The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue
Year: 2016
Type: preprint
Abstract: Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1β. Conversely, inducible expression of PGC-1β in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN-mTOR-TFE3-PGC-1β pathway-separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue.
Source: Genes & Development
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Funders: American Diabetes Association, Tuberous Sclerosis Alliance, Foundation for Anesthesia Education and Research, LAM Foundation, University of Pennsylvania, Toyobo Biotechnology Foundation, National Research Foundation, National Research Foundation of Korea, National Institutes of Health, Perelman School of Medicine, University of Pennsylvania, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G106513794, G1282434780, G1442900148, G1477836796, G1520264287, G1562478528, G159650530, G1906021585, Molecular Mechanisms of Rapamycin's effects on Health and longevity., G2590212363, Training Program in Cell and Molecular Biology, PGC-1 Coactivators in Muscle Angiogenesis and Ischemia, G3933042922, G5284453959, G5600538792, G5881945070, G6139728891, G683675403, G7211347063, G7227154987, G779047860, G8072167325, G8084287657, G9000134944, G9000140883, G9000232846, G9000307706, G9000322763, Research Training for Anesthetists, University of Pennsylvania Diabetes Research Center, G91632081
OpenAlex ID: W2559545972