mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes.
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.
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.
Annabel Y
AY
Minard
Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
Shi-Xiong
SX
Tan
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.
Pengyi
P
Yang
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
Daniel J
DJ
Fazakerley
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
Westa
W
Domanova
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
Benjamin L
BL
Parker
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
Sean J
SJ
Humphrey
Systems Biology Section, Epigenetics & Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Raja
R
Jothi
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
Jacqueline
J
Stöckli
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.
David E
DE
James
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052242:Adiponectin / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D003847:Deoxyglucose / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007553:Isotope Labeling; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D050507:Subcutaneous Fat, Abdominal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
D052242:Adiponectin; C499919:Adipoq protein, mouse; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D020543:Proteome; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D003847:Deoxyglucose; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
FGF21; UCP1; adipocyte; insulin resistance; mTOR; mTORC1; obesity; phosphoproteome; phosphoproteomics; signaling
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