The Brain and Leptin Resistance and Implications for Food-Related Disorders

  • Nina Eikelis
  • Gavin Lambert


Obesity and the chronic diseases associated with obesity are rapidly becoming a public health crisis in the world. The existence of a circulating factor with effects on body weight has long been anticipated. The discovery of the hormone leptin in 1994 dramatically accelerated the pace of research in obesity and the neurobiology of feeding. Following the initial characterization of leptin, the concept of a peripheral satiety signal gained new credibility. Early research typically focused on the weight-reducing effects of leptin, consequently leading to the idea of leptin as an antiobesity hormone. Subsequent studies, however, have indicated that leptin plays a role in many functions related to energy balance Many insights into leptin function have been gained from rodent models of obesity, which either lack functional leptin or do not respond to its effects due to the mutation in the leptin receptor gene. An obvious and important search has begun to see whether a significant proportion of human obesity can be due to mutations in the ob gene. The coding region of the leptin gene has been sequenced from hundreds of people, but mutations have not been found. Although mutations other than in the coding region may affect leptin messenger RNA, the demonstration that most obese individuals have high circulating leptin levels did exclude the possibility that the problem lied in the ob gene itself. Indeed, human obesity does not appear to be due to impairment in leptin or its receptor. Overweight and obese humans are hyperleptinemic but they seem to be resistant to leptin, which means they do not respond to high levels of leptin in blood. Biological processes potentially involved in leptin resistance include transport of leptin into the brain, alterations of leptin hypothalamic receptor expression, and downstream signaling pathways. This chapter focuses on possible mechanisms that may underlie leptin resistance.


Anorexia Nervosa Eating Disorder Binge Eating Bulimia Nervosa 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The gene that encodes leptin protein


Obese mouse with a mutation in the leptin gene


The gene that encodes leptin receptor


Obese mouse with a recessive mutation in the leptin receptor gene


Splice variant of the leptin receptor gene


Blood–brain barrier


Cerebrospinal fluid


Body mass index


Janus Kinase, implicated in signaling by leptin


Signal transducer and activator of transcription protein


Suppressor of cytokine signaling


  1. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-Brustel Y, Lewin MJ. Nature 1998;394(6695):790–3.PubMedCrossRefGoogle Scholar
  2. Banks WA, Farrell CL. Am J Physiol Endocrinol Metab. 2003;285(1):E10–5.PubMedGoogle Scholar
  3. Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, Lai CF, Tartaglia LA. Proc Natl Acad Sci U S A. 1996;93(16):8374–8.PubMedCrossRefGoogle Scholar
  4. Bjorbaek C, Uotani S, da Silva B, Flier JS. J Biol Chem. 1997;272(51):32686–95.PubMedCrossRefGoogle Scholar
  5. Bjorbaek C, Elmquist JK, Michl P, Ahima RS, van Bueren A, McCall AL, Flier JS. Endocrinology 1998;139(8):3485–91.PubMedCrossRefGoogle Scholar
  6. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV. Lancet 1996;348(9021):159–61.PubMedCrossRefGoogle Scholar
  7. Chua SC, Jr., Koutras IK, Han L, Liu SM, Kay J, Young SJ, Chung WK, Leibel RL. Genomics 1997;45(2):264–70.PubMedCrossRefGoogle Scholar
  8. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B. Nature 1998;392(6674):398–401.PubMedCrossRefGoogle Scholar
  9. Considine RV, Considine EL, Williams CJ, Nyce MR, Magosin SA, Bauer TL, Rosato EL, Colberg J, Caro JF. J Clin Invest 1995;95(6):2986–8.PubMedCrossRefGoogle Scholar
  10. Devos R, Richards JG, Campfield LA, Tartaglia LA, Guisez Y, van der Heyden J, Travernier J, Plaetinck G, Burn P. Proc Natl Acad Sci U S A. 1996;93(11):5668–73.PubMedCrossRefGoogle Scholar
  11. Dunbar JC, Hu Y, Lu H. Diabetes 1997;46(12):2040–3.PubMedCrossRefGoogle Scholar
  12. Eckert ED, Pomeroy C, Raymond N, Kohler PF, Thuras P, Bowers CY. J Clin Endocrinol Metab. 1998;83(3):791–5.PubMedCrossRefGoogle Scholar
  13. Eikelis N, Lambert G, Wiesner G, Kaye D, Schlaich M, Morris M, Hastings J, Socratous F, Esler M. Am J Physiol Endocrinol Metab. 2004;286(5):E744–52.PubMedCrossRefGoogle Scholar
  14. Eikelis N, Esler M, Barton D, Dawood T, Wiesner G, Lambert G. Mol Psychiatry. 2006;11(9):800–1.PubMedCrossRefGoogle Scholar
  15. Eikelis N, Wiesner G, Lambert G, Esler M. Regul Pept. 2007;139(1–3):45–51.PubMedCrossRefGoogle Scholar
  16. El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS. J Clin Invest. 2000;105(12):1827–32.PubMedCrossRefGoogle Scholar
  17. Elmquist JK, Elias CF, Saper CB. Neuron 1999;22(2):221–32.PubMedCrossRefGoogle Scholar
  18. Esler M, Vaz M, Collier G, Nestel P, Jennings G, Kaye D, Seals D, Lambert G. Lancet 1998;351(9106):879.PubMedCrossRefGoogle Scholar
  19. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, Friedman JM. Proc Natl Acad Sci U S A. 1997;94(13):7001–5.PubMedCrossRefGoogle Scholar
  20. Golden PL, Maccagnan TJ, Pardridge WM. J Clin Invest. 1997;99(1):14–8.PubMedCrossRefGoogle Scholar
  21. Grasso P, Leinung MC, Ingher SP, Lee DW. Endocrinology 1997;138(4):1413–8.PubMedCrossRefGoogle Scholar
  22. Guan XM, Hess JF, Yu H, Hey PJ, van der Ploeg LH. Mol Cell Endocrinol. 1997;133(1):1–7.PubMedCrossRefGoogle Scholar
  23. Hashimoto H, Fujihara H, Kawasaki M, Saito T, Shibata M, Otsubo H, Takei Y, Ueta Y. Endocrinology 2007;148(4):1638–47.PubMedCrossRefGoogle Scholar
  24. Hassink SG, de Lancey E, Sheslow DV, Smith-Kirwin SM, O’Connor DM, Considine RV, Opentanova I, Dostal K, Spear ML, Leef K, Ash M, Spitzer AR, Funanage VL. Pediatrics 1997;100(1):E1.PubMedCrossRefGoogle Scholar
  25. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. J Clin Invest. 1997;100(2):270–8.PubMedCrossRefGoogle Scholar
  26. Hebebrand J, Blum WF, Barth N, Coners H, Englaro P, Juul A, Ziegler A, Warnke A, Rascher W, Remschmidt H. Mol Psychiatry. 1997;2(4):330–4.PubMedCrossRefGoogle Scholar
  27. Hennessy JW, Grossman SP. Physiol Behav. 1976;17(1):103–9.PubMedCrossRefGoogle Scholar
  28. Jimerson DC, Mantzoros C, Wolfe BE, Metzger ED. J Clin Endocrinol Metab. 2000;85(12):4511–4.PubMedCrossRefGoogle Scholar
  29. Kaye W, Gendall K, Strober M. Biol Psychiatry. 1998; 44(9):825–38.PubMedCrossRefGoogle Scholar
  30. Kennedy GC. Proc R Soc Lond B Biol Sci. 1953;140(901):578–96.PubMedCrossRefGoogle Scholar
  31. Klein DA, Mayer LE, Schebendach JE, Walsh BT. Psychoneuroendocrinology 2007;32(5):539–47.PubMedCrossRefGoogle Scholar
  32. Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF. Diabetes 1996;45(11):1511–5.PubMedCrossRefGoogle Scholar
  33. Kontoyannia P, Katsilambros N, Theophanides C, Dragines E. Eur Neurol. 1974;11(2):128–32.PubMedCrossRefGoogle Scholar
  34. Lonnqvist F, Arner P, Nordfors L, Schalling M. Nat Med. 1995;1(9):950–3.PubMedCrossRefGoogle Scholar
  35. Madej T, Boguski MS, Bryant SH. FEBS Lett. 1995;373(1):13–8.PubMedCrossRefGoogle Scholar
  36. Maffei M, Stoffel M, Barone M, Moon B, Dammerman M, Ravussin E, Bogardus C, Ludwig DS, Flier JS, Talley M, et al. Diabetes 1996;45(5):679–82.PubMedCrossRefGoogle Scholar
  37. Mantzoros C, Flier JS, Lesem MD, Brewerton TD, Jimerson DC. J Clin Endocrinol Metab. 1997;82(6):1845–51.PubMedCrossRefGoogle Scholar
  38. Mark AL, Shaffer RA, Correia ML, Morgan DA, Sigmund CD, Haynes WG. J Hypertens. 1999;17(12 Pt 2):1949–53.PubMedCrossRefGoogle Scholar
  39. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. FEBS Lett. 1996;387(2–3):113–6.PubMedCrossRefGoogle Scholar
  40. Mercer JG, Moar KM, Hoggard N. Endocrinology 1998;139(1):29–34.PubMedCrossRefGoogle Scholar
  41. Misra A, Ganesh S, Shahiwala A, Shah SP. J Pharm Pharm Sci. 2003;6(2):252–73.PubMedGoogle Scholar
  42. 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. Nature 1997;387(6636):903–8.PubMedCrossRefGoogle Scholar
  43. Monteleone P, Martiadis V, Colurcio B, Maj M. Psychosom Med. 2002;64(6):874–9.PubMedCrossRefGoogle Scholar
  44. Morash B, Li A, Murphy PR, Wilkinson M, Ur E. Endocrinology 1999;140(12):5995–8.PubMedCrossRefGoogle Scholar
  45. Newcomer JW, Selke G, Melson AK, Gross J, Vogler GP, Dagogo-Jack S. Arch Gen Psychiatry. 1998;55(11):995–1000.PubMedCrossRefGoogle Scholar
  46. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL. Science 2004;304(5667):110–5.PubMedCrossRefGoogle Scholar
  47. Porte D Jr., Woods SC. Diabetologia 1981;20(Suppl):274–80.CrossRefGoogle Scholar
  48. Remschmidt H, Schmidt MCG. Prediction of long-term outcome in anorectic patients from longitudinal weight measurements during inpatient treatment: a cross validation study. Child and youth psychiatry: Europen perspectives, vol. 1. Anorexia Nervosa. Toronto: Hogrefe & Huber; 1990. p. 150–67.Google Scholar
  49. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr. Nat Med. 1996;2(5):589–93.Google Scholar
  50. Sclafani A, Ackroff K, Schwartz GJ. Physiol Behav. 2003;78(2):285–94.PubMedCrossRefGoogle Scholar
  51. Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, Becker GW, Bowsher RR, Stephens TW, Caro JF. J Clin Invest. 1996;98(6):1277–82.PubMedCrossRefGoogle Scholar
  52. Strader AD, Woods SC. Gastroenterology 2005;128(1):175–91.PubMedCrossRefGoogle Scholar
  53. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. Nat Genet. 1998;18(3):213–5.PubMedCrossRefGoogle Scholar
  54. Tartaglia LA. J Biol Chem. 1997;272(10):6093–6.PubMedGoogle Scholar
  55. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, et al. Cell 1995;83(7):1263–71.PubMedCrossRefGoogle Scholar
  56. Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, Sybertz EJ, Strader CD, Davis HR Jr. J Clin Invest. 1997;99(3):385–90.Google Scholar
  57. Villanueva EC, Myers MG Jr. Int J Obes (Lond). 2008;32(Suppl 7):S8–12.CrossRefGoogle Scholar
  58. Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, Sattar N. Circulation 2001;104(25):3052–6.PubMedCrossRefGoogle Scholar
  59. Wiesner G, Vaz M, Collier G, Seals D, Kaye D, Jennings G, Lambert G, Wilkinson D, Esler M. J Clin Endocrinol Metab. 1999;84(7):2270–4.PubMedCrossRefGoogle Scholar
  60. Wilsey J, Zolotukhin S, Prima V, Scarpace PJ. Am J Physiol Regul Integr Comp Physiol. 2003;285(5):R1011–20.PubMedGoogle Scholar
  61. Wolfe BE, Metzger E, Jimerson DC. Psychopharmacol Bull. 1997;33(3):345–54.PubMedGoogle Scholar
  62. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Nature 1994;372(6505):425–32.PubMedCrossRefGoogle Scholar
  63. Zlokovic BV, Jovanovic S, Miao W, Samara S, Verma S, Farrell CL. Endocrinology 2000;141(4):1434–41.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Human Neurotransmitters Laboratory, Vascular and Hypertension DivisionBaker IDI Heart and Diabetes InstituteMelbourneAustralia

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