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

Genes Dev. 2016 Nov 15;30(22):2551-2564. doi: 10.1101/gad.287953.116. Epub 2016 Dec 2.


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: FLCN; TFE3; adipose tissue; beige fat; mTOR; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Respiration / genetics
  • Cytoplasm / metabolism
  • Gene Deletion
  • Male
  • Mice
  • Mitochondria / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Bhd protein, mouse
  • Nuclear Proteins
  • PGC1B protein, mouse
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Tcfe3 protein, mouse
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 70-kDa