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Visualization and Quantification of Brown and Beige Adipose Tissues in Mice using [18F]FDG Micro-PET/MR Imaging
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The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue

Shogo Wada1, Michael Neinast1, Cholsoon Jang1,2

  • 1Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Genes & Development
|December 4, 2016
PubMed

Insights

Folliculin (FLCN) regulates fat browning through a novel mechanistic target of rapamycin (mTOR) pathway involving TFE3 and PGC-1β. This pathway is distinct from the canonical TSC-mTOR-S6K pathway.

Area of Science:

  • Cell Biology
  • Metabolism
  • Molecular Biology

Background:

  • Noncanonical mechanistic target of rapamycin (mTOR) pathways are not well understood.
  • Mutations in tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, characterized by kidney tumors.
  • FLCN's role in adipose tissue has not been previously explored.

Purpose of the Study:

  • To investigate the role of folliculin (FLCN) in regulating adipose tissue browning.
  • To elucidate the molecular mechanisms by which FLCN influences adipose tissue metabolism.
  • To identify novel pathways regulating adipose tissue browning.

Main Methods:

  • Adipose-specific deletion of FLCN in animal models.
  • Analysis of mTOR signaling and TFE3 localization.
  • Assessment of PGC-1 transcriptional coactivators and adipose tissue browning markers.
  • Genetic manipulation of TFE3 and PGC-1β expression.

Main Results:

  • FLCN deletion in adipose tissue leads to TFE3 release from mTOR-dependent cytoplasmic retention.
  • This results in the induction of PGC-1 coactivators, driving mitochondrial biogenesis and adipose tissue browning.
  • The FLCN-mTOR-TFE3-PGC-1β pathway is independent of canonical TSC-mTOR-S6K signaling.
  • Codeletion of TFE3 or PGC-1β rescues adipose tissue browning in FLCN knockout models.

Conclusions:

  • A novel FLCN-mTOR-TFE3-PGC-1β pathway regulates adipose tissue browning.
  • This pathway is distinct from the canonical TSC-mTOR-S6K pathway.
  • FLCN plays a critical role in controlling adipose tissue metabolism and energy expenditure.
Keywords:
FLCNTFE3adipose tissuebeige fatmTORmitochondria

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