Skip to main content

Leptin in normal physiology and leptin resistance

Abstract

Since the discovery of leptin as an adipokine in 1994, much progress has been made in the research about leptin. Circulating leptin binds to leptin receptor, activates STAT3-dependent and STAT3-independent signaling pathways, and plays an effective role in energy homeostasis, neuroendocrine function and metabolism mainly through acting on the central nervous system, especially the hypothalamus. Leptin resistance is considered as a key risk factor for obesity. Various mechanisms have been formulated in order to explain leptin resistance, including impairment in leptin transport, attenuation in leptin signaling, ER stress, inflammation and deficiency in autophagy. Here, we review our current knowledge about leptin action, leptin signaling and leptin resistance, hoping to provide new ideas for the battle against obesity.

摘要

自从1994年瘦素作为一个脂肪细胞因子被发现, 关于瘦素的研究已经取得了很多进展。瘦素与瘦素受体的结合, 在中枢神经系统, 特别是在下丘脑中激活STAT3依赖和非依赖的信号通路, 在维持能量稳态, 神经内分泌作用和代谢等方面都发挥了很重要的作用。瘦素抵抗是肥胖的一个重要危险因素。目前关于瘦素抵抗的机制有很多, 包括瘦素运输受损, 瘦素信号通路削弱, 内质网应激, 炎症和自噬缺陷。在此, 我们对瘦素的功能, 瘦素的信号通路, 瘦素抵抗等进行综述, 希望可以为对抗肥胖的研究提供新的思路。

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Haslam DW, James WP (2005) Obesity. Lancet 366:1197–1209

    PubMed  Article  Google Scholar 

  2. 2.

    Pfeifer A, Hoffmann LS (2015) Brown, beige, and white: the new color code of fat and its pharmacological implications. Annu Rev Pharmacol Toxicol 55:207–227

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Fasshauer M, Bluher M (2015) Adipokines in health and disease. Trends Pharmacol Sci 36:461–470

    CAS  PubMed  Article  Google Scholar 

  4. 4.

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

    ADS  CAS  PubMed  Article  Google Scholar 

  5. 5.

    Ingalls AM, Dickie MM, Snell GD (1950) Obese, a new mutation in the house mouse. J Hered 41:317–318

    CAS  PubMed  Google Scholar 

  6. 6.

    Hummel KP, Dickie MM, Coleman DL (1966) Diabetes, a new mutation in the mouse. Science 153:1127–1128

    ADS  CAS  PubMed  Article  Google Scholar 

  7. 7.

    Hervey GR (1959) The effects of lesions in the hypothalamus in parabiotic rats. J Physiol 145:336–352

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Coleman DL (1973) Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9:294–298

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Leibel RL, Bahary N, Friedman JM (1990) Genetic variation and nutrition in obesity: approaches to the molecular genetics of obesity. World Rev Nutr Diet 63:90–101

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Bahary N, Leibel RL, Joseph L et al (1990) Molecular mapping of the mouse db mutation. Proc Natl Acad Sci USA 87:8642–8646

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Halaas JL, Gajiwala KS, Maffei M et al (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543–546

    ADS  CAS  PubMed  Article  Google Scholar 

  12. 12.

    Tartaglia LA, Dembski M, Weng X et al (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Lee GH, Proenca R, Montez JM et al (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635

    ADS  CAS  PubMed  Article  Google Scholar 

  14. 14.

    Zhang F, Basinski MB, Beals JM et al (1997) Crystal structure of the obese protein leptin-E100. Nature 387:206–209

    ADS  CAS  PubMed  Article  Google Scholar 

  15. 15.

    Dardeno TA, Chou SH, Moon HS et al (2010) Leptin in human physiology and therapeutics. Front Neuroendocrinol 31:377–393

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Park HK, Ahima RS (2014) Leptin signaling. F1000Prime Rep 6:73

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Considine RV, Sinha MK, Heiman ML et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Hube F, Lietz U, Igel M et al (1996) Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm Metab Res 28:690–693

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Rosenbaum M, Leibel RL (1999) Clinical review 107: Role of gonadal steroids in the sexual dimorphisms in body composition and circulating concentrations of leptin. J Clin Endocrinol Metab 84:1784–1789

    CAS  PubMed  Google Scholar 

  20. 20.

    Ahima RS, Prabakaran D, Mantzoros C et al (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252

    ADS  CAS  PubMed  Article  Google Scholar 

  21. 21.

    Moon HS, Dalamaga M, Kim SY et al (2013) Leptin’s role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr Rev 34:377–412

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Pan H, Guo J, Su Z (2014) Advances in understanding the interrelations between leptin resistance and obesity. Physiol Behav 130:157–169

    ADS  CAS  PubMed  Article  Google Scholar 

  23. 23.

    Gao Y, Li Z, Gabrielsen JS et al (2015) Adipocyte iron regulates leptin and food intake. J Clin Invest 125:3281–3291

    Google Scholar 

  24. 24.

    Garcia-Serrano S, Gutierrez-Repiso C, Gonzalo M et al (2015) C-peptide modifies leptin and visfatin secretion in human adipose tissue. Obesity (Silver Spring) 23:1607–1615

    CAS  Article  Google Scholar 

  25. 25.

    Sinha MK, Ohannesian JP, Heiman ML et al (1996) Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 97:1344–1347

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Wada N, Hirako S, Takenoya F et al (2014) Leptin and its receptors. J Chem Neuroanat 61–62:191–199

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Hileman SM, Tornoe J, Flier JS et al (2000) Transcellular transport of leptin by the short leptin receptor isoform ObRa in Madin-Darby Canine Kidney cells. Endocrinology 141:1955–1961

    CAS  PubMed  Google Scholar 

  28. 28.

    Hileman SM, Pierroz DD, Masuzaki H et al (2002) Characterization of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinology 143:775–783

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Tu H, Kastin AJ, Hsuchou H et al (2008) Soluble receptor inhibits leptin transport. J Cell Physiol 214:301–305

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Zhou Y, Rui L (2013) Leptin signaling and leptin resistance. Front Med 7:207–222

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Rosenbaum M, Leibel RL (2014) 20 years of leptin: role of leptin in energy homeostasis in humans. J Endocrinol 223:T83–T96

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Dalamaga M, Chou SH, Shields K et al (2013) Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab 18:29–42

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Matarese G, Moschos S, Mantzoros CS (2005) Leptin in immunology. J Immunol 174:3137–3142

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Park HK, Ahima RS (2015) Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 64:24–34

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Chou SH, Mantzoros C (2014) 20 years of leptin: role of leptin in human reproductive disorders. J Endocrinol 223:T49–T62

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Schwartz MW, Seeley RJ, Campfield LA et al (1996) Identification of targets of leptin action in rat hypothalamus. J Clin Invest 98:1101–1106

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Scott MM, Lachey JL, Sternson SM et al (2009) Leptin targets in the mouse brain. J Comp Neurol 514:518–532

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Munzberg H, Morrison CD (2015) Structure, production and signaling of leptin. Metabolism 64:13–23

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Ste ML, Miura GI, Marsh DJ et al (2000) A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci USA 97:12339–12344

    ADS  Article  Google Scholar 

  40. 40.

    Ollmann MM, Wilson BD, Yang YK et al (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278:135–138

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Fernandes MF, Matthys D, Hryhorczuk C et al (2015) Leptin suppresses the rewarding effects of running via STAT3 signaling in dopamine neurons. Cell Metab 22:741–749

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Mantzoros CS, Qu D, Frederich RC et al (1996) Activation of beta(3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 45:909–914

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Pierroz DD, Ziotopoulou M, Ungsunan L et al (2002) Effects of acute and chronic administration of the melanocortin agonist MTII in mice with diet-induced obesity. Diabetes 51:1337–1345

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Scarpace PJ, Matheny M, Pollock BH et al (1997) Leptin increases uncoupling protein expression and energy expenditure. Am J Physiol 273:E226–E230

    CAS  PubMed  Google Scholar 

  45. 45.

    Kim KW, Donato JJ, Berglund ED et al (2012) FOXO1 in the ventromedial hypothalamus regulates energy balance. J Clin Invest 122:2578–2589

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

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

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Harvey J (2007) Leptin: a diverse regulator of neuronal function. J Neurochem 100:307–313

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Bjorbaek C, Kahn BB (2004) Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 59:305–331

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Minokoshi Y, Kim YB, Peroni OD et al (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343

    ADS  CAS  PubMed  Article  Google Scholar 

  50. 50.

    Cohen B, Novick D, Rubinstein M (1996) Modulation of insulin activities by leptin. Science 274:1185–1188

    ADS  CAS  PubMed  Article  Google Scholar 

  51. 51.

    Maiorana A, Del BC, Cianfarani S (2007) Adipose tissue: a metabolic regulator. Potential implications for the metabolic outcome of subjects born small for gestational age (SGA). Rev Diabet Stud 4:134–146

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    German JP, Wisse BE, Thaler JP et al (2010) Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 59:1626–1634

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Huynh FK, Levi J, Denroche HC et al (2010) Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance. Diabetes 59:3032–3040

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Siegrist-Kaiser CA, Pauli V, Juge-Aubry CE et al (1997) Direct effects of leptin on brown and white adipose tissue. J Clin Invest 100:2858–2864

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Zeng W, Pirzgalska RM, Pereira MM et al (2015) Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163:84–94

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Dodd GT, Decherf S, Loh K et al (2015) Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160:88–104

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Guo K, McMinn JE, Ludwig T et al (2007) Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities. Endocrinology 148:3987–3997

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Bates SH, Kulkarni RN, Seifert M et al (2005) Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metab 1:169–178

    CAS  PubMed  Article  Google Scholar 

  59. 59.

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

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Lee JY, Muenzberg H, Gavrilova O et al (2008) Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity. PLoS ONE 3:e1639

    ADS  PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Samuel-Mendelsohn S, Inbar M, Weiss-Messer E et al (2011) Leptin signaling and apoptotic effects in human prostate cancer cell lines. Prostate 71:929–945

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Bjorbak C, Lavery HJ, Bates SH et al (2000) SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem 275:40649–40657

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Xu AW, Kaelin CB, Takeda K et al (2005) PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115:951–958

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Varela L, Horvath TL (2012) Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13:1079–1086

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

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

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Cota D, Proulx K, Smith KA et al (2006) Hypothalamic mTOR signaling regulates food intake. Science 312:927–930

    ADS  CAS  PubMed  Article  Google Scholar 

  67. 67.

    Paz-Filho G, Mastronardi CA, Licinio J (2015) Leptin treatment: facts and expectations. Metabolism 64:146–156

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Chou K, Perry CM (2013) Metreleptin: first global approval. Drugs 73:989–997

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Heymsfield SB, Greenberg AS, Fujioka K et al (1999) Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568–1575

    CAS  PubMed  Article  Google Scholar 

  70. 70.

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

    CAS  PubMed  Google Scholar 

  71. 71.

    Myers MJ, Heymsfield SB, Haft C et al (2012) Challenges and opportunities of defining clinical leptin resistance. Cell Metab 15:150–156

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Dietrich MO, Spuch C, Antequera D et al (2008) Megalin mediates the transport of leptin across the blood-CSF barrier. Neurobiol Aging 29:902–912

    CAS  PubMed  Article  Google Scholar 

  73. 73.

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

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Schwartz MW, Peskind E, Raskind M et al (1996) Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 2:589–593

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Caro JF, Kolaczynski JW, Nyce MR et al (1996) Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348:159–161

    CAS  PubMed  Article  Google Scholar 

  76. 76.

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

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Banks WA, Kastin AJ, Huang W et al (1996) Leptin enters the brain by a saturable system independent of insulin. Peptides 17:305–311

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Crujeiras AB, Carreira MC, Cabia B et al (2015) Leptin resistance in obesity: an epigenetic landscape. Life Sci 140:57–63

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Oh-I S, Shimizu H, Sato T et al (2005) Molecular mechanisms associated with leptin resistance: n-3 polyunsaturated fatty acids induce alterations in the tight junction of the brain. Cell Metab 1:331–341

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Banks WA, Coon AB, Robinson SM et al (2004) Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 53:1253–1260

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Munzberg H, Flier JS, Bjorbaek C (2004) Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 145:4880–4889

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    El-Haschimi K, Pierroz DD, Hileman SM et al (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105:1827–1832

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Bjorbaek C, Elmquist JK, Frantz JD et al (1998) Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1:619–625

    CAS  PubMed  Article  Google Scholar 

  84. 84.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    White CL, Whittington A, Barnes MJ et al (2009) HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms. Am J Physiol Endocrinol Metab 296:E291–E299

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Wilsey J, Scarpace PJ (2004) Caloric restriction reverses the deficits in leptin receptor protein and leptin signaling capacity associated with diet-induced obesity: role of leptin in the regulation of hypothalamic long-form leptin receptor expression. J Endocrinol 181:297–306

    CAS  PubMed  Article  Google Scholar 

  87. 87.

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

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Ozcan L, Ergin AS, Lu A et al (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9:35–51

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Zhang X, Zhang G, Zhang H et al (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135:61–73

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Williams KW et al (2014) Xbp1 s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab 20:471–482

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Ramirez S, Claret M (2015) Hypothalamic ER stress: a bridge between leptin resistance and obesity. FEBS Lett 589:1678–1687

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Liu J, Lee J, Salazar HM et al (2015) Treatment of obesity with celastrol. Cell 161:999–1011

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Meng Q, Cai D (2011) Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IkappaB kinase beta (IKKbeta)/NF-kappaB pathway. J Biol Chem 286:32324–32332

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Quan W, Kim HK, Moon EY et al (2012) Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153:1817–1826

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Kaushik S, Rodriguez-Navarro JA, Arias E et al (2011) Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab 14:173–183

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Milanski M, Degasperi G, Coope A et al (2009) Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci 29:359–370

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Kleinridders A, Schenten D, Konner AC et al (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10:249–259

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Valdearcos M, Robblee MM, Benjamin DI et al (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9:2124–2138

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Farooqi IS et al (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356:237–247

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Hribal ML, Fiorentino TV, Sesti G (2014) Role of C reactive protein (CRP) in leptin resistance. Curr Pharm Des 20:609–615

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Kettner NM, Mayo SA, Hua J et al (2015) Circadian dysfunction induces leptin resistance in mice. Cell Metab 22:448–459

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Knight ZA, Hannan KS, Greenberg ML et al (2010) Hyperleptinemia is required for the development of leptin resistance. PLoS ONE 5:e11376

    ADS  PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103.

    Ottaway N, Mahbod P, Rivero B et al (2015) Diet-induced obese mice retain endogenous leptin action. Cell Metab 21:877–882

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Myers MJ (2015) Leptin keeps working, even in obesity. Cell Metab 21:791–792

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Kim WG, Park JW, Willingham MC et al (2013) Diet-induced obesity increases tumor growth and promotes anaplastic change in thyroid cancer in a mouse model. Endocrinology 154:2936–2947

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Basic Research Program of China (2013CB530601, 2011CB910201), the National Natural Science Foundation of China (31571401, 81270954, 31030048, 81390350), the Shanghai Rising Star Program (13QH1400800). The Department of Biochemistry and Molecular Biology at Fudan University Shanghai Medical College is supported by the Shanghai Leading Academic Discipline Projects B110 and by “985” Project 985III-YFX0302.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Xi Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

SPECIAL TOPIC: Lipid Metabolism and Human Metabolic Disorder.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, S., Li, X. Leptin in normal physiology and leptin resistance. Sci. Bull. 61, 1480–1488 (2016). https://doi.org/10.1007/s11434-015-0951-4

Download citation

Keywords

  • Leptin biology
  • Leptin function
  • Leptin signaling
  • Leptin resistance
  • Energy homeostasis

关键词

  • 瘦素的生物学
  • 瘦素的作用
  • 瘦素的信号通路
  • 瘦素抵抗
  • 能量稳态