Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Central nervous system control of metabolism

Nature volume 491, pages 357–363 (2012)Cite this article

Subjects

Abstract

Although it is a widely held thought that direct hormone action on peripheral tissues is sufficient to mediate the control of nutrient handling, the role of the central nervous system in certain aspects of metabolism has long been recognized. Furthermore, recent findings have suggested a more general role for the central nervous system in metabolic control, and have revealed the importance of a number of cues and hypothalamic circuits. The brain's contributions to metabolic control are more readily revealed and play a crucial part in catabolic states or in hormone deficiencies that mimic starvation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hypothalamic pathways in the control of metabolism.
Figure 2: Cellular signalling pathways modulated by leptin and insulin.
Figure 3: CNS melanocortin action.

Similar content being viewed by others

References

  1. Levin, B. E. Neuronal glucose sensing: still a physiological orphan? Cell Metab. 6, 252–254 (2007).

    CAS  PubMed  Google Scholar 

  2. Levin, B. E. & Sherwin, R. S. Peripheral glucose homeostasis: does brain insulin matter? J. Clin. Invest. 121, 3392–3395 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain–liver circuit regulates glucose homeostasis. Cell Metab. 1, 53–61 (2005).

    CAS  PubMed  Google Scholar 

  4. Taborsky, G. J. Jr. Islets have a lot of nerve! Or do they? Cell Metab. 14, 5–6 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Wiesli, P. et al. Acute psychological stress affects glucose concentrations in patients with type 1 diabetes following food intake but not in the fasting state. Diabetes Care 28, 1910–1915 (2005).

    PubMed  Google Scholar 

  6. McCowen, K. C., Malhotra, A. & Bistrian, B. R. Stress-induced hyperglycemia. Crit. Care Clin. 17, 107–124 (2001).

    CAS  PubMed  Google Scholar 

  7. 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)

    CAS  PubMed  Google Scholar 

  8. Evans, M. L. & Sherwin, R. S. Blood glucose and the brain in diabetes: between a rock and a hard place? Curr. Diab. Rep. 2, 101–102 (2002).

    PubMed  Google Scholar 

  9. Ritter, S., Li, A. J., Wang, Q. & Dinh, T. T. The value of looking backward: the essential role of the hindbrain in counter regulatory responses to glucose deficit. Endocrinology 152, 4019–4032 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Schwartz, M. W. & Porte, D. Jr. Diabetes, obesity, and the brain. Science 307, 375–379 (2005).

    ADS  CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  12. Rossetti, L. et al. Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J. Biol. Chem. 272, 27758–27763 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Ahima, R. S. Central actions of adipocyte hormones. Trends Endocrinol. Metab. 16, 307–313 (2005).

    CAS  PubMed  Google Scholar 

  18. D'Alessio, D. A., Sandoval, D. A. & Seeley, R. J. New ways in which GLP-1 can regulate glucose homeostasis. J. Clin. Invest. 115, 3406–3408 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Briggs, D. I. & Andrews, Z. B. Metabolic status regulates ghrelin function on energy homeostasis. Neuroendocrinology 93, 48–57 (2011).

    CAS  PubMed  Google Scholar 

  20. Heppner, K. M., Tong, J., Kirchner, H., Nass, R. & Tschop, M. H. The ghrelin O-acyltransferase-ghrelin system: a novel regulator of glucose metabolism. Curr. Opin. Endocrinol. Diabetes Obes. 18, 50–55 (2011).

    CAS  PubMed  Google Scholar 

  21. Kleinridders, A., Konner, A. C. & Bruning, J. C. CNS-targets in control of energy and glucose homeostasis. Curr. Opin. Pharmacol. 9, 794–804 (2009).

    CAS  PubMed  Google Scholar 

  22. Hribal, M. L., Oriente, F. & Accili, D. Mouse models of insulin resistance. Am. J. Physiol. Endocrinol. Metab. 282, E977–E981 (2002).

    CAS  PubMed  Google Scholar 

  23. Williams, K. W., Scott, M. M. & Elmquist, J. K. Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in a dispersed neuronal network. Eur. J. Pharmacol. 660, 2–12 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  25. Pocai, A., Muse, E. D. & Rossetti, L. Did a muscle fuel gauge conquer the brain? Nature Med. 12, 50–51 (2006).

    CAS  PubMed  Google Scholar 

  26. Cota, D. et al. Hypothalamic mTOR signaling regulates food intake. Science 312, 927–930 (2006).

    ADS  CAS  PubMed  Google Scholar 

  27. Diano, S. & Horvath, T. L. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol. Med. 18, 52–58 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  29. Vanpatten, S., Karkanias, G. B., Rossetti, L. & Cohen, D. E. Intracerebroventricular leptin regulates hepatic cholesterol metabolism. Biochem. J. 379, 229–233 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nogueiras, R. et al. The central melanocortin system directly controls peripheral lipid metabolism. J. Clin. Invest. 117, 3475–3488 (2007). Using pharmacological and genetic approaches in rodents, this article demonstrates a role for endogenous CNS melanocortin action in the control of whole-body lipid metabolism.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Burdakov, D. & Alexopoulos, H. Metabolic state signalling through central hypocretin/orexin neurons. J. Cell. Mol. Med. 9, 795–803 (2005).

    PubMed  PubMed Central  Google Scholar 

  32. Myers, M. G. Jr, Munzberg, H., Leinninger, G. M. & Leshan, R. L. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab. 9, 117–123 (2009). This review highlights the idea that most LRb neurons in the brain are distinct from the canonical pro-opiomelanocortin and AgRP neurons and lie outside the arcuate nucleus.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    ADS  CAS  PubMed  Google Scholar 

  34. Sadagurski, M. et al. IRS2 signaling in LepR-b neurons suppresses Foxo1 to control energy balance independently of leptin action. Cell Metab. 15, 703–712 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Taguchi, A., Wartschow, L. M. & White, M. F. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369–372 (2007).

    ADS  CAS  PubMed  Google Scholar 

  36. Patterson, C. M. et al. Leptin action via LepR-b Tyr1077 contributes to the control of energy balance and female reproduction. Mol. Metab. http://dx.doi.org/10.1016/j.molmet.2012.05.001 (25 July 2012).

  37. Bates, S. H. et al. STAT3 signaling is required for leptin regulation of energy balance but not reproduction. Nature 421, 856–859 (2003).

    ADS  CAS  PubMed  Google Scholar 

  38. Buettner, C. et al. Critical role of STAT3 in leptin's metabolic actions. Cell Metab. 4, 49–60 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Robertson, S. et al. Insufficiency of Janus kinase 2-autonomous leptin receptor signals for most physiologic leptin actions. Diabetes 59, 782–790 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Jiang, L. et al. Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis. Proc. Natl Acad. Sci. USA 105, 18619–18624 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Barnes, M. B., Lawson, M. A. & Beverly, J. L. Rate of fall in blood glucose and recurrent hypoglycemia affect glucose dynamics and noradrenergic activation in the ventromedial hypothalamus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1815–R1820 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Levin, B. E., Magnan, C., Dunn-Meynell, A. & Le Foll, C. Metabolic sensing and the brain: who, what, where, and how? Endocrinology 152, 2552–2557 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chan, O., Lawson, M., Zhu, W., Beverly, J. L. & Sherwin, R. S. ATP-sensitive K+ channels regulate the release of GABA in the ventromedial hypothalamus during hypoglycemia. Diabetes 56, 1120–1126 (2007).

    CAS  PubMed  Google Scholar 

  44. Kang, L. et al. Glucokinase is a critical regulator of ventromedial hypothalamic neuronal glucosensing. Diabetes 55, 412–420 (2006).

    CAS  PubMed  Google Scholar 

  45. Elias, C. F. et al. Chemical characterization of leptin-activated neurons in the rat brain. J. Comp. Neurol. 423, 261–281 (2000).

    CAS  PubMed  Google Scholar 

  46. Haque, M. S. et al. Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats. Diabetes 48, 1706–1712 (1999).

    CAS  PubMed  Google Scholar 

  47. 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).

    CAS  PubMed  Google Scholar 

  48. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    PubMed  Google Scholar 

  50. Kim, K. W. et al. FOXO1 in the ventromedial hypothalamus regulates energy balance. J. Clin. Invest. 122, 2578–2589 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Bergen, H. T., Mizuno, T. M., Taylor, J. & Mobbs, C. V. Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin. Endocrinology 139, 4483–4488 (1998).

    CAS  PubMed  Google Scholar 

  52. Coppari, R. et al. The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metab. 1, 63–72 (2005). This article reports the reactivation of LRb specifically in the arcuate nucleus; although this only slightly altered food intake and adiposity, glucose homeostasis was markedly improved, suggesting an important role for arcuate-nucleus leptin action in the control of glucose homeostasis independently of energy balance.

    CAS  PubMed  Google Scholar 

  53. Morton, G. J. et al. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fak/fak) rats. Endocrinology 144, 2016–2024 (2003).

    CAS  PubMed  Google Scholar 

  54. Morton, G. J. et al. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab. 2, 411–420 (2005). Using molecular–viral and pharmacological approaches, the authors show that insulin-dependent signalling pathways in the arcuate nucleus are crucial for the control of glucose homeostasis by leptin.

    CAS  PubMed  Google Scholar 

  55. Schwartz, M. W. Central nervous system regulation of food intake. Obesity (Silver Spring) 14, 1S–8S (2006).

    ADS  CAS  Google Scholar 

  56. Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 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).

    CAS  PubMed  Google Scholar 

  59. Padilla, S. L., Carmody, J. S. & Zeltser, L. M. Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nature Med. 16, 403–405 (2010).

    CAS  PubMed  Google Scholar 

  60. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Huo, L. et al. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 9, 537–547 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Hill, J. W. et al. Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology 150, 4874–4882 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Perez-Tilve, D. et al. Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nature Neurosci. 13, 877–882 (2010).

    CAS  PubMed  Google Scholar 

  64. Shrestha, Y. B. et al. Central melanocortin stimulation increases phosphorylated perilipin A and hormone-sensitive lipase in adipose tissues. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R140–R149 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  66. Ste, M. L., Miura, G. I., Marsh, D. J., Yagaloff, K. & Palmiter, R. D. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc. Natl Acad. Sci. USA 97, 12339–12344 (2000).

    ADS  Google Scholar 

  67. Butler, A. A. et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141, 3518–3521 (2000).

    CAS  PubMed  Google Scholar 

  68. Sutton, G. M. et al. Diet–genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors. Endocrinology 147, 2183–2196 (2006).

    CAS  PubMed  Google Scholar 

  69. Chen, A. S. et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet. 26, 97–102 (2000).

    CAS  PubMed  Google Scholar 

  70. Butler, A. A. The melanocortin system and energy balance. Peptides 27, 281–290 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  72. de Backer, M. W. et al. Melanocortin receptor-mediated effects on obesity are distributed over specific hypothalamic regions. Int. J. Obes. (Lond.) 35, 629–641 (2011).

    CAS  Google Scholar 

  73. Cherrington, A. D. The role of hepatic insulin receptors in the regulation of glucose production. J. Clin. Invest. 115, 1136–1139 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S. & Goldstein, J. L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73–76 (1999).

    ADS  CAS  PubMed  Google Scholar 

  75. Oral, E. A. et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346, 570–578 (2002).

    CAS  PubMed  Google Scholar 

  76. Wang, M. Y. et al. Leptin therapy in insulin-deficient type I diabetes. Proc. Natl Acad. Sci. USA 107, 4813–4819 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  77. German, J. P. et al. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 59, 1626–1634 (2010). In this article, the authors show that brain leptin injection — in the absence of endogenous or exogenous insulin — suffices to normalize blood glucose.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Williams, D. L., Kaplan, J. M. & Grill, H. J. The role of the dorsal vagal complex and the vagus nerve in feeding effects of melanocortin-3/4 receptor stimulation. Endocrinology 141, 1332–1337 (2000).

    CAS  PubMed  Google Scholar 

  80. Boghossian, S., Park, M. & York, D. A. Melanocortin activity in the amygdala controls appetite for dietary fat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R385–R393 (2010).

    CAS  PubMed  Google Scholar 

  81. Balthasar, N. et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493–505 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Begriche, K. et al. Melanocortin-3 receptors are involved in adaptation to restricted feeding. Genes Brain Behav. 11, 291–302 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank members of the Myers and Olson laboratories for discussions and scientific insight. M.G.M. is supported by the Marilyn H. Vincent Foundation and by grants from the National Institutes of Health and the American Heart Association.

Author information

Authors and Affiliations

  1. Division of Metabolism, Department of Internal Medicine, Endocrinology and Diabetes, University of Michigan, Ann Arbor, 48105, Michigan, USA

    Martin G. Myers Jr

  2. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, 48105, Michigan, USA

    Martin G. Myers Jr

  3. Neuroscience Program, University of Michigan, Ann Arbor, 48105, Michigan, USA

    Martin G. Myers Jr

  4. Division of Endocrinology, Department of Pediatrics, University of Michigan, Ann Arbor, 48105, Michigan, USA

    David P. Olson

Authors
  1. Martin G. Myers Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David P. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin G. Myers Jr.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Myers, M., Olson, D. Central nervous system control of metabolism. Nature 491, 357–363 (2012). https://doi.org/10.1038/nature11705

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11705

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing