Regulation of satiation centers in health and obesity

健康和肥胖中饱食中心的监管

• 批准号: 10678993
• 负责人: John Nicholas Betley
• 金额: $ 35.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678993
• 关键词: Acute; Affect; Afferent Neurons; Anterior; Attenuated; Body Weight decreased; Brain; Cell Nucleus; Cerebellar Nuclei; Cerebellum; Chemicals; Chronic; Cues; Data; Development; Diet; Eating; Energy Intake; Energy Metabolism; Feeding behaviors; Food; Generations; Glutamates; Goals; Health; Hyperphagia; Hypothalamic structure; Lateral; Lesion; Metabolism; Monitor; Motor output; Mus; Neurons; Nutrient; Obesity; Operative Surgical Procedures; Pathway interactions; Pharmacotherapy; Physiological; Population; Prevalence; Public Health; Regulation; Research; Satiation; Sensory; Signal Pathway; Signal Transduction; Smell Perception; Synapses; Taste Perception; Testing; Therapeutic; Vagus nerve structure; Viral; Vision; Weight Gain; brain pathway; comorbidity; diet-induced obesity; experimental study; feeding; gut-brain axis; hindbrain; human subject; loss of function; neural; neurotransmission; novel; obesity development; obesity prevention; obesity treatment; pre-clinical assessment; prevent; response; therapeutic target; tool; translational approach

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.

项目概要 肥胖和相关合并症的流行是一个主要的公共卫生问题，具有重大意义 针对已知的食物摄入抑制的减肥药物疗法。 机制（例如后脑和下丘脑回路）在持续促进 这表明存在尚未识别的调节食物摄入的节点，并揭示了这一点。 这种机制有望开发出更有效的肥胖治疗方法。 最近使用“反向翻译”方法来识别和表征新的小脑群体 神经元及其对进食行为的重要性从人类受试者开始并跟进。 在小鼠的机制实验中，我们发现前、外侧深部的谷氨酸能神经元 小脑核 (aDCN-lat) 被食物激活，能够显着减少膳食量。 数据表明，谷氨酸 aDCN-lat 神经元是进食行为的关键调节因子，并强调 在此，我们利用这些发现来了解这一人群作为肥胖治疗的潜在目标。 这些小脑神经元的活动是如何受到调节的，以及它在肥胖中是如何改变的。 目的是 (1) 揭示激活小脑饱足感神经元的感觉、营养和肠脑通路，(2) 确定这些神经元的活动在肥胖症中如何变化，并且（3）测试这些神经元的长期活动是否 这些结果将提供一个神经元足以预防或逆转饮食引起的肥胖的结果。 全面了解小脑的进食行为机制，阐明一种新的饱足感 大脑中的中心可能是开发肥胖疗法的目标。