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In 1994, a gene (the ob gene) was identified in genetically obese insulin resistant mice, Nature. 1994 Dec 1;372(6505):425-32 with a human homologue gene also being described. ob/ob mice were shown to have a mutation in the ob gene which resulted in absence of a functional protein-Leptin. Later db/db mice were described which had the protein but were resistant to it's actions. The protein produced was named Leptin from the Greek word leptos, meaning thin. In these genetically obese ob(-/-) mice, mutations in the ob gene results in a total lack of Leptin production leading to severe obesity. When Leptin is administered to these mice, the mice decrease their food intake, their metabolic rate increases, and they lose significant amounts of weight suggesting that Leptin may facilitate negative energy balance. The obvious question was whether a similar defect or effect was to be found in humans. Further investigation has demonstrated the wider metabolic role of Leptin in glucose and lipid pathways, and its role as a neuroendocrine hormone with effects on the reproductive system , Int J Obes Relat Metab Disord. 2002 Nov;26(11):1407-33 the immune system, the hemopoietic system, the autonomic nervous system, brain and bone development as well as the hypothalamo-pituitary-adrenal and thyroidal axes. Ann Intern Med. 1999 Apr 20;130(8):671-80 The role of Leptin in obesity will be predominantly discussed with brief description of effects on other systems.
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Leptin is predominantly produced and secreted from the adipose tissue, but it is also expressed in low levels in the gastric epithelium, muscle placenta Nat Med. 1997 Sep;3(9):1029-33 and CNS. 20% of circulating Leptin is bound to plasma proteins Diabetes. 1996 Nov;45(11):1638-43 with lean humans having higher levels of the free form.J Clin Invest. 1996 Sep 15;98(6):1277-82 Bound Leptin does not seem to be bioactive although immunoassays detect both bound and free forms. Leptin receptors are widely distributed in peripheral organs ensuring that Leptin's actions are more widespread than merely on the central nervous system. Leptin receptors have been demonstrated on pancreatic beta and delta cells but do not seem to be present on alpha cells. Diabetes. 1997 Jun;46(6):1087-93. Six isoforms of the Leptin receptor have been described (ObRa, ObRb, ObRc, ObRd, ObRe, -the circulating soluble Leptin receptor and ObRf). J Biol Chem. 1997 Mar 7;272(10):6093-6. ObRb "the long form of the Leptin receptor" is essential for the actions of Leptin, as opposed to the short form -ObRa. J Biol Chem. 1997 Dec 19;272(51):32686-95. ObRb mRNA is present in the pancreatic beta cells, Biochem Biophys Res Commun. 1996 Jul 16;224(2):522-7 in higher proportion than ObRa mRNA, (although the short form of the actual receptor predominates in the islets) and thus a regulation of Insulin secretion from the pancreas by Leptin is made possible, producing an adipoinsular axis. db/db strain of mice which show resistance to Leptin action have a specific absence of expression of the ObRb isoform with resultant hyperinsulinaemia, one that cannot be corrected by exogenous Leptin infusion.
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