Central nervous system control of food intake and body weight


The capacity to adjust food intake in response to changing energy requirements is essential for survival. Recent progress has provided an insight into the molecular, cellular and behavioural mechanisms that link changes of body fat stores to adaptive adjustments of feeding behaviour. The physiological importance of this homeostatic control system is highlighted by the severe obesity that results from dysfunction of any of several of its key components. This new information provides a biological context within which to consider the global obesity epidemic and identifies numerous potential avenues for therapeutic intervention and future research.

Figure 1: Model for negative-feedback regulation of food intake in response to changes in body fat content.
Figure 2: Model for integration of adiposity- and satiety-related inputs.
Figure 3: Model for integration of adiposity- and reward-related inputs.
Figure 4: Hypothalamic neurocircuits and signal transduction mechanisms involved in energy homeostasis.


  1. 1

    Sims, E. A. et al. Endocrine and metabolic effects of experimental obesity in man. Recent Prog. Horm. Res. 29, 457–496 (1973)

    CAS  PubMed  Google Scholar 

  2. 2

    Leibel, R. L., Rosenbaum, M. & Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332, 621–628 (1995)

    CAS  Article  Google Scholar 

  3. 3

    Kennedy, G. The role of depot fat in the hypothalamic control of food intake in the rat. Proc. R. Soc. Lond. B 140, 578–592 (1953)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Schwartz, M. W., Woods, S. C., Porte, D. Jr, Seeley, R. J. & Baskin, D. G. Central nervous system control of food intake. Nature 404, 661–671 (2000)

    CAS  Article  Google Scholar 

  5. 5

    Garofalo, R. S. Genetic analysis of insulin signaling in Drosophila. Trends Endocrinol. Metab. 13, 156–162 (2002)

    CAS  Article  Google Scholar 

  6. 6

    Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997)

    CAS  Article  Google Scholar 

  7. 7

    Doyon, C., Drouin, G., Trudeau, V. L. & Moon, T. W. Molecular evolution of leptin. Gen. Comp. Endocrinol. 124, 188–198 (2001)

    CAS  Article  Google Scholar 

  8. 8

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

    ADS  CAS  Article  Google Scholar 

  9. 9

    Farooqi, I. S. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884 (1999)

    CAS  Article  Google Scholar 

  10. 10

    Heymsfield, S. B. et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. J. Am. Med. Assoc. 282, 1568–1575 (1999)

    CAS  Article  Google Scholar 

  11. 11

    De Souza, C. T. et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146, 4192–4199 (2005)

    CAS  Article  Google Scholar 

  12. 12

    Munzberg, H., Flier, J. S. & Bjorbaek, C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 145, 4880–4889 (2004)

    Article  Google Scholar 

  13. 13

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

    ADS  CAS  Article  Google Scholar 

  14. 14

    Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001)

    CAS  Article  Google Scholar 

  15. 15

    Batterham, R. L. et al. Gut hormone PYY3–36 physiologically inhibits food intake. Nature 418, 650–654 (2002)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Cummings, D. E. et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50, 1714–1719 (2001)

    CAS  Article  Google Scholar 

  17. 17

    Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Wren, A. M. et al. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992 (2001)

    CAS  Article  Google Scholar 

  20. 20

    Cummings, D. E. et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N. Engl. J. Med. 346, 1623–1630 (2002)

    Article  Google Scholar 

  21. 21

    Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Leibowitz, S. F. & Alexander, J. T. Hypothalamic serotonin in control of eating behaviour, meal size, and body weight. Biol. Psychiatry 44, 851–864 (1998)

    CAS  Article  Google Scholar 

  23. 23

    Leibowitz, S. F., Roossin, P. & Rosenn, M. Chronic norepinephrine injection into the hypothalamic paraventricular nucleus produces hyperphagia and increased body weight in the rat. Pharmacol. Biochem. Behav. 21, 801–808 (1984)

    CAS  Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

    Loftus, T. M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000)

    ADS  CAS  Article  Google Scholar 

  26. 26

    He, W., Lam, T. K., Obici, S. & Rossetti, L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nature Neurosci. 9, 227–233 (2006)

    CAS  Article  Google Scholar 

  27. 27

    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  Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

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

    ADS  CAS  Article  Google Scholar 

  30. 30

    Strubbe, J. H. & Woods, S. C. The timing of meals. Psychol. Rev. 111, 128–141 (2004)

    Article  Google Scholar 

  31. 31

    Gibbs, J., Young, R. C. & Smith, G. P. Cholecystokinin decreases food intake in rats. J. Comp. Physiol. Psychol. 84, 488–495 (1973)

    CAS  Article  Google Scholar 

  32. 32

    Emond, M., Schwartz, G. J., Ladenheim, E. E. & Moran, T. H. Central leptin modulates behavioural and neural responsivity to CCK. Am. J. Physiol. 276, R1545–R1549 (1999)

    CAS  PubMed  Google Scholar 

  33. 33

    Morton, G. J. et al. Leptin action in the forebrain regulates the hindbrain response to satiety signals. J. Clin. Invest. 115, 703–710 (2005)

    CAS  Article  Google Scholar 

  34. 34

    Grill, H. J. et al. Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 143, 239–246 (2002)

    CAS  Article  Google Scholar 

  35. 35

    Elmquist, J. K., Bjorbaek, C., Ahima, R. S., Flier, J. S. & Saper, C. B. Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395, 535–547 (1998)

    CAS  Article  Google Scholar 

  36. 36

    Blevins, J. E., Schwartz, M. W. & Baskin, D. G. Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brainstem nuclei controlling meal size. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R87–R96 (2004)

    CAS  Article  Google Scholar 

  37. 37

    Kelley, A. E., Baldo, B. A., Pratt, W. E. & Will, M. J. Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward. Physiol. Behav. 86, 773–795 (2005)

    CAS  Article  Google Scholar 

  38. 38

    Rolls, E. T. Taste, olfactory, and food texture processing in the brain, and the control of food intake. Physiol. Behav. 85, 45–56 (2005)

    CAS  Article  Google Scholar 

  39. 39

    Kringelbach, M. L., O'Doherty, J., Rolls, E. T. & Andrews, C. Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness. Cereb. Cortex 13, 1064–1071 (2003)

    CAS  Article  Google Scholar 

  40. 40

    Kelley, A. E. & Berridge, K. C. The neuroscience of natural rewards: relevance to addictive drugs. J. Neurosci. 22, 3306–3311 (2002)

    CAS  Article  Google Scholar 

  41. 41

    Stuber, G. D., Evans, S. B., Higgins, M. S., Pu, Y. & Figlewicz, D. P. Food restriction modulates amphetamine-conditioned place preference and nucleus accumbens dopamine release in the rat. Synapse 46, 83–90 (2002)

    CAS  Article  Google Scholar 

  42. 42

    Carroll, M. E., France, C. P. & Meisch, R. A. Food deprivation increases oral and intravenous drug intake in rats. Science 205, 319–321 (1979)

    ADS  CAS  Article  Google Scholar 

  43. 43

    Fulton, S., Woodside, B. & Shizgal, P. Modulation of brain reward circuitry by leptin. Science 287, 125–128 (2000)

    ADS  CAS  Article  Google Scholar 

  44. 44

    Figlewicz, D. P. et al. Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats. Behav. Neurosci. 118, 479–487 (2004)

    CAS  Article  Google Scholar 

  45. 45

    Figlewicz, D. P. Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R882–R892 (2003)

    CAS  Article  Google Scholar 

  46. 46

    Flier, J. S. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350 (2004)

    CAS  Article  Google Scholar 

  47. 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  Article  Google Scholar 

  48. 48

    Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997)

    ADS  CAS  Article  Google Scholar 

  49. 49

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

    ADS  CAS  Article  Google Scholar 

  50. 50

    Thornton, J. E., Cheung, C. C., Clifton, D. K. & Steiner, R. A. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138, 5063–5066 (1997)

    CAS  Article  Google Scholar 

  51. 51

    Shutter, J. R. et al. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 11, 593–602 (1997)

    CAS  Article  Google Scholar 

  52. 52

    Yaswen, L., Diehl, N., Brennan, M. B. & Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nature Med. 5, 1066–1070 (1999)

    CAS  Article  Google Scholar 

  53. 53

    Seeley, R. J. et al. Melanocortin receptors in leptin effects. Nature 390, 349 (1997)

    ADS  CAS  Article  Google Scholar 

  54. 54

    Erickson, J., Clegg, K. & Palmiter, R. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381, 415–418 (1996)

    ADS  CAS  Article  Google Scholar 

  55. 55

    Qian, S. et al. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol. Cell. Biol. 22, 5027–5035 (2002)

    CAS  Article  Google Scholar 

  56. 56

    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)

    ADS  CAS  Article  Google Scholar 

  57. 57

    Gropp, E. et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nature Neurosci. 8, 1289–1291 (2005)

    CAS  Article  Google Scholar 

  58. 58

    Bewick, G. A. et al. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 19, 1680–1682 (2005)

    CAS  Article  Google Scholar 

  59. 59

    Xu, A. W. et al. Effects of hypothalamic neurodegeneration on energy balance. PLoS Biol. 3, e415 (2005)

    Article  Google Scholar 

  60. 60

    Lambert, P. D. et al. Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc. Natl Acad. Sci. USA 98, 4652–4657 (2001)

    ADS  CAS  Article  Google Scholar 

  61. 61

    Kokoeva, M. V., Yin, H. & Flier, J. S. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310, 679–683 (2005)

    ADS  CAS  Article  Google Scholar 

  62. 62

    Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nature Rev. Mol. Cell Biol. 7, 85–96 (2006)

    CAS  Article  Google Scholar 

  63. 63

    Bjorbaek, C., Uotani, S., da Silva, B. & Flier, J. S. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J. Biol. Chem. 272, 32686–32695 (1997)

    CAS  Article  Google Scholar 

  64. 64

    Xu, A. W. et al. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J. Clin. Invest. 115, 951–958 (2005)

    CAS  Article  Google Scholar 

  65. 65

    Niswender, K. D. et al. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413, 794–795 (2001)

    ADS  CAS  Article  Google Scholar 

  66. 66

    Niswender, K. D. et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52, 227–231 (2003)

    CAS  Article  Google Scholar 

  67. 67

    Kitamura, T. et al. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nature Med. 12, 534–540 (2006)

    CAS  Article  Google Scholar 

  68. 68

    Spanswick, D., Smith, M. A., Mirshamsi, S., Routh, V. H. & Ashford, M. L. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nature Neurosci. 3, 757–758 (2000)

    CAS  Article  Google Scholar 

  69. 69

    Choudhury, A. I. et al. The role of insulin receptor substrate 2 in hypothalamic and β cell function. J. Clin. Invest. 115, 940–950 (2005)

    CAS  Article  Google Scholar 

  70. 70

    van den Top, M., Lee, K., Whyment, A. D., Blanks, A. M. & Spanswick, D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nature Neurosci. 7, 493–494 (2004)

    CAS  Article  Google Scholar 

  71. 71

    Jaworski, J., Spangler, S., Seeburg, D. P., Hoogenraad, C. C. & Sheng, M. Control of dendritic arborization by the phosphoinositide-3′-kinase–Akt–mammalian target of rapamycin pathway. J. Neurosci. 25, 11300–11312 (2005)

    CAS  Article  Google Scholar 

  72. 72

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

    CAS  Article  Google Scholar 

  73. 73

    Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004)

    ADS  CAS  Article  Google Scholar 

  74. 74

    Sternson, S. M., Shepherd, G. M. & Friedman, J. M. Topographic mapping of VMH → arcuate nucleus microcircuits and their reorganization by fasting. Nature Neurosci. 8, 1356–1363 (2005)

    CAS  Article  Google Scholar 

  75. 75

    Berthoud, H. R. Mind versus metabolism in the control of food intake and energy balance. Physiol. Behav. 81, 781–793 (2004)

    CAS  Article  Google Scholar 

Download references


This work was supported by NIH grants, the Diabetes Endocrinology Research Center and Clinical Nutrition Research Unit of the University of Washington, and by a grant from the Murdock Charitable Trust. We acknowledge assistance in manuscript preparation provided by C. Balach; discussions with research fellows and faculty at the University of Washington; and wisdom gained from a conference on feeding behaviour held at the Banbury Center, New York, in May 2006.

Author information



Corresponding author

Correspondence to M. W. Schwartz.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Morton, G., Cummings, D., Baskin, D. et al. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006). https://doi.org/10.1038/nature05026

Download citation

Further reading


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.


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