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Leptin revisited: its mechanism of action and potential for treating diabetes

Key Points

  • Leptin is a hormone that is produced by adipose tissue and regulates appetite, body weight, neuroendocrine functions and glycaemia.

  • In this Review, we first discuss data from leptin-based clinical trials. The results from these trials indicate that leptin therapy fails to improve metabolic defects in people who have elevated levels of circulating leptin and hence are leptin-resistant. Conversely, regardless of the disease context, leptin therapy is very effective in improving metabolic imbalances in individuals who have severe hypoleptinaemia.

  • The defects underlying leptin resistance could include impaired transport of leptin across the blood–brain barrier, impaired neuronal leptin signalling in target neurons and altered signalling in downstream targets. Evidence suggests that activation of inflammatory pathways and endoplasmic reticulum stress contribute to the development of leptin resistance.

  • In the presence of insulin, the glucose-lowering effects of leptin are probably mediated by leptin receptor (LEPR)-expressing neurons within the arcuate nucleus of the hypothalamus: specifically, by pro-opiomelanocortin (POMC)-expressing neurons. The neurocircuitry controlled by POMC-expressing neurons could be exploited to lower glycaemia in patients with type 2 diabetes.

  • In the absence of insulin, the glucose-lowering effects of leptin are probably also mediated by LEPR-expressing neurons within the brain, but the biochemical identity of these neurons is still unknown. Once identified, this brain-controlled pathway could be exploited to improve hyperglycaemia in patients with type 1 diabetes.

  • A better understanding of the leptin–CNS (central nervous system)–glycaemia pathway is clearly needed, as this may provide opportunities for the identification of new drug targets and therapeutics that can circumvent the obstacle of leptin resistance and ultimately help to improve the quality and length of life of the millions of people suffering from obesity and/or diabetes.

Abstract

Since the discovery of leptin in 1994, we now have a better understanding of the cellular and molecular mechanisms underlying its biological effects. In addition to its established anti-obesity effects, leptin exerts antidiabetic actions that are independent of its regulation of body weight and food intake. In particular, leptin can correct diabetes in animal models of type 1 and type 2 diabetes. In addition, long-term leptin replacement therapy improves glycaemic control, insulin sensitivity and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. These results have spurred enthusiasm for the use of leptin therapy to treat diabetes. Here, we review the current understanding of the glucoregulatory functions of leptin, emphasizing its central mechanisms of action and lessons learned from clinical studies, and discuss possible therapeutic applications of leptin in the treatment of type 1 and type 2 diabetes.

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Figure 1: Neuronal leptin receptor activation and inactivation.
Figure 2: Cellular mechanisms that cause leptin resistance in rodents.
Figure 3: Mediators, pathways and mechanisms underlying the antidiabetic actions of leptin.

References

  1. Brown, M. S. & Goldstein, J. L. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7, 95–96 (2008).

  2. Danaei, G. et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378, 31–40 (2011).

    CAS  Google Scholar 

  3. Czyzyk, A. & Szczepanik, Z. Diabetes mellitus and cancer. Eur. J. Intern. Med. 11, 245–252 (2000).

    CAS  PubMed  Google Scholar 

  4. Mazzone, T., Chait, A. & Plutzky, J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 371, 1800–1809 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Daneman, D. Type 1 diabetes. Lancet 367, 847–858 (2006).

    CAS  PubMed  Google Scholar 

  6. Cryer, P. E. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N. Engl. J. Med. 350, 2272–2279 (2004).

    CAS  PubMed  Google Scholar 

  7. Borchers, A. T., Uibo, R. & Gershwin, M. E. The geoepidemiology of type 1 diabetes. Autoimmun. Rev. 9, A355–A365 (2010).

    PubMed  Google Scholar 

  8. Larsen, J. et al. Silent coronary atheromatosis in type 1 diabetic patients and its relation to long-term glycemic control. Diabetes 51, 2637–2641 (2002).

    CAS  PubMed  Google Scholar 

  9. Orchard, T. J. et al. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 26, 1374–1379 (2003).

    PubMed  Google Scholar 

  10. Hoerger, T. J., Segel, J. E., Gregg, E. W. & Saaddine, J. B. Is glycemic control improving in U.S. adults? Diabetes Care 31, 81–86 (2008).

    PubMed  Google Scholar 

  11. Friedman, J. M. Leptin at 14 y of age: an ongoing story. Am. J. Clin. Nutr. 89, 973S–979S (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Flier, J. S. & Maratos-Flier, E. Lasker lauds leptin. Cell 143, 9–12 (2010).

    CAS  PubMed  Google Scholar 

  13. Lee, G. H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996). This paper reports the cloning of the murine Lepr gene and shows that a mutation in this gene causes the metabolic imbalance observed in db/db mice.

    CAS  PubMed  Google Scholar 

  14. 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 

  15. Donato, J. Jr. et al. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J. Clin. Invest. 121, 355–368 (2011).

    PubMed  Google Scholar 

  16. Berglund, E., Vianna, C. R., Coppari, R. & Elmquist, J. Direct leptin action on POMC neurons regulates hepatic insulin sensitivity in mice. J. Clin. Invest. 122, 1000–1009 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Huo, L. et al. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 9, 537–547 (2009). This study is the first to indicate that LEPRs on POMC-expressing neurons have the capacity to mediate the effects of leptin on glucose homeostasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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). This study demonstrates that the insulin-resistant state can be reversed by leptin administration in the context of lipodystrophy in mice.

    CAS  PubMed  Google Scholar 

  19. Petersen, K. F. et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 109, 1345–1350 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Oral, E. A. et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346, 570–578 (2002). This study demonstrates that the insulin-resistant state can be reversed by leptin administration in the context of lipodystrophy in humans.

    CAS  PubMed  Google Scholar 

  21. 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  PubMed  Google Scholar 

  22. Farooqi, I. S. & O'Rahilly, S. Leptin: a pivotal regulator of human energy homeostasis. Am J. Clin. Nutr. 89, 980S–984S (2009).

    CAS  PubMed  Google Scholar 

  23. Paz-Filho, G., Wong, M. L. & Licinio, J. Ten years of leptin replacement therapy. Obes. Rev. 12, e315–e323 (2011).

    CAS  PubMed  Google Scholar 

  24. Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med. 1, 1155–1161 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  26. Hukshorn, C. J. et al. Weekly subcutaneous pegylated recombinant native human leptin (PEG-OB) administration in obese men. J. Clin. Endocrinol. Metab. 85, 4003–4009 (2000).

    CAS  PubMed  Google Scholar 

  27. Roth, J. D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA 105, 7257–7262 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ravussin, E. et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity 17, 1736–1743 (2009).

    CAS  PubMed  Google Scholar 

  29. Ebihara, K. et al. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J. Clin. Endocrinol. Metab. 92, 532–541 (2007).

    CAS  PubMed  Google Scholar 

  30. Chong, A. Y., Lupsa, B. C., Cochran, E. K. & Gorden, P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 53, 27–35 (2010).

    CAS  PubMed  Google Scholar 

  31. Haque, W. A., Shimomura, I., Matsuzawa, Y. & Garg, A. Serum adiponectin and leptin levels in patients with lipodystrophies. J. Clin. Endocrinol. Metab. 87, 2395 (2002).

    CAS  PubMed  Google Scholar 

  32. Simha, V., et al. Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J. Clin. Endocrinol. Metab. 97, 785–792 (2012).

    CAS  PubMed  Google Scholar 

  33. Grinspoon, S. & Carr, A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N. Engl. J. Med. 352, 48–62 (2005).

    CAS  PubMed  Google Scholar 

  34. Sekhar, R. V. et al. Leptin replacement therapy does not improve the abnormal lipid kinetics of hypoleptinemic patients with HIV-associated lipodystrophy syndrome. Metabolism 27 Apr 2012 (doi:10.1016/j.metabol.2012.03.013).

    CAS  PubMed  Google Scholar 

  35. Falutz, J. et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled Phase 3 trials with safety extension data. J. Clin. Endocrinol. Metab. 95, 4291–4304 (2010).

    CAS  PubMed  Google Scholar 

  36. Javor, E. D. et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 41, 753–760 (2005).

    CAS  PubMed  Google Scholar 

  37. Chou, S. H. et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc. Natl Acad. Sci. USA 108, 6585–6590 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sienkiewicz, E. et al. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 60, 1211–1221 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Fujikawa, T., Chuang, J. C., Sakata, I., Ramadori, G. & Coppari, R. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc. Natl Acad. Sci. USA 107, 17391–17396 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Yu, X., Park, B. H., Wang, M. Y., Wang, Z. V. & Unger, R. H. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc. Natl Acad. Sci. USA 105, 14070–14075 (2008). This study is the first to suggest that the effects of leptin on glucose homeostasis can be independent of the effects of insulin.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Park, J. Y. et al. Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. J. Clin. Endocrinol. Metab. 93, 26–31 (2008).

    CAS  PubMed  Google Scholar 

  43. Cummings, B. P. et al. Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. Proc. Natl Acad. Sci. USA 108, 14670–14675 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    CAS  PubMed  Google Scholar 

  45. 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 study is the first to indicate that LEPR-expressing neurons in the ARH can mediate the effects of leptin on glucose homeostasis.

    CAS  PubMed  Google Scholar 

  46. Mittendorfer, B. et al. Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes 60, 1474–1477 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Moon, H. S. et al. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes 60, 1647–1656 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

    CAS  PubMed  Google Scholar 

  49. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994). This paper reports the discovery of leptin and demonstrates that a mutation in the gene encoding leptin causes the metabolic imbalance seen in ob/ob mice.

    CAS  PubMed  Google Scholar 

  50. Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  52. Bjørbæk, C. Central leptin receptor action and resistance in obesity. J. Investig. Med. 57, 789–794 (2009).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. Caro, J. F. et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161 (1996).

    CAS  PubMed  Google Scholar 

  55. Banks, W. A., DiPalma, C. R. & Farrell, C. L. Impaired transport of leptin across the blood–brain barrier in obesity. Peptides 20, 1341–1345 (1999).

    CAS  PubMed  Google Scholar 

  56. Banks, W. A. & Farrell, C. L. Impaired transport of leptin across the blood–brain barrier in obesity is acquired and reversible. Am. J. Physiol. 285, e10–e15 (2003).

    CAS  Google Scholar 

  57. Wilsey, J., Zolotukhin, S., Prima, V. & Scarpace, P. J. Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity. Am. J. Physiol. 285, R1011–R1020 (2003).

    CAS  Google Scholar 

  58. Bjørbæk, 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).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  61. Enriori, P. J. et al. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 5, 181–194 (2007).

    CAS  PubMed  Google Scholar 

  62. Gamber, K. M. et al. Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity. PLoS ONE 7, e30485 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  64. van de Wall, E. et al. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149, 1773–1785 (2008).

    CAS  PubMed  Google Scholar 

  65. Banks, W. A. The blood–brain barrier as a cause of obesity. Curr. Pharm. Des. 14, 1606–1614 (2008).

    CAS  PubMed  Google Scholar 

  66. Herde, M. K., Geist, K., Campbell, R. E. & Herbison, A. E. Gonadotropin-releasing hormone neurons extend complex highly branched dendritic trees outside the blood–brain barrier. Endocrinology 152, 3832–3841 (2011).

    CAS  PubMed  Google Scholar 

  67. Faouzi, M. et al. Differential accessibility of circulating leptin to individual hypothalamic sites. Endocrinology 148, 5414–5423 (2007).

    CAS  PubMed  Google Scholar 

  68. Bjørbæk, 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).

    PubMed  Google Scholar 

  69. Howard, J. K. et al. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nature Med. 10, 734–738 (2004).

    CAS  PubMed  Google Scholar 

  70. Mori, H. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nature Med. 10, 739–743 (2004).

    CAS  PubMed  Google Scholar 

  71. Kievit, P. et al. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab. 4, 123–132 (2006).

    CAS  PubMed  Google Scholar 

  72. Loh, K. et al. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab. 14, 684–699 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bence, K. K. et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nature Med. 12, 917–924 (2006).

    CAS  PubMed  Google Scholar 

  74. Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).

    CAS  PubMed  Google Scholar 

  76. Zabolotny, J. M. et al. Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J. Biol. Chem. 283, 14230–14241 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, X. et al. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61–73 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Knight, Z. A., Hannan, K. S., Greenberg, M. L. & Friedman, J. M. Hyperleptinemia is required for the development of leptin resistance. PLoS ONE 5, e11376 (2010).

    PubMed  PubMed Central  Google Scholar 

  79. Benomar, Y. et al. Leptin but not ciliary neurotrophic factor (CNTF) induces phosphotyrosine phosphatase-1B expression in human neuronal cells (SH-SY5Y): putative explanation of CNTF efficacy in leptin-resistant state. Endocrinology 150, 1182–1191 (2009).

    CAS  PubMed  Google Scholar 

  80. Bjørbæk, C., El-Haschimi, K., Frantz, J. D. & Flier, J. S. The role of SOCS-3 in leptin signaling and leptin resistance. J. Biol. Chem. 274, 30059–30065 (1999).

    PubMed  Google Scholar 

  81. Ingalls, A. M., Dickie, M. M. & Snell, G. D. Obese, a new mutation in the house mouse. J. Hered. 41, 317–318 (1950).

    CAS  PubMed  Google Scholar 

  82. Hummel, K. P., Dickie, M. M. & Coleman, D. L. Diabetes, a new mutation in the mouse. Science 153, 1127–1128 (1966).

    CAS  PubMed  Google Scholar 

  83. Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995). This paper is the first to report the cloning of LEPRs.

    CAS  PubMed  Google Scholar 

  84. Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995). This study is the first to suggest that the effects of leptin on glucose homeostasis are direct and not secondary to its effects on food intake or body weight.

    CAS  PubMed  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. Lin, C. Y., Higginbotham, D. A., Judd, R. L. & White, B. D. Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats. Am. J. Physiol. 282, e1084–e1091 (2002).

    CAS  Google Scholar 

  87. Chinookoswong, N., Wang, J. L. & Shi, Z. Q. Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 48, 1487–1492 (1999).

    CAS  PubMed  Google Scholar 

  88. Cone, R. D. Anatomy and regulation of the central melanocortin system. Nature Neurosci. 8, 571–578 (2005).

    CAS  PubMed  Google Scholar 

  89. Bagnol, D. et al. Anatomy of an endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain. J. Neurosci. 19, RC26 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kishi, T. et al. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J. Comp. Neurol. 457, 213–235 (2003).

    CAS  PubMed  Google Scholar 

  91. 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 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. Williams, K. W. et al. Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J. Neurosci. 30, 2472–2479 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 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  PubMed  PubMed Central  Google Scholar 

  95. Claret, M. et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J. Clin. Invest. 117, 2325–2336 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Williams, K. W., Coppari, R. & Elmquist, J. K. “AMPing up” our understanding of the hypothalamic control of energy balance. J. Clin. Invest. 117, 2089–2092 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Al-Qassab, H. et al. Dominant role of the p110β isoform of PI3K over p110α in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab. 10, 343–354 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Low, M. J. Role of proopiomelanocortin neurons and peptides in the regulation of energy homeostasis. J. Endocrinol. Invest. 27, 95–100 (2004).

    CAS  PubMed  Google Scholar 

  99. Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72–76 (1998).

    CAS  PubMed  Google Scholar 

  100. Foo, K. S., Brismar, H. & Broberger, C. Distribution and neuropeptide coexistence of nucleobindin-2 mRNA/nesfatin-like immunoreactivity in the rat CNS. Neuroscience 156, 563–579 (2008).

    CAS  PubMed  Google Scholar 

  101. Meister, B. et al. Hypothalamic proopiomelanocortin (POMC) neurons have a cholinergic phenotype. Eur. J. Neurosci. 24, 2731–2740 (2006).

    PubMed  Google Scholar 

  102. Hentges, S. T., Otero-Corchon, V., Pennock, R. L., King, C. M. & Low, M. J. Proopiomelanocortin expression in both GABA and glutamate neurons. J. Neurosci. 29, 13684–13690 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Piper, M. L., Unger, E. K., Myers, M. G. Jr & Xu, A. W. Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol. Endocrinol. 22, 751–759 (2008).

    CAS  PubMed  Google Scholar 

  104. 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 

  105. Coleman, D. L. & Hummel, K. P. The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia 9, 287–293 (1973).

    CAS  PubMed  Google Scholar 

  106. Banno, R. et al. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J. Clin. Invest. 120, 720–734 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ibrahim, N. et al. Hypothalamic proopiomelanocortin neurons are glucose responsive and express KATP channels. Endocrinology 144, 1331–1340 (2003).

    CAS  PubMed  Google Scholar 

  108. Parton, L. E. et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228–232 (2007). This study describes the crucial molecular component and physiological relevance of glucose-sensing mechanisms in hypothalamic neurons.

    CAS  PubMed  Google Scholar 

  109. Hill, J. W. et al. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J. Clin. Invest. 118, 1796–1805 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 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 

  111. Malaisse, W., Malaisse-Lagae, F., Wright, P. H. & Ashmore, J. Effects of adrenergic and cholinergic agents upon insulin secretion in vitro. Endocrinology 80, 975–978 (1967).

    CAS  PubMed  Google Scholar 

  112. Ramadori, G., et al. SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab. 14, 301–312 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 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 

  114. Buettner, C. et al. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nature Med. 14, 667–675 (2008).

    CAS  PubMed  Google Scholar 

  115. Uyama, N., Geerts, A. & Reynaert, H. Neural connections between the hypothalamus and the liver. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 280, 808–820 (2004).

    PubMed  Google Scholar 

  116. Kalsbeek, A., Fliers, E., Hofman, M. A., Swaab, D. F. & Buijs, R. M. Vasopressin and the output of the hypothalamic biological clock. J. Neuroendocrinol. 22, 362–372 (2010).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  118. Banno, R. et al. Central administration of melanocortin agonist increased insulin sensitivity in diet-induced obese rats. FEBS Lett. 581, 1131–1136 (2007).

    CAS  PubMed  Google Scholar 

  119. Heijboer, A. C. et al. Intracerebroventricular administration of melanotan II increases insulin sensitivity of glucose disposal in mice. Diabetologia 48, 1621–1626 (2005).

    CAS  PubMed  Google Scholar 

  120. da Silva, A. A., do Carmo, J. M., Freeman, J. N., Tallam, L. S. & Hall, J. E. A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin. Diabetes 58, 1749–1756 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Leckstrom, A., Lew, P. S., Poritsanos, N. J. & Mizuno, T. M. Treatment with a melanocortin agonist improves abnormal lipid metabolism in streptozotocin-induced diabetic mice. Neuropeptides 45, 123–129 (2011).

    CAS  PubMed  Google Scholar 

  122. Cone, R. D. Studies on the physiological functions of the melanocortin system. Endocr. Rev. 27, 736–749 (2006).

    CAS  PubMed  Google Scholar 

  123. Taylor, G. W. Periodontal treatment and its effects on glycemic control: a review of the evidence. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 87, 311–316 (1999).

    CAS  PubMed  Google Scholar 

  124. van den Hoek, A. M. et al. Leptin deficiency per se dictates body composition and insulin action in ob/ob mice. J. Neuroendocrinol. 20, 120–127 (2008).

    CAS  PubMed  Google Scholar 

  125. German, J. et al. Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology 150, 4502–4511 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Harlan, S. M. et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ. Res. 108, 808–812 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Li, J. H. et al. Hepatic muscarinic acetylcholine receptors are not critically involved in maintaining glucose homeostasis in mice. Diabetes 58, 2776–2787 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Hedbacker, K. et al. Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metab. 11, 11–22 (2010).

    CAS  PubMed  Google Scholar 

  129. Levi, J. et al. Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance. Endocrinology 152, 3385–3395 (2011).

    CAS  PubMed  Google Scholar 

  130. Kojima, S. et al. Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides 30, 962–966 (2009).

    CAS  PubMed  Google Scholar 

  131. Hidaka, S. et al. Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. FASEB J. 16, 509–518 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Koch, L. et al. Central insulin action regulates peripheral glucose and fat metabolism in mice. J. Clin. Invest. 118, 2132–2147 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Chen, L., Philippe, J. & Unger, R. H. Glucagon responses of isolated α cells to glucose, insulin, somatostatin, and leptin. Endocr. Pract. 17, 819–825 (2011).

    PubMed  Google Scholar 

  135. Denroche, H. C. et al. Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 60, 1414–1423 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Unger, R. H. & Cherrington, A. D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4–12 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Lee, Y., Wang, M. Y., Du, X. Q., Charron, M. J. & Unger, R. H. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60, 391–397 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. German, J. P. et al. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 59, 1626–1634 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Garg, A. Lipodystrophies: genetic and acquired body fat disorders. J. Clin. Endocrinol. Metab. 96, 3313–3325 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Rahmouni, K. & Haynes, W. G. Leptin and the cardiovascular system. Recent Prog. Horm. Res. 59, 225–244 (2004).

    CAS  PubMed  Google Scholar 

  141. Seth, R., Knight, W. D. & Overton, J. M. Combined amylin-leptin treatment lowers blood pressure and adiposity in lean and obese rats. Int. J. Obes. 35, 1183–1192 (2011).

    CAS  Google Scholar 

  142. Matarese, G. et al. Leptin accelerates autoimmune diabetes in female NOD mice. Diabetes 51, 1356–1361 (2002).

    CAS  PubMed  Google Scholar 

  143. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Rev. 7, 606–619 (2006).

    CAS  Google Scholar 

  144. Wong, K. K., Engelman, J. A. & Cantley, L. C. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20, 87–90 (2010).

    CAS  PubMed  Google Scholar 

  145. Bowker, S. L., Majumdar, S. R., Veugelers, P. & Johnson, J. A. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29, 254–258 (2006).

    PubMed  Google Scholar 

  146. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Shetty, G. K. et al. Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet. Eur. J. Endocrinol. 165, 249–254 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Vadacca, M., Margiotta, D. P., Navarini, L. & Afeltra, A. Leptin in immuno-rheumatological diseases. Cell. Mol. Immunol. 8, 203–212 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Takeda, S. et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 111, 305–317 (2002).

    CAS  PubMed  Google Scholar 

  150. Ducy, P. et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100, 197–207 (2000).

    CAS  PubMed  Google Scholar 

  151. Moller, D. E. Metabolic disease drug discovery — “hitting the target” is easier said than done. Cell Metab. 15, 19–24 (2012).

    CAS  PubMed  Google Scholar 

  152. Bailey, C. J. & Turner, R. C. Metformin. N. Engl. J. Med. 334, 574–579 (1996).

    CAS  PubMed  Google Scholar 

  153. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Owen, M. R., Doran, E. & Halestrap, A. P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Mihaylova, M. M. et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145, 607–621 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. El-Mir, M. Y. et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223–228 (2000).

    CAS  PubMed  Google Scholar 

  157. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Rotella, C. M., Monami, M. & Mannucci, E. Metformin beyond diabetes: new life for an old drug. Curr. Diabetes Rev. 2, 307–315 (2006).

    CAS  PubMed  Google Scholar 

  159. Selvin, E. et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch. Intern. Med. 168, 2070–2080 (2008).

    PubMed  PubMed Central  Google Scholar 

  160. Lehmann, J. M. et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). J. Biol. Chem. 270, 12953–12956 (1995).

    CAS  PubMed  Google Scholar 

  161. Semple, R. K., Chatterjee, V. K. & O'Rahilly, S. PPARγ and human metabolic disease. J. Clin. Invest. 116, 581–589 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Willson, T. M., Lambert, M. H. & Kliewer, S. A. Peroxisome proliferator-activated receptor γ and metabolic disease. Annu. Rev. Biochem. 70, 341–367 (2001).

    CAS  PubMed  Google Scholar 

  163. Choi, J. H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature 466, 451–456 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Home, P. D. et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373, 2125–2135 (2009).

    CAS  PubMed  Google Scholar 

  165. Joosen, A. M., Bakker, A. H., Gering, M. J. & Westerterp, K. R. The effect of the PPARγ ligand rosiglitazone on energy balance regulation. Diabetes Metab. Res. Rev. 22, 204–210 (2006).

    CAS  PubMed  Google Scholar 

  166. Larsen, P. J. et al. Differential influences of peroxisome proliferator-activated receptors γ and -α on food intake and energy homeostasis. Diabetes 52, 2249–2259 (2003).

    CAS  PubMed  Google Scholar 

  167. Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, 2427–2443 (2006).

    CAS  PubMed  Google Scholar 

  168. Festuccia, W. T. et al. Peroxisome proliferator-activated receptor-γ-mediated positive energy balance in the rat is associated with reduced sympathetic drive to adipose tissues and thyroid status. Endocrinology 149, 2121–2130 (2008).

    CAS  PubMed  Google Scholar 

  169. Shimizu, H. et al. Troglitazone reduces plasma leptin concentration but increases hunger in NIDDM patients. Diabetes Care 21, 1470–1474 (1998).

    CAS  PubMed  Google Scholar 

  170. Lu, M. et al. Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nature Med. 17, 618–622 (2011).

    CAS  PubMed  Google Scholar 

  171. Ryan, K. K. et al. A role for central nervous system PPAR-γ in the regulation of energy balance. Nature Med. 17, 623–626 (2011).

    CAS  PubMed  Google Scholar 

  172. Choi, J. H. et al. Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature 477, 477–481 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Woodcock, J., Sharfstein, J. M. & Hamburg, M. Regulatory action on rosiglitazone by the U.S. Food and Drug Administration. N. Engl. J. Med. 363, 1489–1491 (2010).

    PubMed  Google Scholar 

  174. Tahrani, A. A., Bailey, C. J., Del Prato, S. & Barnett, A. H. Management of type 2 diabetes: new and future developments in treatment. Lancet 378, 182–197 (2011).

    CAS  PubMed  Google Scholar 

  175. Lebovitz, H. E. Type 2 diabetes mellitus — current therapies and the emergence of surgical options. Nature Rev. Endocrinol. 7, 408–419 (2011).

    CAS  Google Scholar 

  176. Nathan, D. M. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 353, 2643–2653 (2005).

    PubMed  Google Scholar 

  177. Maahs, D. M. & Rewers, M. Mortality and renal disease in type 1 diabetes mellitus — progress made, more to be done. J. Clin. Endocrinol. Metab. 91, 3757–3759 (2006).

    PubMed  Google Scholar 

  178. Steffes, M. W., Sibley, S., Jackson, M. & Thomas, W. β-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 26, 832–836 (2003).

    PubMed  Google Scholar 

  179. Bluestone, J. A., Herold, K. & Eisenbarth, G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464, 1293–1300 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Liu, H. Y. et al. Insulin is a stronger inducer of insulin resistance than hyperglycemia in mice with type 1 diabetes mellitus (T1DM). J. Biol. Chem. 284, 27090–27100 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Shulman, G. I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785–789 (1963).

    CAS  PubMed  Google Scholar 

  184. Boden, G. & Shulman, G. I. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β-cell dysfunction. Eur. J. Clin. Invest. 32 (Suppl. 3), 14–23 (2002).

    CAS  PubMed  Google Scholar 

  185. Cryer, P. E. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J. Clin. Invest. 116, 1470–1473 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Cryer, P. E. The barrier of hypoglycemia in diabetes. Diabetes 57, 3169–3176 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Cryer, P. E. Hypoglycemia: still the limiting factor in the glycemic management of diabetes. Endocr. Pract. 14, 750–756 (2008).

    PubMed  Google Scholar 

  188. Cryer, P. E. Preventing hypoglycaemia: what is the appropriate glucose alert value? Diabetologia 52, 35–37 (2009).

    CAS  PubMed  Google Scholar 

  189. Agarwal, A. K. & Garg, A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-γ gene in a patient with familial partial lipodystrophy. J. Clin. Endocrinol. Metab. 87, 408–411 (2002).

    CAS  PubMed  Google Scholar 

  190. Gandotra, S. et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N. Engl. J. Med. 364, 740–748 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Hudon, S. E. et al. HIV-protease inhibitors block the enzymatic activity of purified Ste24p. Biochem. Biophys. Res. Commun. 374, 365–368 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Apostolova, N., Blas-Garcia, A. & Esplugues, J. V. Mitochondrial toxicity in HAART: an overview of in vitro evidence. Curr. Pharm. Des. 17, 2130–2144 (2011).

    CAS  PubMed  Google Scholar 

  193. Devos, R. et al. Ligand-independent dimerization of the extracellular domain of the leptin receptor and determination of the stoichiometry of leptin binding. J. Biol. Chem. 272, 18304–18310 (1997).

    CAS  PubMed  Google Scholar 

  194. Ghilardi, N. & Skoda, R. C. The leptin receptor activates Janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol. Endocrinol. 11, 393–399 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Mistrik, P., Moreau, F. & Allen, J. M. BiaCore analysis of leptin–leptin receptor interaction: evidence for 1:1 stoichiometry. Anal. Biochem. 327, 271–277 (2004).

    CAS  PubMed  Google Scholar 

  197. Couturier, C. & Jockers, R. Activation of the leptin receptor by a ligand-induced conformational change of constitutive receptor dimers. J. Biol. Chem. 278, 26604–26611 (2003).

    CAS  PubMed  Google Scholar 

  198. Ingley, E. & Klinken, S. P. Cross-regulation of JAK and Src kinases. Growth Factors 24, 89–95 (2006).

    CAS  PubMed  Google Scholar 

  199. Li, M., Li, Z., Morris, D. L. & Rui, L. Identification of SH2B2β as an inhibitor for SH2B1- and SH2B2α-promoted Janus kinase-2 activation and insulin signaling. Endocrinology 148, 1615–1621 (2007).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  201. De Souza, D. et al. SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry 41, 9229–9236 (2002).

    CAS  PubMed  Google Scholar 

  202. 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).

    CAS  PubMed  Google Scholar 

  203. Fukuda, M. et al. Monitoring FoxO1 localization in chemically identified neurons. J. Neurosci. 28, 13640–13648 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Cao, Y. et al. PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure. PLoS ONE 6, e18324 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Auernhammer, C. J., Bousquet, C. & Melmed, S. Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter. Proc. Natl Acad. Sci. USA 96, 6964–6969 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Guo, L., Munzberg, H., Stuart, R. C., Nillni, E. A. & Bjørbæk, C. N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin. Proc. Natl Acad. Sci. USA 101, 11797–11802 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  209. Plum, L. et al. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nature Med. 15, 1195–1201 (2009).

    CAS  PubMed  Google Scholar 

  210. van den Brink, G. R. et al. Leptin signaling in human peripheral blood mononuclear cells, activation of p38 and p42/44 mitogen-activated protein (MAP) kinase and p70 S6 kinase. Mol. Cell Biol. Res. Commun. 4, 144–150 (2000).

    CAS  PubMed  Google Scholar 

  211. Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P. & Blenis, J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl Acad. Sci. USA 101, 13489–13494 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Gong, Y. et al. The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J. Biol. Chem. 282, 31019–31027 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  214. Won, J. C. et al. Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin. Obesity 17, 1861–1865 (2009).

    CAS  PubMed  Google Scholar 

  215. 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  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors of this article are supported by grants from the American Heart Association (0930366N to R.C.), the American Diabetes Association (7-09-BS-17 and 7-12-BS-010 to C.B.), the Richard and Susan Smith Family Foundation Pinnacle Program Project (7-05-PPG-02 to C.B.), the Boston Obesity Nutrition Research Center (DK46200 to C.B.) and by grants from the US National Institutes of Health (DK080836 to R.C.; DK60673, DK65743 and DK94040 to C.B.).

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Glossary

Type 2 diabetes

An illness characterized by insulin resistance, elevated blood levels of glucose, insulin and lipids, and estimated to affect more than 300 million people worldwide.

Type 1 diabetes

An illness characterized by the loss of pancreatic β-cells, lack of insulin, hyperglycaemia, cachexia and ketoacidosis, and estimated to affect millions of people worldwide.

Lipodystrophy

A rare condition that can be inherited or acquired, and is typically characterized by varying adipose tissue loss and distribution.

Hyperleptinaemia

A condition in which leptin levels in the blood are elevated, typically in obesity.

Leptin resistance

A condition in which endogenous and exogenous leptin is less effective at mediating its actions: for example, at reducing food intake or lowering glucose and lipids levels in the blood.

Hypoleptinaemia

A condition in which the level of leptin in the blood is below normal owing to reduced fat mass: for example, in patients with anorexia, lipodystrophy or hypothalamic amenorrhea.

Amylin

A hormone that is co-secreted with insulin from pancreatic β-cells; amylin slows gastric emptying and promotes satiety.

Euglycaemia

Normal levels of glucose in the blood.

Amenorrhea

A condition characterized by the absence of menstrual periods in a woman of reproductive age.

Common obesity

A condition that is characterized by increased body weight due to excess adipose mass, as well as hyperleptinaemia, and is associated with an increased risk of developing type 2 diabetes, cardiovascular disease, cancer and non-alcoholic fatty liver disease.

First-order neurons

In a neurocircuitry aimed at orchestrating responses to changes in a circulating cue, first-order neurons are equipped with the molecular tools to monitor the levels of the circulating cue (for example, they express the cognate receptor for the circulating ligand).

Second-order neurons

In a neurocircuitry aimed at orchestrating responses to changes in a circulating cue, second-order neurons receive direct synaptic inputs from first-order neurons.

Koletsky rats

Rats that are homozygous for a nonsense mutation in the leptin receptor gene, causing lack of leptin receptor function and hence altered metabolic homeostasis.

Hepatic vagotomy

Severing of the hepatic branch of the vagus nerve, resulting in lack of vagal efferent and afferent innervations of the liver.

Insulin-like growth factor binding protein 2

(IGFBP2). A protein that is primarily produced by the liver and that may mediate a proportion of the antidiabetic actions of leptin.

Alloxan

A pyrimidine derivative taken up by cells via facilitated transport through glucose transporter 2; this compound is used in research laboratories to destroy insulin-producing cells in animals.

Polyuria

Abnormally elevated levels of urine production; a condition that can be seen in patients with uncontrolled diabetes.

Hyperketonaemia

A condition characterized by a high level of ketone bodies in the blood; this can be seen after prolonged fasting, the use of a ketogenic diet or due to lack of insulin, typically in individuals with type 1 diabetes.

Pancreatic α-cells

Endocrine cells of the pancreas that secrete the hormone glucagon; the proper functionality of these cells is crucial for preventing a life-threatening reduction in blood glucose levels.

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Coppari, R., Bjørbæk, C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 11, 692–708 (2012). https://doi.org/10.1038/nrd3757

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