Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure

描述（由申请人提供）：本提案的长期目标是阐明调节细胞能量平衡的机制。在这里，我们关注的是脂肪组织中的能量调节，重点关注棕色脂肪。对棕色脂肪生物能量学的兴趣正在迅速获得动力，因为最近认识到成年人拥有大量的棕色脂肪或棕色脂肪样细胞，这些细胞可能表现出有利于代谢的“脂肪燃烧”特性。据推测，通过治疗增加棕色脂肪的能量消耗可以预防肥胖。然而，重要的是，我们对控制脂肪组织能量消耗或棕色脂肪分化和功能的分子信号知之甚少。本提案的目的是验证雷帕霉素复合物2 （mTORC2）的机制靶点是棕色脂肪代谢和能量消耗的关键调节因子的假设。为了验证这一点，我们正在采用多学科方法，利用基因工程小鼠、原代细胞系和药理学试剂来研究mTORC2及其底物调节脂肪组织能量平衡的机制。我们的工作产生了非常有趣和意想不到的初步发现，表明抑制mTORC2可重编程细胞代谢，并可能增加棕色脂肪的活性。在Specific Aim 1中，我们阐明了mTORC2重编程代谢的机制。在具体目标2中，我们使用新型小鼠模型测试了我们的假设和初步发现的体内相关性。在Specific Aim 3中，我们询问是否通过药物抑制mTORC2可以治疗病理性脂肪堆积。阐明棕色脂肪中mTORC2控制下的代谢调控回路将对推进靶向细胞生物能量学的治疗具有重要意义。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the mechanisms that regulate cellular energy balance. Here, we are focusing on energy regulation in adipose tissue with a weighted focus on brown fat. Interest in brown fat bioenergetics is rapidly gaining momentum because of the recent realization that adult humans possess a significant quantity of brown fat or brown fat-like cells that may exhibit metabolically favorable "fat burning" properties. It is speculated that therapeutically increasing brown fat energy expenditure could defend against obesity. Importantly however, very little is known about the molecular signals that control energy expenditure in adipose tissue, or brown fat differentiation and function. The objective of this proposal is to test the hypothesis that the mechanistic target of rapamycin complex 2 (mTORC2) is a critical regulator of metabolism and energy expenditure in brown fat. To test this, we are taking a multidisciplinary approach utilizing genetically engineered mice, primary cell lines, and pharmacological agents to study the mechanisms by which mTORC2 and its substrates regulate energy balance in adipose tissue. Our work is yielding very interesting and unexpected preliminary findings that suggest inhibiting mTORC2 reprograms cellular metabolism and may increase brown fat activity. In Specific Aim 1, we elucidate the mechanism by which mTORC2 reprograms metabolism. In Specific Aim 2, we test the in vivo relevance of our hypothesis and our preliminary findings using novel mouse models. In Specific Aim 3, we ask if pharmacologically inhibiting mTORC2 can treat pathological fat accumulation. Elucidating the metabolic regulatory circuits under mTORC2 control in brown fat will have important implications in advancing therapies targeting cellular bioenergetics.