PMID- 27913603
OWN - NLM
STAT- MEDLINE
DCOM- 20170614
LR  - 20231213
IS  - 1549-5477 (Electronic)
IS  - 0890-9369 (Print)
IS  - 0890-9369 (Linking)
VI  - 30
IP  - 22
DP  - 2016 Nov 15
TI  - The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning 
      of adipose tissue.
PG  - 2551-2564
AB  - Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly 
      understood. Mutations in the tumor suppressor folliculin (FLCN) cause 
      Birt-Hogg-Dube 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-1beta. Conversely, inducible expression of PGC-1beta in white 
      adipose tissue is sufficient to induce beige fat gene expression in vivo. These 
      data thus unveil a novel FLCN-mTOR-TFE3-PGC-1beta pathway-separate from the 
      canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue.
CI  - (c) 2016 Wada et al.; Published by Cold Spring Harbor Laboratory Press.
FAU - Wada, Shogo
AU  - Wada S
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Neinast, Michael
AU  - Neinast M
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Jang, Cholsoon
AU  - Jang C
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
AD  - Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey 
      08544, USA.
FAU - Ibrahim, Yasir H
AU  - Ibrahim YH
AD  - Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New 
      York, New York, 10021, USA.
FAU - Lee, Gina
AU  - Lee G
AD  - Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New 
      York, New York, 10021, USA.
FAU - Babu, Apoorva
AU  - Babu A
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Li, Jian
AU  - Li J
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Hoshino, Atsushi
AU  - Hoshino A
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Rowe, Glenn C
AU  - Rowe GC
AD  - Division of Cardiovascular Disease, University of Alabama, Birmingham, Alabama 
      35294, USA.
FAU - Rhee, James
AU  - Rhee J
AD  - Department of Anesthesia and Critical Care, Cardiovascular Research Center, 
      Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
FAU - Martina, Jose A
AU  - Martina JA
AD  - Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, 
      National Institutes of Health, Bethesda, Maryland 20814, USA.
FAU - Puertollano, Rosa
AU  - Puertollano R
AD  - Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, 
      National Institutes of Health, Bethesda, Maryland 20814, USA.
FAU - Blenis, John
AU  - Blenis J
AD  - Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New 
      York, New York, 10021, USA.
FAU - Morley, Michael
AU  - Morley M
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Baur, Joseph A
AU  - Baur JA
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Seale, Patrick
AU  - Seale P
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Arany, Zoltan
AU  - Arany Z
AD  - Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
LA  - eng
GR  - R01 DK098656/DK/NIDDK NIH HHS/United States
GR  - R01 HL121266/HL/NHLBI NIH HHS/United States
GR  - R01 DK107667/DK/NIDDK NIH HHS/United States
GR  - P30 DK079626/DK/NIDDK NIH HHS/United States
GR  - T32 GM007229/GM/NIGMS NIH HHS/United States
GR  - R01 HL094499/HL/NHLBI NIH HHS/United States
GR  - R01 GM051405/GM/NIGMS NIH HHS/United States
GR  - T32 GM007592/GM/NIGMS NIH HHS/United States
GR  - R01 DK103008/DK/NIDDK NIH HHS/United States
GR  - P30 DK019525/DK/NIDDK NIH HHS/United States
GR  - R01 AG043483/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20161202
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (Bhd protein, mouse)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Ppargc1b protein, mouse)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 136896-33-8 (Tcfe3 protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adipose Tissue, Brown/*metabolism
MH  - Adipose Tissue, White/*metabolism
MH  - Animals
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism
MH  - Cell Respiration/genetics
MH  - Cytoplasm/metabolism
MH  - Gene Deletion
MH  - Male
MH  - Mice
MH  - Mitochondria/genetics
MH  - Nuclear Proteins/genetics/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transcription Factors/genetics/metabolism
MH  - Tumor Suppressor Proteins/genetics/*metabolism
PMC - PMC5159669
OTO - NOTNLM
OT  - FLCN
OT  - TFE3
OT  - adipose tissue
OT  - beige fat
OT  - mTOR
OT  - mitochondria
EDAT- 2016/12/04 06:00
MHDA- 2017/06/15 06:00
PMCR- 2017/05/15
CRDT- 2016/12/04 06:00
PHST- 2016/08/01 00:00 [received]
PHST- 2016/11/07 00:00 [accepted]
PHST- 2016/12/04 06:00 [pubmed]
PHST- 2017/06/15 06:00 [medline]
PHST- 2016/12/04 06:00 [entrez]
PHST- 2017/05/15 00:00 [pmc-release]
AID - gad.287953.116 [pii]
AID - 10.1101/gad.287953.116 [doi]
PST - ppublish
SO  - Genes Dev. 2016 Nov 15;30(22):2551-2564. doi: 10.1101/gad.287953.116. Epub 2016 
      Dec 2.