Laboratory of Molecular Genetics, The Rockefeller University, New York, NY 10065, USA.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.
Cell Metab. 2015 Dec 1;22(6):1059-67. doi: 10.1016/j.cmet.2015.10.012. Epub 2015 Nov 19.
In this report we evaluated the functions of hypothalamic amylin in vivo and in vitro. Profiling of hypothalamic neurons revealed that islet amyloid polypeptide (Iapp, precursor to amylin) is expressed in neurons in the lateral hypothalamus, arcuate nucleus, medial preoptic area, and elsewhere. Hypothalamic expression of lapp is markedly decreased in ob/ob mice and normalized by exogenous leptin. In slices, amylin and leptin had similar electrophysiologic effects on lateral hypothalamic leptin receptor ObRb-expressing neurons, while the amylin antagonist AC187 inhibited their activity and blunted the effect of leptin. Finally, i.c.v. infusion of AC187 acutely reduced the anorectic effects of leptin. These data show that hypothalamic amylin is transcriptionally regulated by leptin, that it can act directly on ObRb neurons in concert with leptin, and that it regulates feeding. These findings provide a potential mechanism for the increased efficacy of a metreleptin/pramlintide combination therapy for obesity.
在本报告中，我们评估了下丘脑淀粉样肽在体内和体外的功能。对下丘脑神经元的分析表明，胰岛淀粉样多肽（Iapp，淀粉样肽的前体）在外侧下丘脑、弓状核、内侧视前区和其他部位的神经元中表达。ob/ob 小鼠的下丘脑 lapp 表达明显减少，外源性瘦素使其正常化。在切片中，淀粉样肽和瘦素对外侧下丘脑表达瘦素受体 ObRb 的神经元具有相似的电生理作用，而淀粉样肽拮抗剂 AC187 抑制其活性并减弱瘦素的作用。最后，脑室输注 AC187 可急性降低瘦素的厌食作用。这些数据表明，下丘脑淀粉样肽受瘦素转录调控，它可以与瘦素一起直接作用于 ObRb 神经元，并调节摄食。这些发现为 metreleptin/pramlintide 联合治疗肥胖症的疗效增加提供了一种潜在的机制。
