The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue

  1. Zoltan Arany1
  1. 1Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
  2. 2Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA;
  3. 3Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, New York, 10021, USA;
  4. 4Division of Cardiovascular Disease, University of Alabama, Birmingham, Alabama 35294, USA;
  5. 5Department of Anesthesia and Critical Care, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
  6. 6Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA
  1. Corresponding author: zarany{at}mail.med.upenn.edu
  1. 7 These authors contributed equally to this work.

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.

Keywords

Footnotes

  • Received August 1, 2016.
  • Accepted November 7, 2016.

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