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Cell Rep. 2016 Sep 27;17(1):29-36. doi: 10.1016/j.celrep.2016.08.086.

mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes.

Author information

1
The Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
2
Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
3
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; School of Mathematics and Statistics, University of Sydney, Sydney, NSW 2006, Australia.
4
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
5
Systems Biology Section, Epigenetics & Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
6
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; School of Medicine, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: david.james@sydney.edu.au.

Abstract

FGF21 improves the metabolic profile of obese animals through its actions on adipocytes. To elucidate the signaling network responsible for mediating these effects, we quantified dynamic changes in the adipocyte phosphoproteome following acute exposure to FGF21. FGF21 regulated a network of 821 phosphosites on 542 proteins. A major FGF21-regulated signaling node was mTORC1/S6K. In contrast to insulin, FGF21 activated mTORC1 via MAPK rather than through the canonical PI3K/AKT pathway. Activation of mTORC1/S6K by FGF21 was surprising because this is thought to contribute to deleterious metabolic effects such as obesity and insulin resistance. Rather, mTORC1 mediated many of the beneficial actions of FGF21 in vitro, including UCP1 and FGF21 induction, increased adiponectin secretion, and enhanced glucose uptake without any adverse effects on insulin action. This study provides a global view of FGF21 signaling and suggests that mTORC1 may act to facilitate FGF21-mediated health benefits in vivo.

KEYWORDS:

FGF21; UCP1; adipocyte; insulin resistance; mTOR; mTORC1; obesity; phosphoproteome; phosphoproteomics; signaling

PMID:
27681418
DOI:
10.1016/j.celrep.2016.08.086
[Indexed for MEDLINE]
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