ASPROSIN NEUTRALIZATION AS A NOVEL ANTI-OBESITY TREATMENT

项目摘要 在没有食物的情况下生存的能力是地球上进化和生命的基石。哺乳动物的反应是 通过激活刺激食欲的机制来禁食，同时增加肝葡萄糖 在寻求和获取外源性卡路里的同时，大脑需要保持营养和警觉。 这是通过大脑和肝脏中的一系列酶促反应和过程来实现的， 都是由一系列激素精确协调的 我们最近发现了一种叫做白色脂肪肽的蛋白质激素，它可以调节哺乳动物的葡萄糖稳态。 从那时起，我们发现白色脂肪肽也通过激活下丘脑中的食欲原性AgRP神经元来调节食欲。 下丘脑的弓状核。这导致下游促凋亡POMC神经元抑制， 依赖GABA的方式这种白色脂肪肽介导的事件链导致食欲刺激和 积累肥胖和体重。人类白色脂肪肽的遗传缺陷导致一种综合征 其特征是食欲不振和极度消瘦，被携带类似突变的小鼠模仿， 通过纠正白色脂肪肽缺乏症而获救肥胖的人类和小鼠表现出病理性升高， 循环白色脂肪肽水平和使用单克隆抗体中和血浆白色脂肪肽降低食欲 和体重，除了改善它们的血糖谱。因此，白色脂肪肽，除了 执行生糖功能，是一种促食欲激素，抗白色脂肪肽抗体显示出治疗作用。 作为抗肥胖/抗糖尿病双重作用剂的潜力。这项建议是根据这些意见提出的 其广泛的目的是提高我们对白色脂肪肽的食欲作用和抗肥胖潜力的理解 白色脂肪肽中和疗法我们力求做到这一点在以下3个目标：1）确定的贡献 对AgRP神经元活化的影响。2)确定SK 3-的必要性和充分性 介导的外向钾电流对阿司匹林介导的AgRP神经元激活和食欲刺激的影响。 3)绘制抗白色脂肪肽单克隆抗体的抗肥胖潜力图。在完成这些目标后，我们 期望确定白色脂肪肽对食欲和肥胖的中枢调节的相关性，以及这是如何实现的。 可以操纵该过程以治疗性地影响肥胖。

PROJECT SUMMARY The ability to survive periods without food is the cornerstone of evolution and life on earth. Mammals respond to fasting by activating mechanisms that stimulate appetite, while at the same time increasing hepatic glucose production in order to keep the brain nourished and alert while exogenous calories are sought and acquired. This is accomplished through a cascade of enzymatic reactions and processes in the brain and the liver that are precisely coordinated by an array of hormones. We recently discovered a protein hormone called asprosin that regulates mammalian glucose homeostasis. Since then, we have found that asprosin also regulates appetite by activating orexigenic AgRP neurons in the arcuate nucleus of the hypothalamus. This results in downstream anorexigenic POMC neuron inhibition, in a GABA-dependent manner. This asprosin-mediated chain of events leads to appetite stimulation and a drive to accumulate adiposity and body weight. Genetic deficiency of asprosin in humans results in a syndrome characterized by low appetite and extreme leanness, phenocopied by mice carrying similar mutations, and fully rescued by correcting the asprosin deficiency. Obese humans and mice display pathologically elevated circulating asprosin levels, and neutralization of plasma asprosin using monoclonal antibodies reduces appetite and body weight in such mice, in addition to improving their glycemic profile. Thus, asprosin, in addition to performing a glucogenic function, is an orexigenic hormone, and anti-asprosin antibodies show therapeutic potential as dual-action anti-obesity/anti-diabetes agents. This proposal seeks to build on these observations with a broad aim of enhancing our understanding of asprosin's orexigenic effect and the anti-obesity potential of asprosin-neutralization therapy. We seek to do so within the following 3 aims: 1) Determine the contribution of adipose-derived asprosin on AgRP neuron activation. 2) Determine the necessity and sufficiency of the SK3- mediated outward potassium current on asprosin-mediated AgRP neuron activation and appetite stimulation. 3) Map the anti-obesity potential of anti-asprosin monoclonal antibodies. At the completion of these aims we expect to determine the relevance of asprosin on central regulation of appetite and adiposity, and how this process can be manipulated to therapeutically impact obesity.