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The hardship of obesity: a soft-wired hypothalamus

Nature Neuroscience volume 8, pages 561–565 (2005)Cite this article

Abstract

Food intake and energy expenditure are determinants of metabolic phenotype and are regulated by the CNS. Although humans have a well-balanced homeostatic feedback loop, obesity and metabolic disorders are spreading rapidly and carry a heavy toll of morbidity and mortality. The past decade has witnessed major advances in the understanding of basic metabolic processes, the brain circuitry that determines appropriate and, but, inappropriate behavioral and humoral responses to changing metabolic cues remains largely ill defined. This review summarizes current knowledge of the brain anatomy that supports food intake and energy expenditure and discusses cellular mechanisms such as synaptic plasticity that may provide clues toward the development of successful central therapies to combat metabolic disorders, including obesity and diabetes.

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Figure 1: Schematic of three hypothalamic peptidergic systems, which show rapid synaptic perikaryal remodeling in response to peripheral metabolic changes.
Figure 2: Schematic showing relative changes in body weight and food intake in wild-type (yellow), ob/ob PBS-replaced (red) and ob/ob leptin-replaced (purple) mice.

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References

  1. Friedman, J.M. & Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    Article  CAS  Google Scholar 

  2. Elmquist, J.K., Elias, C.F. & Saper, C.B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221–232 (1999).

    Article  CAS  Google Scholar 

  3. Kalra, S.P. et al. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20, 68–100 (1999).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  5. Sherrington, C. Sir . Cutaneous sensation. in Textbook of Physiology (ed. Sharpey-Schaefer, E.A.) 920–1001 (Pentland, Edinburgh, 1900).

    Google Scholar 

  6. Cannon, W.B. & Washburn, A.L. An explanation of hunger. Am. J. Physiol. 29, 441 (1912).

    Article  Google Scholar 

  7. Carlson, A.J. in Control of Hunger in Health and Disease 2nd impr. (Univ. of Chicago Press, Chicago, 1916).

    Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Campfield, L.A., Smith, F.J., Guisez, Y., Devos, R. & Burn, P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549 (1995).

    Article  CAS  Google Scholar 

  12. Tartaglia, L.A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).

    Article  CAS  Google Scholar 

  13. Mercer, J.G. et al. Localization of leptin receptor mRNA and the long splice variant (O-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 387, 113–116 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. Pelletier, G. & Dube, D. Electron microscopic immunohistochemical localization of α-msh in the rat brain. Am. J. Anat. 150, 201–205 (1977).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Ollmann, M.M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Elias, C.F. et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786 (1999).

    Article  CAS  Google Scholar 

  22. 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  Google Scholar 

  23. Horvath, T.L., Naftolin, F., Kalra, S.P. & Leranth, C. Neuropeptide-Y innervation of beta-endorphin-containing cells in the rat mediobasal hypothalamus: a light and electron microscopic double immunostaining analysis. Endocrinology 131, 2461–2467 (1992).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Cowley, M.A. Hypothalamic melanocortin neurons integrate signals of energy state. Eur. J. Pharmacol. 480, 3–11 (2003).

    Article  CAS  Google Scholar 

  26. Broberger, C., Johansen, J., Johansson, C., Schalling, M. & Hokfelt, T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc. Natl. Acad. Sci. USA 95, 15043–15048 (1998).

    Article  CAS  Google Scholar 

  27. Mezey, E. et al. Distribution of the pro-opiomelanocortin derived peptides, adrenocorticotrope hormone, α-melanocyte-stimulating hormone and β-endorphin (ACTH, α-MSH, β-END) in the rat hypothalamus. Brain Res. 328, 341–347 (1985).

    Article  CAS  Google Scholar 

  28. Elias, C.F. et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21, 1375–1385 (1998).

    Article  CAS  Google Scholar 

  29. Qu, D. et al. A role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature 380, 243–247 (1996).

    Article  CAS  Google Scholar 

  30. Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).

    Article  CAS  Google Scholar 

  31. Theodosis, D.T. & Poulain, D.A. Evidence for structural plasticity in the supraoptic nucleus of the rat hypothalamus in relation to gestation and lactation. Neuroscience 11, 183–193 (1984).

    Article  CAS  Google Scholar 

  32. Garcia-Segura, L.M., Baetens, D. & Naftolin, F. Synaptic remodelling in arcuate nucleus after injection of estradiol valerate in adult female rats. Brain Res. 366, 131–136 (1986).

    Article  CAS  Google Scholar 

  33. Horvath, T.L. & Gao, X.B. Input organization and plasticity of hypocretin neurons: possible clues for obesity's association with insomnia. Cell Metabolism 1, 279–286 (2005).

    Article  CAS  Google Scholar 

  34. Horvath, T.L. & Diano, S. The floating blueprint of hypothalamic feeding circuits. Nat. Rev. Neurosci. 5, 662–667 (2004).

    Article  CAS  Google Scholar 

  35. Grill, H.J. & Kaplan, J.M. The neuroanatomical axis for control of energy balance. Front. Neuroendocrinol. 23, 2–40 (2002).

    Article  CAS  Google Scholar 

  36. Bodosi, B. et al. Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R1071–R1079 (2004).

    Article  CAS  Google Scholar 

  37. Bouret, S.G., Draper, S.J. & Simerly, R.B. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110 (2004).

    Article  CAS  Google Scholar 

  38. Chemelli, R.M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999).

    Article  CAS  Google Scholar 

  39. Yamanaka, A. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713 (2003).

    Article  CAS  Google Scholar 

  40. Li, Y., Gao, X.B., Sakurai, T. & van den Pol, A.N. Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system. Neuron 36, 1169–1181 (2002).

    Article  CAS  Google Scholar 

  41. Shepherd, G.M. Introduction to synaptic circuits. in The Synaptic Organization of the Brain. (ed. Shepherd, G.M.) 1–38 (Oxford Univ. Press, New York, 2004).

    Chapter  Google Scholar 

  42. Taheri, S., Lin, L., Austin, D., Young, T., Mignot, E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med., published online 7 December 2004 (10.1371/journal.pmed.0010062).

  43. Spiegel, K., Tasali, E., Penev, P. & Van Cauter, E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann. Intern. Med. 141, 846–850 (2004).

    Article  Google Scholar 

  44. Flier, J.S. & Elmquist, J.K. A good night's sleep: future antidote to the obesity epidemic? Ann. Intern. Med. 141, 885–886 (2004).

    Article  Google Scholar 

  45. Pittenger, C. & Kandel, E.R. In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. Phil. Trans. R. Soc. Lond. B 358, 757–763 (2003).

    Article  Google Scholar 

  46. Malenka, R.C. & Bear, M.F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

    Article  CAS  Google Scholar 

  47. Cooke, S.F. & Bliss, T.V. Long-term potentiation and cognitive drug discovery. Curr. Opin. Investig. Drugs 6, 25–34 (2005).

    CAS  PubMed  Google Scholar 

  48. Schally, A.V. et al. Basic and clinical studies with luteinizing hormone-releasing hormone (LH-RH) and its analogues. J. Reprod. Fertil. Suppl. 20, 119–136 (1973).

    CAS  PubMed  Google Scholar 

  49. Pfaff, D.W. et al. GnRH neurons and other cellular and molecular mechanisms for simple mammalian reproductive behaviors. Recent Prog. Horm. Res. 49, 1–25 (1994).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The work of T.L.H. on the relationship between synaptic plasticity and energy metabolism has been supported by National Institutes of Health grants DK-060711 and RR-014451.

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  1. Department of Obstetrics, Gynecology & Reproductive Sciences and the Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06510, Connecticut, USA

    Tamas L Horvath

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Horvath, T. The hardship of obesity: a soft-wired hypothalamus. Nat Neurosci 8, 561–565 (2005). https://doi.org/10.1038/nn1453

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