Interdisciplinary Graduate Program
Program in Molecular Medicine
First Thesis Advisor
David A. Guertin, Ph.D.
Brown Adipose Tissue, Multiprotein Complexes, TOR Serine-Threonine Kinases, Brown Adipocytes, Lipogenesis, Thermogenesis, Forkhead Box Protein O1, mTORC2
Dissertations, UMMS; Adipose Tissue, Brown; Multiprotein Complexes; TOR Serine-Threonine Kinases; Adipocytes, Brown; Lipogenesis; Thermogenesis; Forkhead Box Protein O1
Recent 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.
Hung, C. mTORC2 Promotes Lipid Storage and Suppresses Thermogenesis in Brown Adipose Tissue in Part Through AKT-Independent Regulation of FoxO1: A Dissertation. (2016). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 845. DOI: 10.13028/M28C72. http://escholarship.umassmed.edu/gsbs_diss/845
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Available for download on Wednesday, November 01, 2017