mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes
Annabel Y. Minard,
Shi-Xiong Tan,
Pengyi Yang,
Daniel J. Fazakerley,
Westa Domanova,
Benjamin L. Parker,
Sean J. Humphrey,
Raja Jothi,
Jacqueline Stöckli,
David E. James
Affiliations
Annabel Y. Minard
The Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
Shi-Xiong Tan
Institute of Molecular and Cell Biology, Singapore 138673, Singapore
Pengyi Yang
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
Daniel J. Fazakerley
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
Westa Domanova
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
Benjamin L. Parker
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
Sean J. Humphrey
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
Raja Jothi
Systems Biology Section, Epigenetics & Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
Jacqueline Stöckli
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
David E. James
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
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.
