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest. 1994;93(2):870–6. doi:10.1172/JCI117042.

    Article  PubMed  CAS  Google Scholar 

  169. Gremlich S, Bonny C, Waeber G, Thorens B. Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem. 1997;272(48):30261–9.

    Article  PubMed  CAS  Google Scholar 

  170. Park S, Ahn IS, da Kim S. Central infusion of leptin improves insulin resistance and suppresses beta-cell function, but not beta-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model. Life Sci. 2010;86(23–24):854–62.

    Article  PubMed  CAS  Google Scholar 

  171. Dobbins RL, Szczepaniak LS, Zhang W, McGarry JD. Chemical sympathectomy alters regulation of body weight during prolonged ICV leptin infusion. Am J Physiol Endocrinol Metab. 2003;284(4):E778–87. doi:10.1152/ajpendo.00128.2002.

    PubMed  CAS  Google Scholar 

  172. Moran TH, Kinzig KP. Gastrointestinal satiety signals II. Cholecystokinin. Am J Physiol Gastrointest Liver Physiol. 2004;286(2):G183–8. doi:10.1152/ajpgi.00434.2003.

    Article  PubMed  CAS  Google Scholar 

  173. Chandra R, Liddle RA. Cholecystokinin. Curr Opin Endocrinol Diabetes Obes. 2007;14(1):63–7. doi:10.1097/MED.0b013e3280122850.

    Article  PubMed  CAS  Google Scholar 

  174. Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest. 2007;117(1):13–23. doi:10.1172/JCI30227.

    Article  PubMed  CAS  Google Scholar 

  175. Cheung GW, Kokorovic A, Lam CK, Chari M, Lam TK. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab. 2009;10(2):99–109.

    Article  PubMed  CAS  Google Scholar 

  176. Schirra J, Nicolaus M, Roggel R, Katschinski M, Storr M, Woerle HJ, et al. Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2006;55(2):243–51.

    Article  PubMed  CAS  Google Scholar 

  177. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet. 1987;2(8571):1300–4.

    Article  PubMed  CAS  Google Scholar 

  178. Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest. 1987;79(2):616–9. doi:10.1172/JCI112855.

    Article  PubMed  CAS  Google Scholar 

  179. Prigeon RL, Quddusi S, Paty B, D'Alessio DA. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab. 2003;285(4):E701–7. doi:10.1152/ajpendo.00024.2003.

    PubMed  CAS  Google Scholar 

  180. Ayala JE, Bracy DP, James FD, Burmeister MA, Wasserman DH, Drucker DJ. Glucagon-like peptide-1 receptor knockout mice are protected from high-fat diet-induced insulin resistance. Endocrinology. 2010;151(10):4678–87.

    Article  PubMed  CAS  Google Scholar 

  181. Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, et al. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest. 2005;115(12):3554–63. doi:10.1172/JCI25764.

    Article  PubMed  CAS  Google Scholar 

  182. Parlevliet ET, de Leeuw van Weenen JE, Romijn JA, Pijl H. GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet. Am J Physiol Endocrinol Metab. 2010;299(2):E318–24.

    PubMed  CAS  Google Scholar 

  183. Yamamoto H, Kishi T, Lee CE, Choi BJ, Fang H, Hollenberg AN, et al. Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites. J Neurosci. 2003;23(7):2939–46.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Stephanie Sisley is funded via NIEHS ESO10957.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Darleen Sandoval.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sisley, S., Sandoval, D. Hypothalamic control of energy and glucose metabolism. Rev Endocr Metab Disord 12, 219–233 (2011). https://doi.org/10.1007/s11154-011-9189-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-011-9189-x

Keywords

Navigation