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Leptin signaling and leptin resistance

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Abstract

Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body weight. Leptin deficiency or genetic defects in the components of the leptin signaling pathways cause obesity. Leptin controls energy balance and body weight mainly through leptin receptor b (LEPRb)-expressing neurons in the brain, particularly in the hypothalamus. These LEPRb-expressing neurons function as the first-order neurons that project to the second-order neurons located within and outside the hypothalamus, forming a neural network that controls the energy homeostasis and body weight. Multiple factors, including inflammation and endoplasmic reticulum (ER) stress, contribute to leptin resistance. Leptin resistance is the key risk factor for obesity. This review is focused on recent advance about leptin action, leptin signaling, and leptin resistance.

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References

  1. Kopelman PG. Obesity as a medical problem. Nature 2000; 404(6778): 635–643

    PubMed  CAS  Google Scholar 

  2. Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M; the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011; 377(9765): 557–567

    Article  PubMed  Google Scholar 

  3. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404(6778): 661–671

    PubMed  CAS  Google Scholar 

  4. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372(6505): 425–432

    Article  PubMed  CAS  Google Scholar 

  5. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83(7): 1263–1271

    Article  PubMed  CAS  Google Scholar 

  6. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O’Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387(6636): 903–908

    Article  PubMed  CAS  Google Scholar 

  7. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998; 18(3): 213–215

    Article  PubMed  CAS  Google Scholar 

  8. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341(12): 879–884

    Article  PubMed  CAS  Google Scholar 

  9. Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, Trussell RA. Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 2004; 89(10): 4821–4826

    Article  PubMed  CAS  Google Scholar 

  10. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O’Rahilly S. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002; 110(8): 1093–1103

    PubMed  CAS  Google Scholar 

  11. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O’Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004; 101(13): 4531–4536

    Article  PubMed  CAS  Google Scholar 

  12. Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM, Schoner BE, Smith DP, Zhang XY, Wery JP, Schevitz RW. Crystal structure of the obese protein leptin-E100. Nature 1997; 387(6629): 206–209

    Article  PubMed  CAS  Google Scholar 

  13. Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 2002; 26(11): 1407–1433

    Article  PubMed  CAS  Google Scholar 

  14. Wrann CD, Eguchi J, Bozec A, Xu Z, Mikkelsen T, Gimble J, Nave H, Wagner EF, Ong SE, Rosen ED. FOSL2 promotes leptin gene expression in human and mouse adipocytes. J Clin Invest 2012; 122(3): 1010–1021

    Article  PubMed  CAS  Google Scholar 

  15. Frederich RC, Hamann A, Anderson S, Löllmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1995; 1(12): 1311–1314

    Article  PubMed  CAS  Google Scholar 

  16. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1(11): 1155–1161

    Article  PubMed  CAS  Google Scholar 

  17. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382(6588): 250–252

    Article  PubMed  CAS  Google Scholar 

  18. Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011; 301(4): E567–E584

    Article  PubMed  CAS  Google Scholar 

  19. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395(6704): 763–770

    Article  PubMed  CAS  Google Scholar 

  20. Bates SH, Myers MG Jr. The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrinol Metab 2003; 14(10): 447–452

    Article  PubMed  CAS  Google Scholar 

  21. Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 2011; 121(6): 2087–2093

    Article  PubMed  CAS  Google Scholar 

  22. Elmquist JK, Bjørbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 1998; 395(4): 535–547

    Article  PubMed  CAS  Google Scholar 

  23. Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF, Friedman JM, Elmquist JK. Leptin targets in the mouse brain. J Comp Neurol 2009; 514(5): 518–532

    Article  PubMed  CAS  Google Scholar 

  24. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996; 98(5): 1101–1106

    Article  PubMed  CAS  Google Scholar 

  25. Shpilman M, Niv-Spector L, Katz M, Varol C, Solomon G, Ayalon-Soffer M, Boder E, Halpern Z, Elinav E, Gertler A. Development and characterization of high affinity leptins and leptin antagonists. J Biol Chem 2011; 286(6): 4429–4442

    Article  PubMed  CAS  Google Scholar 

  26. Elinav E, Niv-Spector L, Katz M, Price TO, Ali M, Yacobovitz M, Solomon G, Reicher S, Lynch JL, Halpern Z, Banks WA, Gertler A. Pegylated leptin antagonist is a potent orexigenic agent: preparation and mechanism of activity. Endocrinology 2009; 150(7): 3083–3091

    Article  PubMed  CAS  Google Scholar 

  27. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, Friedman JM. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci USA 1997; 94(13): 7001–7005

    Article  PubMed  CAS  Google Scholar 

  28. Morris DL, Rui L. Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 2009; 297(6): E1247–E1259

    Article  PubMed  CAS  Google Scholar 

  29. Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 2008; 70(1): 537–556

    Article  PubMed  CAS  Google Scholar 

  30. Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, Lai CF, Tartaglia LA. The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci USA 1996; 93(16): 8374–8378

    Article  PubMed  CAS  Google Scholar 

  31. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996; 84(3): 491–495

    Article  PubMed  CAS  Google Scholar 

  32. Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996; 271(5251): 994–996

    Article  PubMed  CAS  Google Scholar 

  33. Uotani S, Bjørbaek C, Tornøe J, Flier JS. Functional properties of leptin receptor isoforms: internalization and degradation of leptin and ligand-induced receptor downregulation. Diabetes 1999; 48(2): 279–286

    Article  PubMed  CAS  Google Scholar 

  34. Schaab M, Kausch H, Klammt J, Nowicki M, Anderegg U, Gebhardt R, Rose-John S, Scheller J, Thiery J, Kratzsch J. Novel regulatory mechanisms for generation of the soluble leptin receptor: implications for leptin action. PLoS ONE 2012; 7(4): e34787

    Article  PubMed  CAS  Google Scholar 

  35. Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 1997; 15(1): 797–819

    Article  PubMed  CAS  Google Scholar 

  36. Banks AS, Davis SM, Bates SH, Myers MG Jr. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000; 275(19): 14563–14572

    Article  PubMed  CAS  Google Scholar 

  37. Tartaglia LA. The leptin receptor. J Biol Chem 1997; 272(10): 6093–6096

    PubMed  CAS  Google Scholar 

  38. Hekerman P, Zeidler J, Bamberg-Lemper S, Knobelspies H, Lavens D, Tavernier J, Joost HG, Becker W. Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines. FEBS J 2005; 272(1): 109–119

    Article  PubMed  CAS  Google Scholar 

  39. White DW, Kuropatwinski KK, Devos R, Baumann H, Tartaglia LA. Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization. J Biol Chem 1997; 272(7): 4065–4071

    Article  PubMed  CAS  Google Scholar 

  40. Jiang L, Li Z, Rui L. Leptin stimulates both JAK2-dependent and JAK2-independent signaling pathways. J Biol Chem 2008; 283(42): 28066–28073

    Article  PubMed  CAS  Google Scholar 

  41. Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 1996; 14(1): 95–97

    Article  PubMed  CAS  Google Scholar 

  42. Xu AW, Ste-Marie L, Kaelin CB, Barsh GS. Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology 2007; 148(1): 72–80

    Article  PubMed  CAS  Google Scholar 

  43. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 2003; 421(6925): 856–859

    Article  PubMed  CAS  Google Scholar 

  44. Jiang L, You J, Yu X, Gonzalez L, Yu Y, Wang Q, Yang G, Li W, Li C, Liu Y. Tyrosine-dependent and-independent actions of leptin receptor in control of energy balance and glucose homeostasis. Proc Natl Acad Sci USA 2008; 105(47): 18619–18624

    Article  PubMed  CAS  Google Scholar 

  45. Piper ML, Unger EK, Myers MG Jr, Xu AW. Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol Endocrinol 2008; 22(3): 751–759

    Article  PubMed  CAS  Google Scholar 

  46. Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI, Fu XY. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc Natl Acad Sci USA 2004; 101(13): 4661–4666

    Article  PubMed  CAS  Google Scholar 

  47. Gong Y, Ishida-Takahashi R, Villanueva EC, Fingar DC, Münzberg H, Myers MG Jr. The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J Biol Chem 2007; 282(42): 31019–31027

    Article  PubMed  CAS  Google Scholar 

  48. Mütze J, Roth J, Gerstberger R, Hübschle T. Nuclear translocation of the transcription factor STAT5 in the rat brain after systemic leptin administration. Neurosci Lett 2007; 417(3): 286–291

    Article  PubMed  CAS  Google Scholar 

  49. Lee J Y, Muenzberg H, Gavrilova O, Reed J A, Berryman D, Villanueva E C, Louis GW, Leinninger G M, Bertuzzi S, Seeley R J, Robinson G W, Myers M G, Hennighausen L. Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity. PLoS One 2008; 3(2): e1639

    Article  PubMed  CAS  Google Scholar 

  50. Bjørbaek C, Buchholz RM, Davis SM, Bates SH, Pierroz DD, Gu H, Neel BG, Myers MG Jr, Flier JS. Divergent roles of SHP-2 in ERK activation by leptin receptors. J Biol Chem 2001; 276(7): 4747–4755

    Article  PubMed  Google Scholar 

  51. Rahmouni K, Sigmund CD, Haynes WG, Mark AL. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes 2009; 58(3): 536–542

    Article  PubMed  CAS  Google Scholar 

  52. Li C, Friedman JM. Leptin receptor activation of SH2 domain containing protein tyrosine phosphatase 2 modulates Ob receptor signal transduction. Proc Natl Acad Sci USA 1999; 96(17): 9677–9682

    Article  PubMed  CAS  Google Scholar 

  53. He Z, Zhang SS, Meng Q, Li S, Zhu HH, Raquil MA, Alderson N, Zhang H, Wu J, Rui L, Cai D, Feng GS. Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals. Mol Cell Biol 2012; 32(10): 1867–1878

    Article  PubMed  CAS  Google Scholar 

  54. Krajewska M, Banares S, Zhang EE, Huang X, Scadeng M, Jhala US, Feng GS, Krajewski S. Development of diabesity in mice with neuronal deletion of Shp2 tyrosine phosphatase. Am J Pathol 2008; 172(5): 1312–1324

    Article  PubMed  CAS  Google Scholar 

  55. St-Pierre J, Tremblay ML. Modulation of leptin resistance by protein tyrosine phosphatases. Cell Metab 2012; 15(3): 292–297

    Article  PubMed  CAS  Google Scholar 

  56. Zhang EE, Chapeau E, Hagihara K, Feng GS. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci USA 2004; 101(45): 16064–16069

    Article  PubMed  CAS  Google Scholar 

  57. Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, Myers MG Jr. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem 2000; 275(51): 40649–40657

    Article  PubMed  CAS  Google Scholar 

  58. You J, Yu Y, Jiang L, Li W, Yu X, Gonzalez L, Yang G, Ke Z, Li W, Li C, Liu Y. Signaling through Tyr985 of leptin receptor as an age/diet-dependent switch in the regulation of energy balance. Mol Cell Biol 2010; 30(7): 1650–1659

    Article  PubMed  CAS  Google Scholar 

  59. Björnholm M, Münzberg H, Leshan RL, Villanueva EC, Bates SH, Louis GW, Jones JC, Ishida-Takahashi R, Bjørbaek C, Myers MG Jr. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J Clin Invest 2007; 117(5): 1354–1360

    Article  PubMed  CAS  Google Scholar 

  60. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW. Intracellular signalling. Key enzyme in leptininduced anorexia. Nature 2001; 413(6858): 794–795

    Article  PubMed  CAS  Google Scholar 

  61. Kim YB, Uotani S, Pierroz DD, Flier JS, Kahn BB. In vivo administration of leptin activates signal transduction directly in insulin-sensitive tissues: overlapping but distinct pathways from insulin. Endocrinology 2000; 141(7): 2328–2339

    Article  PubMed  CAS  Google Scholar 

  62. Zhao AZ, Huan JN, Gupta S, Pal R, Sahu A. A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding. Nat Neurosci 2002; 5(8): 727–728

    PubMed  CAS  Google Scholar 

  63. Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 2005; 115(4): 951–958

    PubMed  CAS  Google Scholar 

  64. Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF. Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes. J Clin Invest 2004; 114(7): 908–916

    PubMed  CAS  Google Scholar 

  65. Kubota N, Terauchi Y, Tobe K, Yano W, Suzuki R, Ueki K, Takamoto I, Satoh H, Maki T, Kubota T, Moroi M, Okada-Iwabu M, Ezaki O, Nagai R, Ueta Y, Kadowaki T, Noda T. Insulin receptor substrate 2 plays a crucial role in βcells and the hypothalamus. J Clin Invest 2004; 114(7): 917–927

    PubMed  CAS  Google Scholar 

  66. Duan C, Li M, Rui L. SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin. J Biol Chem 2004; 279(42): 43684–43691

    Article  PubMed  CAS  Google Scholar 

  67. Ren D, Li M, Duan C, Rui L. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metab 2005; 2(2): 95–104

    Article  PubMed  CAS  Google Scholar 

  68. Ren D, Zhou Y, Morris D, Li M, Li Z, Rui L. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J Clin Invest 2007; 117(2): 397–406

    Article  PubMed  CAS  Google Scholar 

  69. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 2006; 7(2): 85–96

    Article  PubMed  CAS  Google Scholar 

  70. Kim MS, Pak YK, Jang PG, Namkoong C, Choi YS, Won JC, Kim KS, Kim SW, Kim HS, Park JY, Kim YB, Lee KU. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat Neurosci 2006; 9(7): 901–906

    Article  PubMed  CAS  Google Scholar 

  71. Kitamura T, Feng Y, Kitamura YI, Chua SC Jr, Xu AW, Barsh GS, Rossetti L, Accili D. Forkhead protein FoxO1 mediates Agrpdependent effects of leptin on food intake. Nat Med 2006; 12(5): 534–540

    Article  PubMed  CAS  Google Scholar 

  72. Plum L, Lin HV, Dutia R, Tanaka J, Aizawa KS, Matsumoto M, Kim AJ, Cawley NX, Paik JH, Loh YP, DePinho RA, Wardlaw SL, Accili D. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat Med 2009; 15(10): 1195–1201

    Article  PubMed  CAS  Google Scholar 

  73. Sadagurski M, Leshan RL, Patterson C, Rozzo A, Kuznetsova A, Skorupski J, Jones JC, Depinho RA, Myers MG Jr, White MF. IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action. Cell Metab 2012; 15(5): 703–712

    Article  PubMed  CAS  Google Scholar 

  74. Yang G, Lim CY, Li C, Xiao X, Radda GK, Li C, Cao X, Han W. FoxO1 inhibits leptin regulation of pro-opiomelanocortin promoter activity by blocking STAT3 interaction with specificity protein 1. J Biol Chem 2009; 284(6): 3719–3727

    Article  PubMed  CAS  Google Scholar 

  75. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science 2006; 312(5775): 927–930

    Article  PubMed  CAS  Google Scholar 

  76. Maya-Monteiro CM, Bozza PT. Leptin and mTOR: partners in metabolism and inflammation. Cell Cycle 2008; 7(12): 1713–1717

    Article  PubMed  CAS  Google Scholar 

  77. Blouet C, Ono H, Schwartz GJ. Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab 2008; 8(6): 459–467

    Article  PubMed  CAS  Google Scholar 

  78. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferré P, Birnbaum MJ, Stuck BJ, Kahn BB. AMPkinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004; 428(6982): 569–574

    Article  PubMed  CAS  Google Scholar 

  79. Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin’s effect on food intake. Cell Metab 2012; 16(1): 104–112

    Article  PubMed  CAS  Google Scholar 

  80. Su H, Jiang L, Carter-Su C, Rui L. Glucose enhances leptin signaling through modulation of AMPK activity. PLoS ONE 2012; 7(2): e31636

    Article  PubMed  CAS  Google Scholar 

  81. Donato J Jr, Silva RJ, Sita LV, Lee S, Lee C, Lacchini S, Bittencourt JC, Franci CR, Canteras NS, Elias CF. The ventral premammillary nucleus links fasting-induced changes in leptin levels and coordinated luteinizing hormone secretion. J Neurosci 2009; 29(16): 5240–5250

    Article  PubMed  CAS  Google Scholar 

  82. Leinninger GM, Jo YH, Leshan RL, Louis GW, Yang H, Barrera JG, Wilson H, Opland DM, Faouzi MA, Gong Y, Jones JC, Rhodes CJ, Chua S Jr, Diano S, Horvath TL, Seeley RJ, Becker JB, Münzberg H, Myers MG Jr. Leptin acts via leptin receptorexpressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab 2009; 10(2): 89–98

    Article  PubMed  CAS  Google Scholar 

  83. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 1996; 387(2–3): 113–116

    Article  PubMed  CAS  Google Scholar 

  84. Ring LE, Zeltser LM. Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels. J Clin Invest 2010; 120(8): 2931–2941

    Article  PubMed  CAS  Google Scholar 

  85. Pan W, Hsuchou H, Jayaram B, Khan RS, Huang EY, Wu X, Chen C, Kastin AJ. Leptin action on nonneuronal cells in the CNS: potential clinical applications. Ann N Y Acad Sci 2012; 1264(1): 64–71

    Article  PubMed  CAS  Google Scholar 

  86. Morton GJ, Niswender KD, Rhodes CJ, Myers MG Jr, Blevins JE, Baskin DG, Schwartz MW. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats. Endocrinology 2003; 144(5): 2016–2024

    Article  PubMed  CAS  Google Scholar 

  87. Myers MG Jr, Münzberg H, Leinninger GM, Leshan RL. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab 2009; 9(2): 117–123

    Article  PubMed  CAS  Google Scholar 

  88. Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR, Kuhar MJ, Saper CB, Elmquist JK. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 1998; 21(6): 1375–1385

    Article  PubMed  CAS  Google Scholar 

  89. Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC Jr, Elmquist JK, Lowell BB. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 2004; 42(6): 983–991

    Article  PubMed  CAS  Google Scholar 

  90. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001; 411(6836): 480–484

    Article  PubMed  CAS  Google Scholar 

  91. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385(6612): 165–168

    Article  PubMed  CAS  Google Scholar 

  92. Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 1997; 46(12): 2119–2123

    Article  PubMed  CAS  Google Scholar 

  93. Hillebrand JJ, de Wied D, Adan RA. Neuropeptides, food intake and body weight regulation: a hypothalamic focus. Peptides 2002; 23(12): 2283–2306

    Article  PubMed  CAS  Google Scholar 

  94. Butler AA, Cone RD. The melanocortin receptors: lessons from knockout models. Neuropeptides 2002; 36(2–3): 77–84

    Article  PubMed  CAS  Google Scholar 

  95. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88(1): 131–141

    Article  PubMed  CAS  Google Scholar 

  96. Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, Baetscher M, Cone RD. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 2000; 141(9): 3518–3521

    Article  PubMed  CAS  Google Scholar 

  97. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19(2): 155–157

    Article  PubMed  CAS  Google Scholar 

  98. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Lango Allen H, Lindgren CM, Luan J, Mägi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segrè AV, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, Kilpeläinen TO, Yang J, Bouatia-Naji N, Esko T, Feitosa MF, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben KK, Absher DM, Amin N, Dixon AL, Fisher E, Glazer NL, Goddard ME, Heard-Costa NL, Hoesel V, Hottenga JJ, Johansson A, Johnson T, Ketkar S, Lamina C, Li S, Moffatt MF, Myers RH, Narisu N, Perry JR, Peters MJ, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott LJ, Timpson NJ, Tyrer JP, van Wingerden S, Watanabe RM, White CC, Wiklund F, Barlassina C, Chasman DI, Cooper MN, Jansson JO, Lawrence RW, Pellikka N, Prokopenko I, Shi J, Thiering E, Alavere H, Alibrandi MT, Almgren P, Arnold AM, Aspelund T, Atwood LD, Balkau B, Balmforth AJ, Bennett AJ, Ben-Shlomo Y, Bergman RN, Bergmann S, Biebermann H, Blakemore AI, Boes T, Bonnycastle LL, Bornstein SR, Brown MJ, Buchanan TA, Busonero F, Campbell H, Cappuccio FP, Cavalcanti-Proença C, Chen YD, Chen CM, Chines PS, Clarke R, Coin L, Connell J, Day IN, den Heijer M, Duan J, Ebrahim S, Elliott P, Elosua R, Eiriksdottir G, Erdos MR, Eriksson JG, Facheris MF, Felix SB, Fischer-Posovszky P, Folsom AR, Friedrich N, Freimer NB, Fu M, Gaget S, Gejman PV, Geus EJ, Gieger C, Gjesing AP, Goel A, Goyette P, Grallert H, Grässler J, Greenawalt DM, Groves CJ, Gudnason V, Guiducci C, Hartikainen AL, Hassanali N, Hall AS, Havulinna AS, Hayward C, Heath AC, Hengstenberg C, Hicks AA, Hinney A, Hofman A, Homuth G, Hui J, Igl W, Iribarren C, Isomaa B, Jacobs KB, Jarick I, Jewell E, John U, Jørgensen T, Jousilahti P, Jula A, Kaakinen M, Kajantie E, Kaplan LM, Kathiresan S, Kettunen J, Kinnunen L, Knowles JW, Kolcic I, König IR, Koskinen S, Kovacs P, Kuusisto J, Kraft P, Kvaløy K, Laitinen J, Lantieri O, Lanzani C, Launer LJ, Lecoeur C, Lehtimäki T, Lettre G, Liu J, Lokki ML, Lorentzon M, Luben RN, Ludwig B, Manunta P, Marek D, Marre M, Martin NG, McArdle WL, McCarthy A, McKnight B, Meitinger T, Melander O, Meyre D, Midthjell K, Montgomery GW, Morken MA, Morris AP, Mulic R, Ngwa JS, Nelis M, Neville MJ, Nyholt DR, O’Donnell CJ, O’Rahilly S, Ong KK, Oostra B, Paré G, Parker AN, Perola M, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Rafelt S, Raitakari O, Rayner NW, Ridderstråle M, Rief W, Ruokonen A, Robertson NR, Rzehak P, Salomaa V, Sanders AR, Sandhu MS, Sanna S, Saramies J, Savolainen MJ, Scherag S, Schipf S, Schreiber S, Schunkert H, Silander K, Sinisalo J, Siscovick DS, Smit JH, Soranzo N, Sovio U, Stephens J, Surakka I, Swift AJ, Tammesoo ML, Tardif JC, Teder-Laving M, Teslovich TM, Thompson JR, Thomson B, Tönjes A, Tuomi T, van Meurs JB, van Ommen GJ, Vatin V, Viikari J, Visvikis-Siest S, Vitart V, Vogel CI, Voight BF, Waite LL, Wallaschofski H, Walters GB, Widen E, Wiegand S, Wild SH, Willemsen G, Witte DR, Witteman JC, Xu J, Zhang Q, Zgaga L, Ziegler A, Zitting P, Beilby JP, Farooqi IS, Hebebrand J, Huikuri HV, James AL, Kähönen M, Levinson DF, Macciardi F, Nieminen MS, Ohlsson C, Palmer LJ, Ridker PM, Stumvoll M, Beckmann JS, Boeing H, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Collins FS, Cupples LA, Smith GD, Erdmann J, Froguel P, Grönberg H, Gyllensten U, Hall P, Hansen T, Harris TB, Hattersley AT, Hayes RB, Heinrich J, Hu FB, Hveem K, Illig T, Jarvelin MR, Kaprio J, Karpe F, Khaw KT, Kiemeney LA, Krude H, Laakso M, Lawlor DA, Metspalu A, Munroe PB, Ouwehand WH, Pedersen O, Penninx BW, Peters A, Pramstaller PP, Quertermous T, Reinehr T, Rissanen A, Rudan I, Samani NJ, Schwarz PE, Shuldiner AR, Spector TD, Tuomilehto J, Uda M, Uitterlinden A, Valle TT, Wabitsch M, Waeber G, Wareham NJ, Watkins H, Wilson JF, Wright AF, Zillikens MC, Chatterjee N, McCarroll SA, Purcell S, Schadt EE, Visscher PM, Assimes TL, Borecki IB, Deloukas P, Fox CS, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, Mohlke KL, O’Connell JR, Peltonen L, Schlessinger D, Strachan DP, van Duijn CM, Wichmann HE, Frayling TM, Thorsteinsdottir U, Abecasis GR, Barroso I, Boehnke M, Stefansson K, North KE, McCarthy MI, Hirschhorn JN, Ingelsson E, Loos RJ. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42(11): 937–948

    Article  PubMed  CAS  Google Scholar 

  99. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O’Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M, Vogel CI, Wallace C, Waterworth DM, Weedon MN, Willer CJ, Wraight, Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Jacobs KB, Chanock SJ, Hayes RB, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M, Mohlke KL. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 2008; 40(6): 768–775

    Article  PubMed  CAS  Google Scholar 

  100. Hahn TM, Breininger JF, Baskin DG, Schwartz MW. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1998; 1(4): 271–272

    Article  PubMed  CAS  Google Scholar 

  101. Luo N, Marcelin G, Liu SM, Schwartz G, Chua S Jr. Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency. Endocrinology 2011; 152(3): 883–889

    Article  PubMed  CAS  Google Scholar 

  102. Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T, Plum L, Balthasar N, Hampel B, Waisman A, Barsh GS, Horvath TL, Brüning JC. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 2005; 8(10): 1289–1291

    Article  PubMed  CAS  Google Scholar 

  103. Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 2005; 310(5748): 683–685

    Article  PubMed  CAS  Google Scholar 

  104. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z, Ghatei MA, Bloom SR. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J 2005; 19(12): 1680–1682

    PubMed  CAS  Google Scholar 

  105. Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 2011; 14(3): 351–355

    Article  PubMed  CAS  Google Scholar 

  106. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997; 278(5335): 135–138

    Article  PubMed  CAS  Google Scholar 

  107. Qian S, Chen H, Weingarth D, Trumbauer ME, Novi DE, Guan X, Yu H, Shen Z, Feng Y, Frazier E, Chen A, Camacho RE, Shearman LP, Gopal-Truter S, MacNeil DJ, Van der Ploeg LH, Marsh DJ. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol 2002; 22(14): 5027–5035

    Article  PubMed  CAS  Google Scholar 

  108. Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 2008; 11(9): 998–1000

    Article  PubMed  CAS  Google Scholar 

  109. van de Wall E, Leshan R, Xu AW, Balthasar N, Coppari R, Liu SM, Jo YH, MacKenzie RG, Allison DB, Dun NJ, Elmquist J, Lowell BB, Barsh GS, de Luca C, Myers MG Jr, Schwartz GJ, Chua SC Jr. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 2008; 149(4): 1773–1785

    Article  PubMed  CAS  Google Scholar 

  110. Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern RA, Tang V, Liu SM, Ludwig T, Chua SC Jr, Lowell BB, Elmquist JK. The hypothalamic arcuate nucleus: a key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell Metab 2005; 1(1): 63–72

    Article  PubMed  CAS  Google Scholar 

  111. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2005; 2(6): 411–420

    Article  PubMed  CAS  Google Scholar 

  112. Vong L, Ye C, Yang Z, Choi B, Chua S Jr, Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 2011; 71(1): 142–154

    Article  PubMed  CAS  Google Scholar 

  113. Leshan RL, Greenwald-Yarnell M, Patterson CM, Gonzalez IE, Myers MG Jr. Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance. Nat Med 2012; 18(5): 820–823

    Article  PubMed  CAS  Google Scholar 

  114. Harris M, Aschkenasi C, Elias CF, Chandrankunnel A, Nillni EA, Bjøorbaek C, Elmquist JK, Flier JS, Hollenberg AN. Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. J Clin Invest 2001; 107(1): 111–120

    Article  PubMed  CAS  Google Scholar 

  115. Kim MS, Small CJ, Stanley SA, Morgan DG, Seal LJ, Kong WM, Edwards CM, Abusnana S, Sunter D, Ghatei MA, Bloom SR. The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. J Clin Invest 2000; 105(7): 1005–1011

    Article  PubMed  CAS  Google Scholar 

  116. Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, Ferreira M, Tang V, McGovern RA, Kenny CD, Christiansen LM, Edelstein E, Choi B, Boss O, Aschkenasi C, Zhang CY, Mountjoy K, Kishi T, Elmquist JK, Lowell BB. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 2005; 123(3): 493–505

    Article  PubMed  CAS  Google Scholar 

  117. Ghamari-Langroudi M, Srisai D, Cone RD. Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin. Proc Natl Acad Sci USA 2011; 108(1): 355–360

    Article  PubMed  CAS  Google Scholar 

  118. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt LF. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 2003; 6(7): 736–742

    Article  PubMed  CAS  Google Scholar 

  119. Sternson SM, Shepherd GM, Friedman JM. Topographic mapping of VMH → arcuate nucleus microcircuits and their reorganization by fasting. Nat Neurosci 2005; 8(10): 1356–1363

    Article  PubMed  CAS  Google Scholar 

  120. Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confavreux C, Klemenhagen KC, Tanaka KF, Gingrich JA, Guo XE, Tecott LH, Mann JJ, Hen R, Horvath TL, Karsenty G. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 2009; 138(5): 976–989

    Article  PubMed  CAS  Google Scholar 

  121. Morris DL, Cho KW, Rui L. Critical role of the Src homology 2 (SH2) domain of neuronal SH2B1 in the regulation of body weight and glucose homeostasis in mice. Endocrinology 2010; 151(8): 3643–3651

    Article  PubMed  CAS  Google Scholar 

  122. Coppari R, Bjørbæk C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 2012; 11(9): 692–708

    Article  PubMed  CAS  Google Scholar 

  123. Moraes-Vieira PM, Bassi EJ, Araujo RC, Câmara NO. Leptin as a link between the immune system and kidney-related diseases: leading actor or just a coadjuvant? Obes Rev 2012; 13(8): 733–743

    Article  PubMed  CAS  Google Scholar 

  124. Ceccarini G, Flavell RR, Butelman ER, Synan M, Willnow TE, Bar-Dagan M, Goldsmith SJ, Kreek MJ, Kothari P, Vallabhajosula S, Muir TW, Friedman JM. PET imaging of leptin biodistribution and metabolism in rodents and primates. Cell Metab 2009; 10(2): 148–159

    Article  PubMed  CAS  Google Scholar 

  125. Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin enters the brain by a saturable system independent of insulin. Peptides 1996; 17(2): 305–311

    Article  PubMed  CAS  Google Scholar 

  126. Hileman SM, Pierroz DD, Masuzaki H, Bjørbaek C, El-Haschimi K, Banks WA, Flier JS. Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinology 2002; 143(3): 775–783

    Article  PubMed  CAS  Google Scholar 

  127. Kastin AJ, Pan W, Maness LM, Koletsky RJ, Ernsberger P. Decreased transport of leptin across the blood-brain barrier in rats lacking the short form of the leptin receptor. Peptides 1999; 20(12): 1449–1453

    Article  PubMed  CAS  Google Scholar 

  128. Tu H, Kastin AJ, Hsuchou H, Pan W. Soluble receptor inhibits leptin transport. J Cell Physiol 2008; 214(2): 301–305

    Article  PubMed  CAS  Google Scholar 

  129. Dietrich MO, Spuch C, Antequera D, Rodal I, de Yébenes JG, Molina JA, Bermejo F, Carro E. Megalin mediates the transport of leptin across the blood-CSF barrier. Neurobiol Aging 2008; 29(6): 902–912

    Article  PubMed  CAS  Google Scholar 

  130. El-Haschimi K, Pierroz DD, Hileman SM, Bjørbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 2000; 105(12): 1827–1832

    Article  PubMed  CAS  Google Scholar 

  131. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996; 348(9021): 159–161

    Article  PubMed  CAS  Google Scholar 

  132. Banks WA, DiPalma CR, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity. Peptides 1999; 20(11): 1341–1345

    Article  PubMed  CAS  Google Scholar 

  133. Herde MK, Geist K, Campbell RE, Herbison AE. Gonadotropinreleasing hormone neurons extend complex highly branched dendritic trees outside the blood-brain barrier. Endocrinology 2011; 152(10): 3832–3841

    Article  PubMed  CAS  Google Scholar 

  134. Banks WA, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab 2003; 285(1): E10–E15

    PubMed  CAS  Google Scholar 

  135. Belouzard S, Delcroix D, Rouillé Y. Low levels of expression of leptin receptor at the cell surface result from constitutive endocytosis and intracellular retention in the biosynthetic pathway. J Biol Chem 2004; 279(27): 28499–28508

    Article  PubMed  CAS  Google Scholar 

  136. Diano S, Kalra SP, Horvath TL. Leptin receptor immunoreactivity is associated with the Golgi apparatus of hypothalamic neurons and glial cells. J Neuroendocrinol 1998; 10(9): 647–650

    Article  PubMed  CAS  Google Scholar 

  137. Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet 2009; 18(7): 1323–1331

    Article  PubMed  CAS  Google Scholar 

  138. Rahmouni K, Fath MA, Seo S, Thedens DR, Berry CJ, Weiss R, Nishimura DY, Sheffield VC. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest 2008; 118(4): 1458–1467

    Article  PubMed  CAS  Google Scholar 

  139. Bjørbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1998; 1(4): 619–625

    Article  PubMed  Google Scholar 

  140. Kaszubska W, Falls HD, Schaefer VG, Haasch D, Frost L, Hessler P, Kroeger PE, White DW, Jirousek MR, Trevillyan JM. Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. Mol Cell Endocrinol 2002; 195(1–2): 109–118

    Article  PubMed  CAS  Google Scholar 

  141. Loh K, Fukushima A, Zhang X, Galic S, Briggs D, Enriori PJ, Simonds S, Wiede F, Reichenbach A, Hauser C, Sims NA, Bence KK, Zhang S, Zhang ZY, Kahn BB, Neel BG, Andrews ZB, Cowley MA, Tiganis T. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab 2011; 14(5): 684–699

    Article  PubMed  CAS  Google Scholar 

  142. Gamber KM, Huo L, Ha S, Hairston JE, Greeley S, Bjørbæk C. Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity. PLoS ONE 2012; 7(1): e30485

    Article  PubMed  CAS  Google Scholar 

  143. Bjørbaek C, El-Haschimi K, Frantz JD, Flier JS. The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 1999; 274(42): 30059–30065

    Article  PubMed  Google Scholar 

  144. Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjørbaek C, Flier JS. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 2004; 10(7): 734–738

    Article  PubMed  CAS  Google Scholar 

  145. Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H, Yoshimura A. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 2004; 10(7): 739–743

    Article  PubMed  CAS  Google Scholar 

  146. Peralta S, Carrascosa JM, Gallardo N, Ros M, Arribas C. Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction. Biochem Biophys Res Commun 2002; 296(2): 425–428

    Article  PubMed  CAS  Google Scholar 

  147. Reed AS, Unger EK, Olofsson LE, Piper ML, Myers MG Jr, Xu AW. Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes 2010; 59(4): 894–906

    Article  PubMed  CAS  Google Scholar 

  148. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG. PTP1B regulates leptin signal transduction in vivo. Dev Cell 2002; 2(4): 489–495

    Article  PubMed  CAS  Google Scholar 

  149. Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, Kennedy BP, Tremblay ML. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell 2002; 2(4): 497–503

    Article  PubMed  CAS  Google Scholar 

  150. Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 2006; 12(8): 917–924

    Article  PubMed  CAS  Google Scholar 

  151. Tsou RC, Zimmer DJ, De Jonghe BC, Bence KK. Deficiency of PTP1B in leptin receptor-expressing neurons leads to decreased body weight and adiposity in mice. Endocrinology 2012; 153(9): 4227–4237

    Article  PubMed  CAS  Google Scholar 

  152. Banno R, Zimmer D, De Jonghe BC, Atienza M, Rak K, Yang W, Bence KK. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J Clin Invest 2010; 120(3): 720–734

    Article  PubMed  CAS  Google Scholar 

  153. Morrison CD, White CL, Wang Z, Lee SY, Lawrence DS, Cefalu WT, Zhang ZY, Gettys TW. Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. Endocrinology 2007; 148(1): 433–440

    Article  PubMed  CAS  Google Scholar 

  154. White CL, Whittington A, Barnes MJ, Wang Z, Bray GA, Morrison CD. HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms. Am J Physiol Endocrinol Metab 2009; 296(2): E291–E299

    Article  PubMed  CAS  Google Scholar 

  155. Rousso-Noori L, Knobler H, Levy-Apter E, Kuperman Y, Neufeld-Cohen A, Keshet Y, Akepati VR, Klinghoffer RA, Chen A, Elson A. Protein tyrosine phosphatase epsilon affects body weight by downregulating leptin signaling in a phosphorylation-dependent manner. Cell Metab 2011; 13(5): 562–572

    Article  PubMed  CAS  Google Scholar 

  156. Plum L, Rother E, Münzberg H, Wunderlich FT, Morgan DA, Hampel B, Shanabrough M, Janoschek R, Könner AC, Alber J, Suzuki A, Krone W, Horvath TL, Rahmouni K, Brüning JC. Enhanced leptin-stimulated PI3k activation in the CNS promotes white adipose tissue transdifferentiation. Cell Metab 2007; 6(6): 431–445

    Article  PubMed  CAS  Google Scholar 

  157. Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Münzberg H, Shanabrough M, Burdakov D, Rother E, Janoschek R, Alber J, Belgardt BF, Koch L, Seibler J, Schwenk F, Fekete C, Suzuki A, Mak TW, Krone W, Horvath TL, Ashcroft FM, Brüning JC. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest 2006; 116(7): 1886–1901

    Article  PubMed  CAS  Google Scholar 

  158. Klöckener T, Hess S, Belgardt BF, Paeger L, Verhagen LA, Husch A, Sohn JW, Hampel B, Dhillon H, Zigman JM, Lowell BB, Williams KW, Elmquist JK, Horvath TL, Kloppenburg P, Brüning JC. High-fat feeding promotes obesity via insulin receptor/PI3Kdependent inhibition of SF-1 VMH neurons. Nat Neurosci 2011; 14(7): 911–918

    Article  PubMed  CAS  Google Scholar 

  159. Li Z, Zhou Y, Carter-Su C, Myers MG Jr, Rui L. SH2B1 enhances leptin signaling by both Janus kinase 2 Tyr813 phosphorylationdependent and -independent mechanisms. Mol Endocrinol 2007; 21(9): 2270–2281

    Article  PubMed  CAS  Google Scholar 

  160. Rui L, Carter-Su C. Identification of SH2-bβ as a potent cytoplasmic activator of the tyrosine kinase Janus kinase 2. Proc Natl Acad Sci USA 1999; 96(13): 7172–7177

    Article  PubMed  CAS  Google Scholar 

  161. Morris DL, Cho KW, Zhou Y, Rui L. SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. Diabetes 2009; 58(9): 2039–2047

    Article  PubMed  CAS  Google Scholar 

  162. Song W, Ren D, Li W, Jiang L, Cho KW, Huang P, Fan C, Song Y, Liu Y, Rui L. SH2B regulation of growth, metabolism, and longevity in both insects and mammals. Cell Metab 2010; 11(5): 427–437

    Article  PubMed  CAS  Google Scholar 

  163. Jamshidi Y, Snieder H, Ge D, Spector TD, O’Dell SD. The SH2B gene is associated with serum leptin and body fat in normal female twins. Obesity (Silver Spring) 2007; 15(1): 5–9

    Article  CAS  Google Scholar 

  164. Renström F, Payne F, Nordström A, Brito EC, Rolandsson O, Hallmans G, Barroso I, Nordström P, Franks PW. Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden. Hum Mol Genet 2009; 18(8): 1489–1496

    Article  PubMed  CAS  Google Scholar 

  165. Hester JM, Wing MR, Li J, Palmer ND, Xu J, Hicks PJ, Roh BH, Norris JM, Wagenknecht LE, Langefeld CD, Freedman BI, Bowden DW, Ng MC. Implication of European-derived adiposity loci in African Americans. Int J Obes (Lond) 2012; 36(3): 465–473

    Article  CAS  Google Scholar 

  166. Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, Lettre G, Lim N, Lyon HN, McCarroll SA, Papadakis K, Qi L, Randall JC, Roccasecca RM, Sanna S, Scheet P, Weedon MN, Wheeler E, Zhao JH, Jacobs LC, Prokopenko I, Soranzo N, Tanaka T, Timpson NJ, Almgren P, Bennett A, Bergman RN, Bingham SA, Bonnycastle LL, Brown M, Burtt NP, Chines P, Coin L, Collins FS, Connell JM, Cooper C, Smith GD, Dennison EM, Deodhar P, Elliott P, Erdos MR, Estrada K, Evans DM, Gianniny L, Gieger C, Gillson CJ, Guiducci C, Hackett R, Hadley D, Hall AS, Havulinna AS, Hebebrand J, Hofman A, Isomaa B, Jacobs KB, Johnson T, Jousilahti P, Jovanovic Z, Khaw KT, Kraft P, Kuokkanen M, Kuusisto J, Laitinen J, Lakatta EG, Luan J, Luben RN, Mangino M, McArdle WL, Meitinger T, Mulas A, Munroe PB, Narisu N, Ness AR, Northstone K, O’Rahilly S, Purmann C, Rees MG, Ridderstråle M, Ring SM, Rivadeneira F, Ruokonen A, Sandhu MS, Saramies J, Scott LJ, Scuteri A, Silander K, Sims MA, Song K, Stephens J, Stevens S, Stringham HM, Tung YC, Valle TT, Van Duijn CM, Vimaleswaran KS, Vollenweider P, Waeber G, Wallace C, Watanabe RM, Waterworth DM, Watkins N, Witteman JC, Zeggini E, Zhai G, Zillikens MC, Altshuler D, Caulfield MJ, Chanock SJ, Farooqi IS, Ferrucci L, Guralnik JM, Hattersley AT, Hu FB, Jarvelin MR, Laakso M, Mooser V, Ong KK, Ouwehand WH, Salomaa V, Samani NJ, Spector TD, Tuomi T, Tuomilehto J, Uda M, Uitterlinden AG, Wareham NJ, Deloukas P, Frayling TM, Groop LC, Hayes RB, Hunter DJ, Mohlke KL, Peltonen L, Schlessinger D, Strachan DP, Wichmann HE, McCarthy MI, Boehnke M, Barroso I, Abecasis GR, Hirschhorn JN. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41(1): 25–34

    Article  PubMed  CAS  Google Scholar 

  167. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I, Jonsdottir T, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Jonsson F, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Lauritzen T, Aben KK, Verbeek AL, Roeleveld N, Kampman E, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Becker DM, Gulcher J, Kiemeney LA, Pedersen O, Kong A, Thorsteinsdottir U, Stefansson K. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009; 41(1): 18–24

    Article  PubMed  CAS  Google Scholar 

  168. Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, Saeed S, Hamilton-Shield J, Clayton-Smith J, O’Rahilly S, Hurles ME, Farooqi IS. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010; 463(7281): 666–670

    Article  PubMed  CAS  Google Scholar 

  169. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003; 348(12): 1085–1095

    Article  PubMed  CAS  Google Scholar 

  170. Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J, Ferron C, Froguel P, Vaisse C. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 2003; 12(2): 145–153

    Article  PubMed  CAS  Google Scholar 

  171. Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yagaloff KA, Fisher SL, Burn P, Palmiter RD. Response of melanocortin-4 receptordeficient mice to anorectic and orexigenic peptides. Nat Genet 1999; 21(1): 119–122

    Article  PubMed  CAS  Google Scholar 

  172. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 1998; 20(2): 111–112

    Article  PubMed  CAS  Google Scholar 

  173. Pelleymounter MA, Cullen MJ, Wellman CL. Characteristics of BDNF-induced weight loss. Exp Neurol 1995; 131(2): 229–238

    Article  PubMed  CAS  Google Scholar 

  174. Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O’Rahilly S, Farooqi IS. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 2004; 7(11): 1187–1189

    Article  PubMed  CAS  Google Scholar 

  175. Liao GY, An JJ, Gharami K, Waterhouse EG, Vanevski F, Jones KR, Xu B. Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin. Nat Med 2012; 18(4): 564–571

    Article  PubMed  CAS  Google Scholar 

  176. Knight ZA, Hannan KS, Greenberg ML, Friedman JM. Hyperleptinemia is required for the development of leptin resistance. PLoS ONE 2010; 5(6): e11376

    Article  PubMed  CAS  Google Scholar 

  177. Ernst MB, Wunderlich CM, Hess S, Paehler M, Mesaros A, Koralov SB, Kleinridders A, Husch A, Münzberg H, Hampel B, Alber J, Kloppenburg P, Brüning JC, Wunderlich FT. Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. J Neurosci 2009; 29(37): 11582–11593

    Article  PubMed  CAS  Google Scholar 

  178. Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, Szanda G, Mukhopadhyay B, Chedester L, Liow JS, Innis RB, Cheng K, Rice KC, Deschamps JR, Chorvat RJ, McElroy JF, Kunos G. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab 2012; 16(2): 167–179

    Article  PubMed  CAS  Google Scholar 

  179. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29(1): 415–445

    Article  PubMed  CAS  Google Scholar 

  180. De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 2005; 146(10): 4192–4199

    Article  PubMed  CAS  Google Scholar 

  181. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008; 135(1): 61–73

    Article  PubMed  CAS  Google Scholar 

  182. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006; 116(11): 3015–3025

    Article  PubMed  CAS  Google Scholar 

  183. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DM, Anhe G, Amaral ME, Takahashi HK, Curi R, Oliveira HC, Carvalheira JB, Bordin S, Saad MJ, Velloso LA. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci 2009; 29(2): 359–370

    Article  PubMed  CAS  Google Scholar 

  184. Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, Brüning JC. MyD88 signaling in the CNS is required for development of fatty acidinduced leptin resistance and diet-induced obesity. Cell Metab 2009; 10(4): 249–259

    Article  PubMed  CAS  Google Scholar 

  185. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002; 420(6913): 333–336

    Article  PubMed  CAS  Google Scholar 

  186. Sabio G, Cavanagh-Kyros J, Barrett T, Jung DY, Ko HJ, Ong H, Morel C, Mora A, Reilly J, Kim JK, Davis RJ. Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1. Genes Dev 2010; 24(3): 256–264

    Article  PubMed  CAS  Google Scholar 

  187. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8(7): 519–529

    Article  PubMed  CAS  Google Scholar 

  188. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010; 140(6): 900–917

    Article  PubMed  CAS  Google Scholar 

  189. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG Jr, Ozcan U. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 2009; 9(1): 35–51

    Article  PubMed  CAS  Google Scholar 

  190. Hosoi T, Sasaki M, Miyahara T, Hashimoto C, Matsuo S, Yoshii M, Ozawa K. Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol 2008; 74(6): 1610–1619

    Article  PubMed  CAS  Google Scholar 

  191. Won JC, Jang PG, Namkoong C, Koh EH, Kim SK, Park JY, Lee KU, Kim MS. Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin. Obesity (Silver Spring) 2009; 17(10): 1861–1865

    Article  CAS  Google Scholar 

  192. Ropelle ER, Flores MB, Cintra DE, Rocha GZ, Pauli JR, Morari J, de Souza CT, Moraes JC, Prada PO, Guadagnini D, Marin RM, Oliveira AG, Augusto TM, Carvalho HF, Velloso LA, Saad MJ, Carvalheira JB. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKβ and ER stress inhibition. PLoS Biol 2010; 8(8): e1000465

    Article  PubMed  CAS  Google Scholar 

  193. Malik SA, Mariño G, BenYounès A, Shen S, Harper F, Maiuri MC, Kroemer G. Neuroendocrine regulation of autophagy by leptin. Cell Cycle 2011; 10(17): 2917–2923

    Article  PubMed  CAS  Google Scholar 

  194. Meng Q, Cai D. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IκB kinase beta (IKKβ)/NF- κB pathway. J Biol Chem 2011; 286(37): 32324–32332

    Article  PubMed  CAS  Google Scholar 

  195. Kaushik S, Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S, Schwartz GJ, Cuervo AM, Singh R. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab 2011; 14(2): 173–183

    Article  PubMed  CAS  Google Scholar 

  196. Quan W, Kim HK, Moon EY, Kim SS, Choi CS, Komatsu M, Jeong YT, Lee MK, Kim KW, Kim MS, Lee MS. Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 2012; 153(4): 1817–1826

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Yingjiang Zhou or Liangyou Rui.

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Zhou, Y., Rui, L. Leptin signaling and leptin resistance. Front. Med. 7, 207–222 (2013). https://doi.org/10.1007/s11684-013-0263-5

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