biostudies-literatureWada STuberous Sclerosis AllianceNational Institute of Diabetes and Digestive and Kidney DiseasesNIA NIH HHSToyobo Biotechnology FoundationUniversity of PennsylvaniaNational Heart, Lung, and Blood InstituteNHLBI NIH HHSNational Institutes of HealthNational Research Foundation of KoreaNational Institute on AgingLAM FoundationNIDDK NIH HHSAmerican Diabetes AssociationNIGMS NIH HHS2551-2564https://www.ebi.ac.uk/biostudies/studies/S-EPMC5159669biostudies-literatureUnknown30(22)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.Genes & developmentThe tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue.PMC5159669AG0434831-16-PDF-117R01 GM051405T32 GM-07229P30 DK019525HL121266DK098656T32 GM007229R01 HL094499R01 DK107667R01 DK098656T32GM007592T32 GM007592GM51405P30 DK079626DK107667R01 DK103008R01 AG043483R01 HL121266HL094499Blenis JWada SJang CLi JMorley MPuertollano RLee GHoshino ASeale PNeinast MMartina JARowe GCBabu ARhee JIbrahim YHBaur JAArany ZfalseThe tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue.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.2016-01-01T00:00:00Z2016 Nov2024-10-19T00:08:52.787Z2019-03-27T02:31:39ZS-EPMC51596692791360310.1101/gad.287953.116