Abstract
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.
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Abbreviations
- ob :
-
The gene that encodes leptin protein
- ob/ob :
-
Obese mouse with a mutation in the leptin gene
- db :
-
The gene that encodes leptin receptor
- db/db :
-
Obese mouse with a recessive mutation in the leptin receptor gene
- Ob-Rb :
-
Splice variant of the leptin receptor gene
- BBB:
-
Blood–brain barrier
- CSF:
-
Cerebrospinal fluid
- BMI:
-
Body mass index
- Jak:
-
Janus Kinase, implicated in signaling by leptin
- STAT:
-
Signal transducer and activator of transcription protein
- SOCS:
-
Suppressor of cytokine signaling
References
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.
Banks WA, Farrell CL. Am J Physiol Endocrinol Metab. 2003;285(1):E10–5.
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.
Bjorbaek C, Uotani S, da Silva B, Flier JS. J Biol Chem. 1997;272(51):32686–95.
Bjorbaek C, Elmquist JK, Michl P, Ahima RS, van Bueren A, McCall AL, Flier JS. Endocrinology 1998;139(8):3485–91.
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.
Chua SC, Jr., Koutras IK, Han L, Liu SM, Kay J, Young SJ, Chung WK, Leibel RL. Genomics 1997;45(2):264–70.
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.
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.
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.
Dunbar JC, Hu Y, Lu H. Diabetes 1997;46(12):2040–3.
Eckert ED, Pomeroy C, Raymond N, Kohler PF, Thuras P, Bowers CY. J Clin Endocrinol Metab. 1998;83(3):791–5.
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.
Eikelis N, Esler M, Barton D, Dawood T, Wiesner G, Lambert G. Mol Psychiatry. 2006;11(9):800–1.
Eikelis N, Wiesner G, Lambert G, Esler M. Regul Pept. 2007;139(1–3):45–51.
El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS. J Clin Invest. 2000;105(12):1827–32.
Elmquist JK, Elias CF, Saper CB. Neuron 1999;22(2):221–32.
Esler M, Vaz M, Collier G, Nestel P, Jennings G, Kaye D, Seals D, Lambert G. Lancet 1998;351(9106):879.
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.
Golden PL, Maccagnan TJ, Pardridge WM. J Clin Invest. 1997;99(1):14–8.
Grasso P, Leinung MC, Ingher SP, Lee DW. Endocrinology 1997;138(4):1413–8.
Guan XM, Hess JF, Yu H, Hey PJ, van der Ploeg LH. Mol Cell Endocrinol. 1997;133(1):1–7.
Hashimoto H, Fujihara H, Kawasaki M, Saito T, Shibata M, Otsubo H, Takei Y, Ueta Y. Endocrinology 2007;148(4):1638–47.
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.
Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. J Clin Invest. 1997;100(2):270–8.
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.
Hennessy JW, Grossman SP. Physiol Behav. 1976;17(1):103–9.
Jimerson DC, Mantzoros C, Wolfe BE, Metzger ED. J Clin Endocrinol Metab. 2000;85(12):4511–4.
Kaye W, Gendall K, Strober M. Biol Psychiatry. 1998; 44(9):825–38.
Kennedy GC. Proc R Soc Lond B Biol Sci. 1953;140(901):578–96.
Klein DA, Mayer LE, Schebendach JE, Walsh BT. Psychoneuroendocrinology 2007;32(5):539–47.
Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF. Diabetes 1996;45(11):1511–5.
Kontoyannia P, Katsilambros N, Theophanides C, Dragines E. Eur Neurol. 1974;11(2):128–32.
Lonnqvist F, Arner P, Nordfors L, Schalling M. Nat Med. 1995;1(9):950–3.
Madej T, Boguski MS, Bryant SH. FEBS Lett. 1995;373(1):13–8.
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.
Mantzoros C, Flier JS, Lesem MD, Brewerton TD, Jimerson DC. J Clin Endocrinol Metab. 1997;82(6):1845–51.
Mark AL, Shaffer RA, Correia ML, Morgan DA, Sigmund CD, Haynes WG. J Hypertens. 1999;17(12 Pt 2):1949–53.
Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. FEBS Lett. 1996;387(2–3):113–6.
Mercer JG, Moar KM, Hoggard N. Endocrinology 1998;139(1):29–34.
Misra A, Ganesh S, Shahiwala A, Shah SP. J Pharm Pharm Sci. 2003;6(2):252–73.
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.
Monteleone P, Martiadis V, Colurcio B, Maj M. Psychosom Med. 2002;64(6):874–9.
Morash B, Li A, Murphy PR, Wilkinson M, Ur E. Endocrinology 1999;140(12):5995–8.
Newcomer JW, Selke G, Melson AK, Gross J, Vogler GP, Dagogo-Jack S. Arch Gen Psychiatry. 1998;55(11):995–1000.
Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL. Science 2004;304(5667):110–5.
Porte D Jr., Woods SC. Diabetologia 1981;20(Suppl):274–80.
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.
Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr. Nat Med. 1996;2(5):589–93.
Sclafani A, Ackroff K, Schwartz GJ. Physiol Behav. 2003;78(2):285–94.
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.
Strader AD, Woods SC. Gastroenterology 2005;128(1):175–91.
Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. Nat Genet. 1998;18(3):213–5.
Tartaglia LA. J Biol Chem. 1997;272(10):6093–6.
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.
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.
Villanueva EC, Myers MG Jr. Int J Obes (Lond). 2008;32(Suppl 7):S8–12.
Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, Sattar N. Circulation 2001;104(25):3052–6.
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.
Wilsey J, Zolotukhin S, Prima V, Scarpace PJ. Am J Physiol Regul Integr Comp Physiol. 2003;285(5):R1011–20.
Wolfe BE, Metzger E, Jimerson DC. Psychopharmacol Bull. 1997;33(3):345–54.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Nature 1994;372(6505):425–32.
Zlokovic BV, Jovanovic S, Miao W, Samara S, Verma S, Farrell CL. Endocrinology 2000;141(4):1434–41.
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Eikelis, N., Lambert, G. (2011). The Brain and Leptin Resistance and Implications for Food-Related Disorders. In: Preedy, V., Watson, R., Martin, C. (eds) Handbook of Behavior, Food and Nutrition. Springer, New York, NY. https://doi.org/10.1007/978-0-387-92271-3_84
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