Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure

这项提议的长期目标是阐明调节能量平衡的机制。在这里，我们研究脂肪组织中脂肪处理和能量平衡的调节，特别关注阐明信号转导通路如何与代谢通路相交来控制产热和胰岛素敏感性。健康的脂肪细胞在系统营养供应和热应激的波动时，动态地在合成代谢和分解代谢脂肪代谢之间切换，以支持机体的能量需求。维持这种代谢的灵活性依赖于信号，使从头合成的脂肪酸和三酰甘油与脂肪分解和脂肪酸氧化紧密协调。由于不明原因，超重或肥胖会损害这种代谢灵活性，并导致慢性疾病，如胰岛素抵抗、2型糖尿病、脂肪肝、心血管疾病和某些癌症。这项研究的长期目标是了解脂肪细胞如何感知和响应营养以控制能量平衡的分子基础，以及过度营养如何重新编程这些信号回路从而导致疾病。这项建议的具体目的是阐明雷帕霉素复合体2(MTORC2)的机制靶点(MTORC2)是脂肪细胞脂代谢的关键调节因子，它将全身营养物质的获得与细胞内代谢控制联系在一起。为了测试这一点，我们采取了一种多学科的方法，利用基因工程小鼠、原代细胞系和药理学试剂，结合最先进的蛋白质组学和代谢物图谱，描绘了mTORC2直接和间接控制下的下游代谢回路，这些代谢回路与脂肪组织相关疾病相关。我们之前在该项目中的工作显示，在棕色脂肪细胞中抑制mTORC2可以增强饮食诱导的生热作用，在白色脂肪组织中抑制mTORC2会导致严重的胰岛素抵抗，ChREBP是一种新的mTORC2效应器，它调节mTORC2下游的从头脂肪生成，并且棕色和白色脂肪中mTORC2缺失的后果在表型上类似于糖尿病致高脂饮食对这些组织的影响。在此基础上，我们将在目标1中继续阐明mTORC2调节脂肪细胞代谢的机制，在目标2中研究mTORC2缺失和高脂饮食对脂肪细胞代谢的机制相似性和潜在联系，并在目标3中探索mTORC2直接控制下调节脂肪细胞脂肪代谢的新的转录电路。阐明营养感应信号通路如何将营养信号与脂肪细胞的代谢调节联系起来，对于推进肥胖症、2型糖尿病和相关代谢性疾病的治疗具有重要意义。

The long-term goal of this proposal is to elucidate mechanisms that regulate energy balance. Here, we investigate the regulation of lipid handling and energy homeostasis in adipose tissue with a specific focus on elucidating how signal transduction pathways intersect with metabolic pathways to control thermogenesis and insulin sensitivity. Healthy adipocytes dynamically switch between anabolic and catabolic lipid metabolism upon fluctuations in systemic nutrient availability and thermal stress to support the organism's energetic demands. Maintaining this metabolic flexibility depends upon signals that tightly coordinate de novo fatty acid and triacylglycerol synthesis with lipolysis and fatty acid oxidation. For unclear reasons, overweight or obesity impairs this metabolic flexibility and leads to chronic diseases such as insulin resistance, T2DM, fatty liver disease, cardiovascular disease, and certain cancers. The long-term goal of this research is to understand the molecular basis of how adipocytes sense and respond to nutrients to control energy balance, and how over-nutrition reprograms these signaling circuits to cause disease. The specific objective of this proposal is to elucidate the mechanisms by which the mechanistic target of rapamycin complex 2 (mTORC2), which we previously showed is a key regulator of adipocyte lipid metabolism, links systemic nutrient availability with intracellular metabolic control. To test this, we are taking a multidisciplinary approach utilizing genetically engineered mice, primary cell lines, and pharmacological agents in combination with state-of-the-art proteomics and metabolite profiling to delineate the downstream metabolic circuits under direct and indirect mTORC2 control that are relevant to adipose tissue related diseases. Our previous work on this project revealed that inhibiting mTORC2 in brown adipocytes enhances diet-induced thermogenesis, that inhibiting mTORC2 in white adipose tissue causes severe insulin resistance, that ChREBP is a novel mTORC2 effector that regulates de novo lipogenesis downstream of mTORC2, and that the consequences of mTORC2 loss in brown and white fat are phenotypically similar to the effects of a diabetogenic high fat diet on these tissues. Building upon this knowledge base, we will continue elucidating the mechanisms by which mTORC2 programs adipocyte metabolism in Aim 1, investigate the mechanistic similarities and potential connection between mTORC2 loss and high fat diet on adipocyte metabolism in Aim 2, and investigate a novel transcriptional circuit under direct mTORC2 control that regulates adipocyte lipid metabolism in Aim 3. Elucidating how nutrient-sensing signaling pathways like the mTOR pathway link nutritional signals to metabolic regulation in adipocytes has important implications for advancing therapies to treat obesity, type 2 diabetes, and related metabolic diseases.