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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2016
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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. |
format | Online Article Text |
id | pubmed-5159669 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
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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