Cottrell Elizabeth C, Mercer Julian G
Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Scotland, EH16 4TH, UK.
Handb Exp Pharmacol. 2012(209):3-21. doi: 10.1007/978-3-642-24716-3_1.
The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, and particularly when obesity is associated with a high-fat diet, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development. Leptin receptors are found in each of the major components of the CNS "feeding" circuitry-the brainstem, hypothalamus and distributed reward centres. Through these receptors, leptin exerts influences on signalling and integration within these circuits to alter feeding behaviours. Although some progress is now being made with peptide analogues, the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date. Where clinical benefit from recombinant leptin administration has been achieved, this has been under circumstances of complete endogenous leptin deficiency or relative hypoleptinaemia such as in lipodystrophy.
主要由脂肪组织分泌的瘦素激素，在从能量稳态到生殖等众多神经内分泌功能的调节中起着关键作用。由于瘦素或瘦素受体突变导致的基因缺陷，尽管在人类中很少见，但会导致慢性食欲亢进和大量肥胖的早期发作。然而，在大多数人类肥胖病例中，瘦素水平长期升高。在这些持续高瘦素血症的情况下，特别是当肥胖与高脂肪饮食相关时，会产生瘦素抵抗，通过瘦素受体的信号传导会受到抑制，从而加剧体重增加。在这里，我们综述瘦素受体在进食调节和肥胖发展中的作用。在中枢神经系统“进食”回路的每个主要组成部分——脑干、下丘脑和分布的奖赏中心中都发现了瘦素受体。通过这些受体，瘦素对这些回路中的信号传导和整合产生影响，从而改变进食行为。尽管目前在肽类似物方面取得了一些进展，但迄今为止，瘦素受体尚未被证明适用于小分子药物干预。在通过注射重组瘦素获得临床益处的情况下，是在完全内源性瘦素缺乏或相对低瘦素血症的情况下，如在脂肪营养不良中。
