Neuronal pathways regulating metabolic adaptation

项目摘要 三分之二的美国人超重或肥胖。稳定地降低体重是非常具有挑战性的 这是由于一种代偿性的体内平衡机制--代谢适应--降低了身体的代谢率 以防止体重进一步下降。预防或逆转代谢适应将提供一个强大的新的 肥胖症的治疗;然而，代谢适应和体重的分子和神经元基础 内稳态仍然知之甚少。热量限制（CR）小鼠显示出降低的代谢率， 这表明小鼠可以用作研究代谢适应的模型。使用CR小鼠模型， 该提案旨在研究代谢适应的神经元基础。在初步研究中，申请人 使用最近开发的遗传工具来标记大脑中在热量限制期间活跃的神经元。 随后，这些神经元在非禁食状态下的化学发生性再激活足以降低神经元的存活率。 代谢率表明，这一策略成功地捕获，或陷阱，人口的代谢- 适应调节（MAR）神经元。这项提案的目标是首先确定，然后在分子上， 在卡路里限制期间，对MAR神经元进行生理学表征，以阐明 它们诱导代谢适应。该提案包含一个全面的培训和研究计划， 通过在短期内表征这些神经元，并通过促进建立 一个创新的多学科研究项目，专注于研究能量平衡和体重 长期的自我平衡。在目标1中，申请人将完成初步的大脑功能筛查 区域，以确定MAR神经元的解剖位置，并测试它们的活动是否足够， 这是代谢适应热量限制所必需的。在目标2中，申请人将学习和应用工具来绘制 MAR神经元的突触输入和目标，以识别代谢适应回路的新组件。 在目标3中，申请人将学习和应用技术来监测清醒、行为CR中的神经元活动。 动物，以确定由MAR神经元编码的信息，并产生关于其 在体重平衡反馈回路中起作用。最后，在目标4中，申请人将使用单细胞 转录组学用于分子鉴定MAR神经元，从而能够产生细胞类型特异性试剂， 发现新的靶点来调节它们的活性并防止或逆转体重增加期间的代谢适应 损失具体的技术培训活动，以研究神经元的活动模式，并绘制其突触 将通过几位非常成功的科学家的集中指导来加强联系， 致力于帮助申请人获得专业和智力技能， 哈佛医学院的合作培训环境。这个密集的职业发展计划是 旨在促进申请人的独立研究生涯的成功启动，专注于研究 一个学术机构的能量平衡。

PROJECT SUMMARY Two thirds of the US population are overweight or obese. Stably lowering the body weight is highly challenging due to a compensatory homeostatic mechanism - metabolic adaptation - which lowers the body’s metabolic rate to prevent further weight loss. Preventing or reversing metabolic adaptation would provide a powerful new treatment for obesity; however, the molecular and neuronal basis of metabolic adaptation and body weight homeostasis remain poorly understood. Calorically restricted (CR) mice display decreased metabolic rates, suggesting that mice could be used as a model to study metabolic adaptation. Using a CR mouse model, this proposal aims to investigate the neuronal basis of metabolic adaptation. In preliminary studies, the applicant used recently developed genetic tools to label neurons, across the brain, that are active during caloric restriction. Subsequent chemogenetic reactivation of these neurons in a non-fasted state was sufficient to lower the metabolic rate suggesting that this strategy successfully captured, or TRAPed, a population of metabolic- adaptation-regulating (MAR) neurons. The goal of this proposal is to first identify and then molecularly and physiologically characterize MAR neurons during calorie restriction to shed light on the mechanism by which they induce metabolic adaptation. This proposal contains a comprehensive training and research plan to build upon these initial findings by characterizing these neurons in the short-term, and by facilitating the establishment of an innovative and multidisciplinary research program focused on studying energy balance and body weight homeostasis in the long-term. In Aim 1, the applicant will complete the preliminary functional screen across brain regions to identify the anatomical location of MAR neurons and test whether their activity is both sufficient and necessary for metabolic adaptation to caloric restriction. In Aim 2, the applicant will learn and apply tools to map the synaptic inputs and targets of MAR neurons to identify new components of the metabolic adaptation circuit. In Aim 3, the applicant will learn and apply techniques to monitor neuronal activity in awake, behaving CR animals to determine the information encoded by MAR neurons and generate hypotheses regarding their function in the body weight homeostasis feedback circuit. Finally, in Aim 4, the applicant will use single-cell transcriptomics to molecularly identify MAR neurons, enabling the generation of cell-type-specific reagents and the discovery of new targets to modulate their activity and prevent or reverse metabolic adaptation during weight loss. Specific technical training activities to investigate neuron’s activity patterns and map their synaptic connections will be augmented by focused mentorship from several highly successful scientists who are committed to aiding in the applicant’s acquisition of professional and intellectual skills in the highly energetic and collaborative training environment at Harvard Medical School. This intensive career development plan is designed to facilitate the successful launch of the applicant’s independent research career, focused on studying energy balance at an academic institution.