Regulation of satiation centers in health and obesity

项目总结 肥胖及其相关并发症的流行是一个重大的公共卫生问题，具有显著的 个人和社会后果。针对已知食物摄取抑制的减肥药物疗法 机制(例如，后脑和下丘脑回路)在促进持续的 减肥。这表明存在着调节食物摄入量的尚未确定的结节，并发现了 这些机制为开发更有效的肥胖症治疗方法提供了希望。为此，我们 最近使用了一种“反向翻译”的方法来识别和描述一个新的小脑种群 神经元及其对摄食行为的重要性。从人类受试者开始，然后是 在小鼠的力学实验中，我们发现谷氨酸能神经元在前、外侧深部 小脑核团(aDCN-lat)被食物激活，并具有显著减少食物体积的能力。这些 数据表明，谷氨酸能aDCN-Lat神经元是摄食行为的关键调节者，并强调 将这一人群作为肥胖治疗的潜在目标。在这里，我们利用这些发现来理解 这些小脑神经元的活动是如何被调节的，以及它在肥胖中是如何改变的。这项提案的目标是 是为了(1)揭示激活小脑饱足神经元的感觉、营养和肠脑通路，(2) 确定肥胖时这些神经元的活动是如何变化的，以及(3)测试这些神经元的慢性活动 神经元足以预防或逆转饮食诱导的小鼠肥胖。这些结果将提供一个 全面了解小脑摄食行为的机制，揭示了一种新的饱腹感 这可能是开发肥胖治疗药物的靶点。

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.