Bjørbaek Christian, Kahn Barbara B
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Recent Prog Horm Res. 2004;59:305-31. doi: 10.1210/rp.59.1.305.
The discovery of leptin in 1994 has led to astonishing advances in understanding the regulation of energy balance in rodents and humans. The demonstration of leptin receptors in hypothalamic regions known to play critical roles in regulating energy intake and body weight has produced considerable excitement in the field. Most attention has focused on the central actions of leptin. The receptor is present in several populations of neurons that express specific appetite-regulating neuropeptides for which both expression and release are regulated by leptin. Recent advances show that central leptin action is not limited to influencing energy balance. Leptin regulates a broad variety of processes and behaviors, such as blood pressure, neuroendocrine axes, bone mass, and immune function. The cloning of leptin receptors also led to parallel studies examining their signaling capacities in mammalian cell lines. The long-form receptor regulates multiple intracellular signaling cascades, including the classic janus activating kinase-signal transducer and activator of transcription (JAK-STAT) pathway, consistent with belonging to the cytokine-receptor superfamily and the phosphoinositol-3 kinase and adenosine monophosphate kinase pathways. Progress has been made in understanding the role of individual signaling pathways in vivo and the mechanisms by which specific neuropeptides are regulated. Regulation of the pro-opiomelanocortin (pomc) and the thyrotropin-releasing hormone (trh) genes by leptin is particularly well understood. Novel players in negative regulation of central leptin receptor signaling have been identified and open the possibility that these may be important in the development of leptin resistance and obesity. While initial focus was on the central effects of leptin, important actions have been discovered in peripheral tissues. These include roles of leptin to directly regulate immune cells, pancreatic beta cells, adipocytes, and muscle cells. Recent elucidation of a new signaling pathway in skeletal muscle affecting fatty acid metabolism has implications for regulation of insulin sensitivity and glucose metabolism. Recent progress in understanding central and peripheral leptin receptor signaling provides potential new targets for anti-obesity and anti-diabetes drug development.
1994年瘦素的发现，使人们在理解啮齿动物和人类能量平衡调节方面取得了惊人进展。在已知对调节能量摄入和体重起关键作用的下丘脑区域发现了瘦素受体，这在该领域引起了相当大的轰动。大多数注意力都集中在瘦素的中枢作用上。该受体存在于几个神经元群体中，这些神经元表达特定的食欲调节神经肽，其表达和释放均受瘦素调节。最近的进展表明，中枢瘦素作用不仅限于影响能量平衡。瘦素调节多种过程和行为，如血压、神经内分泌轴、骨量和免疫功能。瘦素受体的克隆还引发了平行研究，以检验其在哺乳动物细胞系中的信号传导能力。长型受体调节多个细胞内信号级联反应，包括经典的janus激活激酶-信号转导子和转录激活子（JAK-STAT）途径，这与它属于细胞因子受体超家族以及磷酸肌醇-3激酶和单磷酸腺苷激酶途径一致。在理解体内单个信号通路的作用以及特定神经肽的调节机制方面已经取得了进展。瘦素对促肾上腺皮质激素原（pomc）和促甲状腺激素释放激素（trh）基因的调节尤其清楚。已经确定了中枢瘦素受体信号负调节中的新参与者，并开启了这些可能在瘦素抵抗和肥胖发展中起重要作用的可能性。虽然最初的重点是瘦素的中枢作用，但在外周组织中也发现了重要作用。这些包括瘦素直接调节免疫细胞、胰腺β细胞、脂肪细胞和肌肉细胞的作用。最近对骨骼肌中影响脂肪酸代谢的新信号通路的阐明，对胰岛素敏感性和葡萄糖代谢的调节具有重要意义。在理解中枢和外周瘦素受体信号传导方面的最新进展为抗肥胖和抗糖尿病药物开发提供了潜在的新靶点。
