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Wired on sugar: the role of the CNS in the regulation of glucose homeostasis

Key Points

  • Recent findings indicate that neuronal populations in the hypothalamus that had already been identified as being crucial to the regulation of energy balance are also essential for the regulation of glucose homeostasis.

  • The melanocortin system within the arcuate nucleus (ARC) of the hypothalamus has an important role in the integration of signals from circulating hormones to maintain both energy and glucose homeostasis.

  • ATP-sensitive potassium channels, ATP-activated protein kinase and mammalian target of rapamycin act as 'general' fuel sensors — they sense changes in overall energy status through changes in ATP. The sensing of fuel and ATP specifically within the hypothalamus has the capacity to modulate both glucose and energy homeostasis.

  • Neuronal populations outside the ARC (including steroidogenic factor 1 neurons within the ventromedial hypothalamus) and multiple populations of neurons within the hindbrain (melanocortin receptor 4-expressing neurons in the sympathetic nervous system and NMDA receptor-expressing neurons) contribute to the regulation of glucose and energy homeostasis.

  • Within the gut, cholecystokinin and glucagon-like peptide 1 provide a conduit for CNS-induced regulation of energy and glucose homeostasis.

  • A key outstanding question in the field is whether the neuronal circuits that are crucial for body weight regulation and that may be dysregulated in obesity also contribute to the poor glucose homeostasis that eventually results in type 2 diabetes mellitus.

  • New strategies such as optogenetics and DREADD (designer receptors exclusively activated by designer drugs) provide an avenue for further understanding the crossroads of glucose and energy homeostasis.

Abstract

Obesity and type 2 diabetes mellitus (T2DM) — disorders of energy homeostasis and glucose homeostasis, respectively — are tightly linked and the incidences of both conditions are increasing in parallel. The CNS integrates information regarding peripheral nutrient and hormonal changes and processes this information to regulate energy homeostasis. Recent findings indicate that some of the neural circuits and mechanisms underlying energy balance are also essential for the regulation of glucose homeostasis. We propose that disruption of these overlapping pathways links the metabolic disturbances associated with obesity and T2DM. A better understanding of these converging mechanisms may lead to therapeutic strategies that target both T2DM and obesity.

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Figure 1: Leptin and insulin actions in the ARC.
Figure 2: Fuel sensing in CNS neurons.
Figure 3: Overlapping CNS circuitries regulate energy balance and glucose homeostasis.

References

  1. Bernard, C. in Homeostasis: Origins of the Concept, 1973 (ed. Langley, L. L.) 129–151 (Dowden, Hutchinson & Ross, Stroudsberg, PA, 1870).

    Google Scholar 

  2. Knowler, W. C. et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 374, 1677–1686 (2009).

    Article  PubMed  Google Scholar 

  3. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P. & Baskin, D. G. Identification of hypothalmic targets of leptin action. J. Clin. Invest. 98, 1101–1106 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hahn, T. M., Breininger, J. F., Baskin, D. G. & Schwartz, M. W. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nature Neurosci. 1, 271–272 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Cone, R. D. Anatomy and regulation of the central melanocortin system. Nature Neurosci. 8, 571–578 (2005). An excellent review on the various players in the melanocortin system and its role in energy balance.

    Article  CAS  PubMed  Google Scholar 

  7. Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Woods, S. C., Seeley, R. J., Porte, D. J. & Schwartz, M. W. Signals that regulate food intake and energy homeostasis. Science 280, 1378–1383 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Brüning, J. C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

    Article  PubMed  Google Scholar 

  10. Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Baskin, D. G., Breininger, J. F. & Schwartz, M. W. Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes 48, 828–833 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Baskin, D. G. et al. Insulin and leptin: dual adipodity signals to the brain for the regulation of food intake and body weight. Brain Res. 848, 114–123 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Schwartz, M. W. et al. Central nervous system control of food intake. Nature 404, 661–671 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Woods, S. C., Lotter, E. C., McKay, L. D. & Porte, D. Jr Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).

    Article  CAS  PubMed  Google Scholar 

  16. Chavez, M., Kaiyala, K., Madden, L. J., Schwartz, M. W. & Woods, S. C. Intraventricular insulin and the level of maintained body weight in rats. Behav. Neurosci. 109, 528–531 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Seeley, R. J. et al. Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. Horm. Metab. Res. 28, 664–668 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Abate, N., Garg, A., Peshock, R. M., Stray-Gundersen, J. & Grundy, S. M. Relationships of generalized and regional adiposity to insulin sensitivity in men. J. Clin. Invest. 96, 88–98 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Woods, S. C., Seeley, R. J., Porte, D. Jr & Schwartz, M. W. Signals that regulate food intake and energy homeostasis. Science 280, 1378–1383 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Cota, D. et al. Hypothalamic mTOR signaling regulates food intake. Science 312, 927–930 (2006). An early demonstration that mTOR is a fuel sensor within the hypothalamus and regulates energy balance.

    Article  CAS  PubMed  Google Scholar 

  21. Clegg, D. J., Wortman, M. D., Benoit, S. C., McOsker, C. C. & Seeley, R. J. Comparison of central and peripheral administration of C75 on food intake, body weight, and conditioned taste aversion. Diabetes 51, 3196–3201 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Loftus, T. M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2299–2300 (2000).

    Article  Google Scholar 

  23. Vaisse, C., Clement, K., B., G.-G. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genet. 20, 113–114 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Clegg, D. J. et al. Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R981–R986 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Ryan, K. K., Woods, S. C. & Seeley, R. J. Central nervous system mechanisms linking the consumption of palatable high-fat diets to the defense of greater adiposity. Cell Metab. 15, 137–149 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. von Mering, J. & Minkowski, O. Diabetes Mellitus nach Pankreasextirpation. Zbl. Klin. Med. 10, 393–394 (1889).

    Google Scholar 

  27. Banting, F. G., Best, C. H., Collip, J. B., Campbell, W. R. & Fletcher, A. A. Pancreatic extracts in the treatment of diabetes mellitus. Can. Med. Assoc. J. 12, 141–146 (1922).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Macleod, J. J. Pancreatic extract and diabetes. Can. Med. Assoc. J. 12, 423–425 (1922).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nature Med. 8, 1376–1382 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Liu, L. et al. Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J. Biol. Chem. 273, 31160–31167 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Obici, S., Feng, Z., Karkanias, G., Baskin, D. G. & Rossetti, L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nature Neurosci. 5, 566–572 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Benoit, S. C. et al. The catabolic action of insulin in the brain is mediated by melanocortins. J. Neurosci. 22, 9048–9052 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Konner, A. C. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell. Metab. 5, 438–449 (2007). An excellent study that systematically activated IRs in AGRP- and/or POMC-expressing neurons to determine the necessity of these receptors for glucose homeostasis.

    Article  CAS  PubMed  Google Scholar 

  34. Lin, H. V. et al. Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59, 337–346 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Pocai, A. et al. Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes 54, 3182–3189 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Gutierrez-Juarez, R., Obici, S. & Rossetti, L. Melanocortin-independent effects of leptin on hepatic glucose fluxes. J. Biol. Chem. 279, 49704–49715 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. German, J. et al. Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology 150, 4502–4511 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Balthasar, N. et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983–991 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Shi, H. et al. Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis. Am. J. Physiol. Endocrinol. Metab. 294, E630–E639 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Berglund, E. D. et al. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J. Clin. Invest. 122, 1000–1009 (2012). An excellent study from the Elmquist laboratory that dissected the physiological role of leptin by manipulating OBRs in mouse models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hill, J. W. et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 11, 286–297 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Williams, K. W. et al. Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J. Neurosci. 30, 2472–2479 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Levin, B. E. Metabolic sensing neurons and the control of energy homeostasis. Physiol. Behav. 89, 486–489 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, R. et al. Effects of oleic acid on distinct populations of neurons in the hypothalamic arcuate nucleus are dependent on extracellular glucose levels. J. Neurophysiol. 95, 1491–1498 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Lam, T. K., Gutierrez-Juarez, R., Pocai, A. & Rossetti, L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943–947 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Obici, S. et al. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271–275 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Su, Y. et al. Hypothalamic leucine metabolism regulates liver glucose production. Diabetes 61, 85–93 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Parton, L. E. et al.Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228–232 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Levin, B. E., Routh, V. H., Kang, L., Sanders, N. M. & Dunn-Meynell, A. A. Neuronal glucosensing: what do we know after 50 years? Diabetes 53, 2521–2528 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain-liver circuit regulates glucose homeostasis. Cell Metab. 1, 53–61 (2005). In this paper, the Rossetti group shows that central inhibition of fat oxidation is dependent on the activation of K ATP channels.

    Article  CAS  PubMed  Google Scholar 

  51. Pocai, A. et al. Hypothalamic KATP channels control hepatic glucose production. Nature 434, 1026–1031 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Kong, D. et al. Glucose stimulation of hypothalamic MCH neurons involves KATP channels, is modulated by UCP2, and regulates peripheral glucose homeostasis. Cell Metab. 12, 545–552 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. Hardie, D. G. & Carling, D. The AMP-activated protein kinase — fuel gauge of the mammalian cell? Eur. J. Biochem. 246, 259–273 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Claret, M. et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J. Clin. Invest. 117, 2325–2336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lindsley, J. E. & Rutter, J. Nutrient sensing and metabolic decisions. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 139, 543–559 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Blouet, C., Ono, H. & Schwartz, G. J. Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab. 8, 459–467 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ono, H. et al. Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J. Clin. Invest. 118, 2959–2968 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Ryan, K. K. et al. A role for central nervous system PPAR-[gamma] in the regulation of energy balance. Nature Med. 17, 623–626 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Derosa, G. & Maffioli, P. Effects of thiazolidinediones and sulfonylureas in patients with diabetes. Diabetes Technol. Ther. 12, 491–501 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Lu, M. et al. Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nature Med. 17, 618–622 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Diano, S. et al. Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nature Med. 17, 1121–1127 (2011). Interesting study showing a role for hypothalamic reactive oxygen species in the modulation of the melanocortin system.

    Article  CAS  PubMed  Google Scholar 

  65. De Fanti, B. A., Hamilton, J. S. & Horwitz, B. A. Meal-induced changes in extracellular 5-HT in medial hypothalamus of lean (Fa/Fa) and obese (fa/fa) Zucker rats. Brain Res. 902, 164–170 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Heisler, L. K. et al. Activation of central melanocortin pathways by fenfluramine. Science 297, 609–611 (2002). A seminal paper that demonstrated that the melanocortin neurocircuitry interacts with the 5-HT system to modulate energy balance.

    Article  CAS  PubMed  Google Scholar 

  67. Nonogaki, K., Strack, A. M., Dallman, M. F. & Tecott, L. H. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nature Med. 4, 1152–1156 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Zhou, L. et al. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 6, 398–405 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ader, M. 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 54, 862–871 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Kiss, J., Leranth, C. & Halasz, B. Serotoninergic endings on VIP-neurons in the suprachiasmatic nucleus and on ACTH-neurons in the arcuate nucleus of the rat hypothalamus. A combination of high resolution autoradiography and electron microscopic immunocytochemistry. Neurosci. Lett. 44, 119–124 (1984).

    Article  CAS  PubMed  Google Scholar 

  71. Xu, Y., Elmquist, J. K. & Fukuda, M. Central nervous control of energy and glucose balance: focus on the central melanocortin system. Ann. NY Acad. Sci. 1243, 1–14 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Xu, Y. et al. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60, 582–589 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wade, J. M. et al. Synergistic impairment of glucose homeostasis in ob/ob mice lacking functional serotonin 2C receptors. Endocrinology 149, 955–961 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Sohn, J. W. et al. Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels. Neuron 71, 488–497 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Qiu, J., Fang, Y., Ronnekleiv, O. K. & Kelly, M. J. Leptin excites proopiomelanocortin neurons via activation of TRPC channels. J. Neurosci. 30, 1560–1565 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Xu, Y. et al. A serotonin and melanocortin circuit mediates D-fenfluramine anorexia. J. Neurosci. 30, 14630–14634 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Obici, S. et al. Central melanocortin receptors regulate insulin action. J. Clin. Invest. 108, 1079–1085 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hetherington, A. & Ranson, S. Hypothalamic lesions and adiposity in the rat. Anat. Rec. 78, 149–172 (1940).

    Article  Google Scholar 

  80. Rohner, F. et al. Immediate effect of lesion of the ventromedial hypothalamic area upon glucose-induced insulin secretion in anaesthetized rats. Diabetologia 13, 239–242 (1977).

    Article  CAS  PubMed  Google Scholar 

  81. Borg, W. P. et al. Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia. J. Clin. Invest. 93, 1677–1682 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Klockener, T. et al. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nature Neurosci. 14, 911–918 (2011). One of many excellent papers from the Bruning laboratory, defining insulin action in SF1 and VMH neurons.

    Article  CAS  PubMed  Google Scholar 

  83. Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Bingham, N. C., Anderson, K. K., Reuter, A. L., Stallings, N. R. & Parker, K. L. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 149, 2138–2148 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang, R. et al. Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight. Endocrinology 149, 5654–5661 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tong, Q. et al. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab. 5, 383–393 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Grill, H. J. Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity 14, 216S–221S (2006).

    Article  PubMed  Google Scholar 

  88. Grill, H. J., Ginsberg, A. B., Seeley, R. J. & Kaplan, J. M. Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight. J. Neurosci. 18, 10128–10135 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rossi, J. et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 13, 195–204 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cheung, G. W., Kokorovic, A., Lam, C. K., Chari, M. & Lam, T. K. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab. 10, 99–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Lam, T. K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nature Med. 11, 320–327 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. DiRocco, R. J. & Grill, H. J. The forebrain is not essential for sympathoadrenal hyperglycemic response to glucoprivation. Science 204, 1112–1114 (1979).

    Article  CAS  PubMed  Google Scholar 

  93. Hisadome, K., Reimann, F., Gribble, F. M. & Trapp, S. CCK stimulation of GLP-1 neurons involves α1-adrenoceptor-mediated increase in glutamatergic synaptic inputs. Diabetes 60, 2701–2709 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rasmussen, B. A. et al. Duodenal activation of cAMP-dependent protein kinase induces vagal afferent firing and lowers glucose production in rats. Gastroenterology 142, 834–843.e3 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Strader, A. D. & Woods, S. C. Gastrointestinal hormones and food intake. Gastroenterology 128, 175–191 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Wang, P. Y. et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 452, 1012–1016 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Lam, C. K. et al. Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production. J. Biol. Chem. 285, 21913–21921 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Shimizu, I., Hirota, M., Ohboshi, C. & Shima, K. Identification and localization of glucagon-like peptide-1 and its receptor in the brain. Endocrinology 121, 1076–1082 (1987).

    Article  CAS  PubMed  Google Scholar 

  99. Barrera, J. G., Sandoval, D. A., D'Alessio, D. A. & Seeley, R. J. GLP-1 and energy balance: an integrated model of short-term and long-term control. Nature Rev. Endocrinol. 7, 507–516 (2011).

    Article  CAS  Google Scholar 

  100. Prigeon, R. L., Quddusi, S., Paty, B. & D'Alessio, D. A. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am. J. Physiol. Endocrinol. Metab. 285, E701–E707 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Sandoval, D. A., Bagnol, D., Woods, S. C., D'Alessio, D. A. & Seeley, R. J. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57, 2046–2054 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cani, P. D. et al. Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor. Diabetes 55, 1484–1490 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Kieffer, T. J. & Habener, J. F. The glucagon-like peptides. Endocr. Rev. 20, 876–913 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Vahl, T. P. et al. Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats. Endocrinology 148, 4965–4973 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Amato, A. et al. Peripheral motor action of glucagon-like peptide-1 through enteric neuronal receptors. Neurogastroenterol. Motil. 22, 664–e203 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Aponte, Y., Atasoy, D. & Sternson, S. M. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neurosci. 14, 351–355 (2011). The first demonstration of the use of optogenetics in the field of energy balance. It used optogenetics to modulate AGRP.

    Article  CAS  PubMed  Google Scholar 

  107. Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011). A ground-breaking study in the field of energy balance that demonstrated the power of DREADD technology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Luquet, S., Perez, F. A., Hnasko, T. S. & Palmiter, R. D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Moore, M. C. et al. Sources of carbon for hepatic glycogen synthesis in the conscious dog. J. Clin. Invest. 88, 578–587 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Xie, H. & Lautt, W. W. Insulin resistance caused by hepatic cholinergic interruption and reversed by acetylcholine administration. Am. J. Physiol. 271, E587–E592 (1996).

    CAS  PubMed  Google Scholar 

  111. Wei, Y., Wang, D., Topczewski, F. & Pagliassotti, M. J. Fructose-mediated stress signaling in the liver: implications for hepatic insulin resistance. J. Nutr. Biochem. 18, 1–9 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Bagger, J. I., Knop, F. K., Holst, J. J. & Vilsbøll, T. Glucagon antagonism as a potential therapeutic target in type 2 diabetes. Diabetes Obes. Metab. 13, 965–971 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 33, S62–S69 (2010).

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Acknowledgements

We are grateful for the helpful comments of S.C. Woods and S.C. Benoit. The work of the laboratory is supported in part by the US National Institutes of Health (NIH) Awards DK56863, DK57900, U01CA141464, DK082480, MH069860, DK082480 and also work with Ethicon Endo-Surgery, F. Hoffman-La Roche, Pfizer and Novo Nordisk A/S. B.E.G. is also supported by NIH Award 1F32HD68103.

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Correspondence to Darleen A. Sandoval.

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D.A.S. has received research support from Ethicon Endo-Surgery, Mannkind and Novo Nordisk. R.J.S. has received research support from Ethicon Endo-Surgery, Mannkind, Novo Nordisk, Pfizer and Roche. R.J.S. has served on scientific advisory boards for Ethicon Endo-Surgery, Angiochem and Novo Nordisk. R.J.S. is also a paid speaker for Merck, Ethicon Endo-Surgery, Pfizer and Novo Nordisk.

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Glossary

Glucose fluxes

Changes in glucose uptake, glucose production by the liver and glucose metabolism within a tissue or cell.

Melanocortin system

Neurons in the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract that express pro-opiomelanocortin, agouti-related protein and neuropeptide Y with downstream actions on melanocortin receptor 3 and melanocortin receptor 4.

Antagonist/inverse agonist

A ligand that can both block a receptor's activity and produce the opposite action of the agonist.

Gluconeogenesis

The process of making glucose from non-glucose precursors such as lactate, glycerol and alanine.

Glycogenolysis

The breakdown of glycogen to glucose.

Hepatic insulin sensitivity

The degree to which insulin suppresses glucose production by the liver.

Glucose tolerance test

(GTT). A test that measures the glucose excursion after a bolus administration of glucose; it is an index of the body's ability to tolerate and/or handle a glucose load.

Insulin tolerance tests

Tests that measure the fall in glucose levels after an injection of a bolus of insulin.

Whole-body insulin sensitivity

The degree to which the body responds to insulin; it is usually assessed by comparing the glucose infusion rate during a hyperinsulinaemic–euglcyaemic clamp in control versus experimental animals.

Mass action of glucose

Refers to glucose uptake into tissues, which is driven by how much glucose there is in the blood.

Insulin resistance

A metabolic state in which the tissues of the body exhibit reduced responsiveness to chronically high levels of insulin in the circulation.

Negative-feedback proteins

Proteins that suppress signalling by other molecules.

Leptin resistance

A state in which the body is no longer responsive to the anorexic effect of exogenous leptin.

Nodose ganglia

Inferior ganglia of the vagus nerve.

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Grayson, B., Seeley, R. & Sandoval, D. Wired on sugar: the role of the CNS in the regulation of glucose homeostasis. Nat Rev Neurosci 14, 24–37 (2013). https://doi.org/10.1038/nrn3409

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