title: The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue.
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.
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shogo
authors.initials: S
authors.lastname: Wada
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Neinast
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Cholsoon
authors.initials: C
authors.lastname: Jang
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, New York, 10021, USA.
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Ibrahim
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, New York, 10021, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Apoorva
authors.initials: A
authors.lastname: Babu
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: Division of Cardiovascular Disease, University of Alabama, Birmingham, Alabama 35294, USA.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.affiliation: Department of Anesthesia and Critical Care, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: James
authors.initials: J
authors.lastname: Rhee
authors.affiliation: Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Martina
authors.affiliation: Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Puertollano
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, New York, 10021, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Morley
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Seale
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D019069:Cell Respiration / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C526060:Bhd protein, mouse; D009687:Nuclear Proteins; C000620215:Ppargc1b protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C068486:Tcfe3 protein, mouse; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: FLCN; TFE3; adipose tissue; beige fat; mTOR; mitochondria