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Molecular and anatomical determinants of central leptin resistance

Nature Neuroscience volume 8, pages 566–570 (2005)Cite this article

Abstract

The increasing incidence of obesity in developed nations is an ever-growing challenge to health care, promoting diabetes and other diseases. The hormone leptin, which is derived from adipose tissue, regulates feeding and energy expenditure. Most forms of obesity are associated with diminished responsiveness to the appetite-suppressing effects of leptin. Here we review the mechanisms by which leptin activates intracellular signals, the roles of these signals in leptin action in vivo, and mechanisms that may attenuate leptin signaling, limiting its action in obese individuals. We highlight data regarding the expression of SOCS3 (a potential mediator of leptin resistance) in the arcuate nucleus of the hypothalamus.

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Figure 1: LRb signaling and proposed role for SOCS3 in LRb signal attenuation.

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. Bates, S.H. & Myers, M.G., Jr. The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrinol. Metab. 14, 447–452 (2003).

    Article  CAS  Google Scholar 

  4. Farooqi, I.S. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 110, 1093–1103 (2002).

    Article  CAS  Google Scholar 

  5. Kamohara, S., Burcelin, R., Halaas, J.L., Friedman, J.M. & Charron, M.J. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389, 374–377 (1997).

    Article  CAS  Google Scholar 

  6. Burcelin, R. et al. Acute intravenuous leptin infusion increases glucose turnover but not skeletal muscle glucose uptake in ob/ob mice. Diabetes 48, 1264–1269 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Schwartz, M.W. et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45, 531–535 (1996).

    Article  CAS  Google Scholar 

  9. Tartaglia, L.A. The leptin receptor. J. Biol. Chem. 272, 6093–6096 (1997).

    Article  CAS  Google Scholar 

  10. Kloek, C. et al. Regulation of Jak kinases by intracellular leptin receptor sequences. J. Biol. Chem. 277, 41547–41555 (2002).

    Article  CAS  Google Scholar 

  11. 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 

  12. 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 

  13. Butler, A.A. & Cone, R.D. The melanocortin receptors: lessons from knockout models. Neuropeptides 36, 77–84 (2002).

    Article  CAS  Google Scholar 

  14. 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 

  15. 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).

    Article  CAS  Google Scholar 

  16. Coppari, R. et al. The hypothalamic arcuate nucleus: A key site for mediating leptin's effects on glucose metabolism and locomotor activity. Cell Metabolism 1, 63–72 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Ihle, J.N. & Kerr, I.M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 11, 69–74 (1995).

    Article  CAS  Google Scholar 

  19. White, D.W., Kuropatwinski, K.K., Devos, R., Baumann, H. & Tartaglia, L.A. Leptin receptor (OB-R) signaling. J. Biol. Chem. 272, 4065–4071 (1997).

    Article  CAS  Google Scholar 

  20. Banks, A.S., Davis, S.M., Bates, S.H. & Myers, M.G., Jr. Activation of downstream signals by the long form of the leptin receptor. J. Biol. Chem. 275, 14563–14572 (2000).

    Article  CAS  Google Scholar 

  21. Bjorbaek, C. et al. Divergent roles of SHP-2 in ERK activation by leptin receptors. J. Biol. Chem. 276, 4747–4755 (2001).

    Article  CAS  Google Scholar 

  22. Bjorbaek, C. et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J. Biol. Chem. 275, 40649–40657 (2000).

    Article  CAS  Google Scholar 

  23. Munzberg, H., Huo, L., Nillni, E.A., Hollenberg, A.N. & Bjorbaek, C. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelano–cortin gene expression by leptin. Endocrinology 144, 2121–2131 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Sasaki, A. et al. CIS3/SOCS3 suppresses erythropoietin signaling by binding the EPO receptor and JAK2. J. Biol. Chem. (2000).

  26. Dunn, S.L. et al. Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and SOCS3. Mol. Endocrinol. (2004).

  27. Feng, J. et al. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. Mol. Cell. Biol. 17, 2497–2501 (1997).

    Article  CAS  Google Scholar 

  28. Carpino, N. et al. Identification, cDNA cloning, and targeted deletion of p70, a novel, ubiquitously expressed SH3 domain-containing protein. Mol. Cell. Biol. 22, 7491–7500 (2002).

    Article  CAS  Google Scholar 

  29. Argetsinger, L.S. et al. Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity. Mol. Cell. Biol. 24, 4955–4967 (2004).

    Article  CAS  Google Scholar 

  30. Feener, E.P., Rosario, F., Dunn, S.L., Stancheva, Z. & Myers, M.G., Jr. Tyrosine phosphorylation of Jak2 in the JH2 domain inhibits cytokine signaling. Mol. Cell. Biol. 24, 4968–4978 (2004).

    Article  CAS  Google Scholar 

  31. Kurzer, J.H. et al. Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta. Mol. Cell. Biol. 24, 4557–4570 (2004).

    Article  CAS  Google Scholar 

  32. 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).

    Article  CAS  Google Scholar 

  33. Argetsinger, L.S. et al. Growth hormone, interferon-γ, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1. J. Biol. Chem. 270, 14685–14692 (1995).

    Article  CAS  Google Scholar 

  34. Burks, D.J. et al. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407, 377–382 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Zhang, E.E., Chapeau, E., Hagihara, K. & Feng, G.S. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc. Natl. Acad. Sci. USA 101, 16064–16069 (2004).

    Article  CAS  Google Scholar 

  37. Gao, Q. et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc. Natl. Acad. Sci. USA 101, 4661–4666 (2004).

    Article  CAS  Google Scholar 

  38. Bates, S.H. et al. LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes 53, 3067–3073 (2004).

    Article  CAS  Google Scholar 

  39. Bates, S.H., Kulkarni, R.N., Seifert, M. & Meyers, M.G. Jr. STAT3-independent signaling contributes to regulation of glucose homeostasis by leptin. Cell Metabolism 1, 169–178 (2005).

    Article  CAS  Google Scholar 

  40. Roth, J. Diabetes and obesity. Diabetes Metab. Rev. 13, 1–2 (1998).

    Article  Google Scholar 

  41. Licinio, J. et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc. Natl. Acad. Sci. USA 101, 4531–4536 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. 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).

    Article  CAS  Google Scholar 

  44. Welt, C.K. et al. Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351, 987–997 (2004).

    Article  CAS  Google Scholar 

  45. Mantzoros, C.S. & Flier, J.S. Editorial: leptin as a therapeutic agent–trials and tribulations. J. Clin. Endocrinol. Metab. 85, 4000–4002 (2000).

    CAS  PubMed  Google Scholar 

  46. Frederich, R.C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314 (1995).

    Article  CAS  Google Scholar 

  47. Van Heek, M. et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J. Clin. Invest. 99, 385–390 (1997).

    Article  CAS  Google Scholar 

  48. El Haschimi, K., Pierroz, D.D., Hileman, S.M., Bjorbaek, C. & Flier, J.S. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J. Clin. Invest. 105, 1827–1832 (2000).

    Article  CAS  Google Scholar 

  49. Banks, W.A. The many lives of leptin. Peptides 25, 331–338 (2004).

    Article  CAS  Google Scholar 

  50. Levin, B.E., Dunn-Meynell, A.A. & Banks, W.A. Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R143–R150 (2004).

    Article  CAS  Google Scholar 

  51. Krisch, B. & Leonhardt, H. The functional and structural border of the neurohemal region of the median eminence. Cell Tissue Res. 192, 327–339 (1978).

    Article  CAS  Google Scholar 

  52. Peruzzo, B. et al. A second look at the barriers of the medial basal hypothalamus. Exp. Brain Res. 132, 10–26 (2000).

    Article  CAS  Google Scholar 

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

  54. Zabolotny, J.M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489–495 (2002).

    Article  CAS  Google Scholar 

  55. Cheng, A. et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell 2, 497–503 (2002).

    Article  CAS  Google Scholar 

  56. Bjorbaek, C., Elmquist, J.K., Frantz, J.D., Shoelson, S.E. & Flier, J.S. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625 (1998).

    Article  CAS  Google Scholar 

  57. Howard, J.K. et al. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat. Med. (2004).

  58. Mori, H. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. (2004).

  59. Tups, A. et al. Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression. Endocrinology 145, 1185–1193 (2004).

    Article  CAS  Google Scholar 

  60. Emanuelli, B. et al. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J. Biol. Chem. 276, 47944–47949 (2001).

    Article  CAS  Google Scholar 

  61. Rui, L., Yuan, M., Frantz, D., Shoelson, S. & White, M.F. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 277, 42394–42398 (2002).

    Article  CAS  Google Scholar 

  62. Ueki, K., Kondo, T. & Kahn, C.R. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol. Cell. Biol. 24, 5434–5446 (2004).

    Article  CAS  Google Scholar 

  63. Rossetti, L. Hypothalamic sensing of fatty acids. Nat. Neurosci. 8 579–584 (2005).

  64. Hu, L., Fernstrom, J.D. & Goldsmith, P.C. Exogenous glutamate enhances glutamate receptor subunit expression during selective neuronal injury in the ventral arcuate nucleus of postnatal mice. Neuroendocrinology 68, 77–88 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

Supported by grants from the National Institutes of Health and the American Diabetes Association (to M.G.M.).

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  1. Division of Metabolism, Department of Medicine and Department of Molecular and Integrative Physiology, Endocrinology and Diabetes, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Heike Münzberg & Martin G Myers Jr

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  2. Martin G Myers Jr
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Correspondence to Martin G Myers Jr.

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Münzberg, H., Myers, M. Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 8, 566–570 (2005). https://doi.org/10.1038/nn1454

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