David A. Guertin, Ph.D.Hung, Chien-Min2022-08-232022-08-232016-10-232016-11-2810.13028/M28C72https://hdl.handle.net/20.500.14038/32218Recent studies suggest adipose tissue plays a critical role in regulating whole body energy homeostasis in both animals and humans. In particular, activating brown adipose tissue (BAT) activity is now appreciated as a potential therapeutic strategy against obesity and metabolic disease. However, the signaling circuits that coordinate nutrient uptake and BAT function are poorly understood. Here, I investigated the role of the nutrient-sensing mTOR signaling pathway in BAT by conditionally deleting Rictor, which encodes an essential component of mTOR Complex 2 (mTORC2) either in brown adipocyte precursors or mature brown adipocytes. In general, inhibiting BAT mTORC2 reduces glucose uptake and de novo lipogenesis pathways while increases lipid uptake and oxidation pathways indicating a switch in fuel utilization. Moreover, several key thermogenic factors (Ucp1, Pgc1α, and Irf4) are elevated in Rictor-deficient BAT, resulting in enhanced thermogenesis. Accordingly, mice with mTORC2 loss in BAT are protected from HFD-induced obesity and metabolic disease at thermoneutrality. In vitro culture experiments further suggest that mTORC2 cell-autonomously regulates the BAT thermogenic program, especially Ucp1 expression, which depends on FoxO1 activity. Mechanistically, mTORC2 appears to inhibit FoxO1 by facilitating its lysine-acetylation but not through the canonical AKT-mediated phosphorylation pathway. Finally, I also provide evidence that β-adrenergic signaling which normally triggers thermogenesis also induces FoxO1 deacetylation in BAT. Based on these data, I propose a model in which mTORC2 functions in BAT as a critical signaling hub for coordinating nutrient uptake, fuel utilization, and thermogenic gene expression. These data provide a foundation for future studies into the mTORC2-FoxO1 signaling axis in different metabolic tissues and physiological conditions.en-USCopyright is held by the author, with all rights reserved.Dissertations, UMMSAdipose Tissue, BrownMultiprotein ComplexesTOR Serine-Threonine KinasesAdipocytes, BrownLipogenesisThermogenesisForkhead Box Protein O1Brown Adipose TissueMultiprotein ComplexesTOR Serine-Threonine KinasesBrown AdipocytesLipogenesisThermogenesisForkhead Box Protein O1mTORC2BiochemistryCellular and Molecular PhysiologyMolecular BiologyDoctoral Dissertationhttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1856&context=gsbs_diss&unstamped=1https://escholarship.umassmed.edu/gsbs_diss/8459416750gsbs_diss/845