Regulation of satiation centers in health and obesity

项目摘要 肥胖和相关合并症的流行是一个主要的公共卫生问题， 个人和社会后果。针对已知食物摄入抑制的减肥药物治疗 机构（例如，后脑和下丘脑回路）在促进持续的 减肥.这表明存在尚未被确定的节点，调节食物摄入量， 这种机制为开发更有效的肥胖症治疗提供了希望。为此我们 最近使用"反向翻译"方法来鉴定和表征一种新的小脑 神经元及其对进食行为的重要性。从人类实验开始， 在小鼠的机械实验中，我们发现，在前，外侧深， 小脑核（aDCN-lat）被食物激活并具有显著减少膳食量的能力。这些 数据表明，多巴胺能aDCN-lat神经元是摄食行为的关键调节因子， 这一人群作为肥胖症治疗的潜在目标。在这里，我们利用这些发现来了解 这些小脑神经元的活动是如何被调节的，以及它在肥胖症中是如何被改变的。本提案的目标 （1）揭示激活小脑饱足神经元的感觉、营养和肠脑通路，（2） 确定这些神经元的活动如何在肥胖症中变化，以及（3）测试这些神经元的慢性活动是否 神经元足以预防或逆转小鼠中饮食诱导的肥胖。这些结果将提供一个 全面了解小脑机制的喂养行为，阐明了一种新的饱足感 大脑中的一个中心，可能是开发肥胖疗法的目标。

PROJECT SUMMARY The prevalence of obesity and associated comorbidities is a major public health concern with significant personal and societal consequences. Weight loss pharmacotherapies that target known food intake-inhibitory mechanisms (e.g., hindbrain and hypothalamic circuits) have been largely unsuccessful at promoting sustained weight loss. This suggests the existence of yet-to-be-identified nodes that regulate food intake, and uncovering such mechanisms holds promise for the development of more effective obesity treatments. To this end, we recently used a “reverse translational” approach to identify and characterize a novel population of cerebellar neurons and their importance to feeding behavior. Starting with human subjects and following up with mechanistic experiments in mice, we discovered that glutamatergic neurons in the anterior, lateral deep cerebellar nuclei (aDCN-lat) are activated by food and have the ability to dramatically reduce meal size. These data demonstrate that glutamatergic aDCN-lat neurons are critical regulators of feeding behavior, and highlight this population as a potential target for obesity therapeutics. Here, we leverage these findings to understand how activity in these cerebellar neurons is regulated and how it is altered in obesity. The goals of this proposal are to (1) reveal the sensory, nutritive, and gut-brain pathways that activate cerebellar satiation neurons, (2) determine how activity in these neurons changes in obesity, and (3) test whether chronic activity in these neurons is sufficient to prevent or reverse diet-induced obesity in mice. These results will provide a comprehensive understanding of cerebellar mechanisms for feeding behavior, illuminating a novel satiation center in the brain that may be targeted for the development obesity therapeutics.