MC3R inhibition as a strategy to maintain weight loss in obesity

提案摘要： 肥胖症和相关代谢综合征的发病率不断增加，这是一个重大的公共卫生问题。 尽管存在用于减肥的行为（饮食和/或锻炼）、手术和药理学方式，但许多方法都是有效的。 由于大脑中的行为和神经内分泌适应， 促进体重恢复。因此，阻止对体重减轻的补偿性适应的途径将 为解决肥胖症治疗难题提供了一种全新的方法。下丘脑刺豚鼠相关肽 （AgRP）神经元被饥饿和节食激活，并有效地参与行为和神经内分泌 神经回路来驱动行为，促进食物摄入量增加和体重反弹。我们发现 黑皮质素3受体在AgRP神经元中密集表达，97%的AgRP神经元含有 MC3R此外，MC 3R的药理学操作双向调节AgRP中的摄食， 神经元依赖性方式，激动MC 3R刺激摄食，拮抗MC 3R抑制摄食， 喂食因此，MC 3R功能受损的小鼠在禁食和禁食后不能正常再进食。 热量限制和不能充分激活神经内分泌反应减肥。在本提案中，我们 将评估MC 3R特异性拮抗剂作为预防代偿性心肌梗死的治疗策略的效用。 对减肥的反应。我们还将确定细胞和分子机制（S）介导 MC 3R拮抗作用的促凋亡作用。本次培训补助金的主要研究员，帕特里克博士 Sweeney在行为神经科学和小鼠喂养行为方面拥有丰富的经验。在此次培训中 斯威尼博士将接受代谢生理学、神经内分泌学、肥胖学 生物学和药理学，来自主要研究导师罗杰·科恩博士。此外，根据 在合作者专家团队的指导下，Sweeney博士将接受大脑切片的实践培训。 电生理学和体内显微镜脑成像。在这方面的指导和培训 K99/R 00应用程序将为Sweeney博士提供必要的技术和概念背景， 启动一项独立的研究计划，重点关注MC 3R神经回路作为肥胖症的治疗靶点 和饮食失调

Proposal Summary: The increasing rates of obesity and associated metabolic syndrome pose a major public health concern. Although behavioral (diet and/or exercise), surgical, and pharmacological modalities exist for weight loss, many individuals are unable to maintain this weight loss due to behavioral and neuroendocrine adaptions in the brain promoting weight re-gain. Therefore, pathways preventing compensatory adaptations to weight loss would provide a wholly novel approach to the conundrum of obesity treatment. Hypothalamic agouti-related peptide (AgRP) neurons are activated by hunger and dieting and potently engage behavioral and neuroendocrine neural circuits to drive behaviors promoting increased food intake and rebound weight gain. Here, we show that the melanocortin 3 receptor is densely expressed in AgRP neurons, with 97% of AgRP neurons containing MC3R. Furthermore, pharmacological manipulation of MC3R bi-directionally regulates feeding in an AgRP neuron dependent manner, with agonism of MC3R stimulating feeding and antagonism of MC3R suppressing feeding. Consistently, mice with impaired MC3R function do not re-feed normally following both fasting and caloric restriction and fail to adequately activate neuroendocrine responses to weight loss. In this proposal, we will evaluate the utility of MC3R specific antagonists as a therapeutic strategy for preventing compensatory responses to weight loss. We will also determine the cellular and molecular mechanism(s) mediating the anorexigenic effects of MC3R antagonism. The principle investigator in this training grant, Dr. Patrick Sweeney, has extensive experience in behavioral neuroscience and mouse feeding behavior. In this training grant, Dr. Sweeney will receive additional training in metabolic physiology, neuroendocrinology, obesity biology, and pharmacology from the primary research mentor, Dr. Roger Cone. Furthermore, under the guidance of an expert team of collaborators, Dr. Sweeney will receive hands on training in brain slice electrophysiology and in vivo endomicroscopic brain imaging. Together, the mentorship and training in this K99/R00 application will provide the necessary technical and conceptual background for Dr. Sweeney to initiate an independent research program focusing on MC3R neural circuits as therapeutic targets for obesity and eating disorders.