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

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...

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Autores principales: Wada, Shogo, Neinast, Michael, Jang, Cholsoon, Ibrahim, Yasir H., Lee, Gina, Babu, Apoorva, Li, Jian, Hoshino, Atsushi, Rowe, Glenn C., Rhee, James, Martina, José A., Puertollano, Rosa, Blenis, John, Morley, Michael, Baur, Joseph A., Seale, Patrick, Arany, Zoltan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159669/
https://www.ncbi.nlm.nih.gov/pubmed/27913603
http://dx.doi.org/10.1101/gad.287953.116
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author Wada, Shogo
Neinast, Michael
Jang, Cholsoon
Ibrahim, Yasir H.
Lee, Gina
Babu, Apoorva
Li, Jian
Hoshino, Atsushi
Rowe, Glenn C.
Rhee, James
Martina, José A.
Puertollano, Rosa
Blenis, John
Morley, Michael
Baur, Joseph A.
Seale, Patrick
Arany, Zoltan
author_facet Wada, Shogo
Neinast, Michael
Jang, Cholsoon
Ibrahim, Yasir H.
Lee, Gina
Babu, Apoorva
Li, Jian
Hoshino, Atsushi
Rowe, Glenn C.
Rhee, James
Martina, José A.
Puertollano, Rosa
Blenis, John
Morley, Michael
Baur, Joseph A.
Seale, Patrick
Arany, Zoltan
author_sort Wada, Shogo
collection PubMed
description 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.
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spelling pubmed-51596692017-05-15 The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue Wada, Shogo Neinast, Michael Jang, Cholsoon Ibrahim, Yasir H. Lee, Gina Babu, Apoorva Li, Jian Hoshino, Atsushi Rowe, Glenn C. Rhee, James Martina, José A. Puertollano, Rosa Blenis, John Morley, Michael Baur, Joseph A. Seale, Patrick Arany, Zoltan Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2016-11-15 /pmc/articles/PMC5159669/ /pubmed/27913603 http://dx.doi.org/10.1101/gad.287953.116 Text en © 2016 Wada et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Wada, Shogo
Neinast, Michael
Jang, Cholsoon
Ibrahim, Yasir H.
Lee, Gina
Babu, Apoorva
Li, Jian
Hoshino, Atsushi
Rowe, Glenn C.
Rhee, James
Martina, José A.
Puertollano, Rosa
Blenis, John
Morley, Michael
Baur, Joseph A.
Seale, Patrick
Arany, Zoltan
The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue
title The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue
title_full The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue
title_fullStr The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue
title_full_unstemmed The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue
title_short The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue
title_sort tumor suppressor flcn mediates an alternate mtor pathway to regulate browning of adipose tissue
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159669/
https://www.ncbi.nlm.nih.gov/pubmed/27913603
http://dx.doi.org/10.1101/gad.287953.116
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