Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure

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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.