ASPROSIN NEUTRALIZATION AS A NOVEL ANTI-OBESITY TREATMENT

阿斯丙素中和作为一种新型的抗肥胖治疗

基本信息

批准号：
10382263
负责人：
Atul Chopra
金额：
$ 40.8万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382263
关键词：
Acute Adipocytes Adipose tissue Adult Anti-Obesity Agents Antibodies Antidiabetic Drugs Appetite Regulation Appetite Stimulants Attenuated Biochemical Reaction Birth Blood - brain barrier anatomy Body Weight Brain Calories Chronic Clinical Cyclic AMP Dependence Depressed mood Desire for food Diabetes Mellitus Eating Energy Metabolism Environment Epitopes Event Evolution Fasting Food Frequencies Genetic Health Hepatic High Fat Diet Hormones Human Hyperphagia Hypothalamic structure Knowledge Laboratories Life Liver LoxP-flanked allele Mammals Maps Mediating Membrane Potentials Metabolic syndrome Modality Monoclonal Antibodies Mus Mutation Neurons Obese Mice Obesity Pathologic Peripheral Phenocopy Planet Earth Plasma Potassium Potassium Channel Process Proteins Reporting Second Messenger Systems Signal Transduction Structure of nucleus infundibularis hypothalami Syndrome Tamoxifen Testing Therapeutic Thinness Time Wiedemann-Rautenstrauch syndrome adiponectin blood glucose regulation diet-induced obesity gamma-Aminobutyric Acid glucose production improved in vivo increased appetite neutralizing antibody novel novel therapeutics obesity development obesity treatment obesogenic overexpression prevent

项目摘要

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.

项目概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。哺乳动物的反应通过激活刺激食欲的机制来禁食，同时增加肝葡萄糖生产，以保持大脑的营养和警觉，同时寻求和获取外源热量。这是通过大脑和肝脏中一系列酶促反应和过程来完成的由一系列激素精确协调。我们最近发现了一种称为白脂素的蛋白质激素，可以调节哺乳动物的葡萄糖稳态。从那时起，我们发现白脂素还可以通过激活大脑中产生食欲的 AgRP 神经元来调节食欲。下丘脑的弓形核。这导致下游厌食 POMC 神经元抑制， GABA依赖方式。这种白脂素介导的一系列事件会刺激食欲并产生欲望积累脂肪和体重。人类白脂素基因缺陷会导致综合征其特点是食欲低下和极度消瘦，携带类似突变的小鼠表现出同样的特征，并且完全通过纠正白脂素缺乏症得以挽救。肥胖的人和小鼠表现出病理性升高循环白脂素水平以及使用单克隆抗体中和血浆白脂素可降低食欲除了改善这些小鼠的血糖状况外，还改善了它们的体重。因此，白脂素除了执行生糖功能，是一种促食欲激素，抗白脂素抗体具有治疗作用作为双重作用的抗肥胖/抗糖尿病药物的潜力。该提案旨在以这些意见为基础广泛的目标是增强我们对白脂素的食欲促进作用和抗肥胖潜力的了解白脂素中和疗法。我们力求实现以下 3 个目标：1) 确定贡献脂肪来源的白脂素对 AgRP 神经元激活的影响。 2）确定SK3的必要性和充分性介导外向钾电流对白脂素介导的 AgRP 神经元激活和食欲刺激的影响。 3) 绘制抗白脂素单克隆抗体的抗肥胖潜力。完成这些目标后我们期望确定白脂素对食欲和肥胖的中枢调节的相关性，以及它如何可以操纵该过程来治疗肥胖。