Review Article | Published:

Central nervous system control of food intake and body weight

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

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

  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)

  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)

  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)

  5. 5

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

  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)

  7. 7

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

  8. 8

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

  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)

  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)

  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)

  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)

  13. 13

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

  14. 14

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

  15. 15

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

  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)

  17. 17

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

  18. 18

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

  19. 19

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

  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)

  21. 21

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

  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)

  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)

  24. 24

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

  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)

  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)

  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)

  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)

  29. 29

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

  30. 30

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

  31. 31

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

  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)

  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)

  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)

  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)

  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)

  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)

  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)

  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)

  40. 40

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

  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)

  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)

  43. 43

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

  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)

  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)

  46. 46

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

  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)

  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)

  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)

  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)

  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)

  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)

  53. 53

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

  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)

  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)

  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)

  57. 57

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

  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)

  59. 59

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

  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)

  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)

  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)

  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)

  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)

  65. 65

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

  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)

  67. 67

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

  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)

  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)

  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)

  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)

  72. 72

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

  73. 73

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

  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)

  75. 75

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

Download references

Acknowledgements

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

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

Further reading

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.

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.