title: Downstream signaling pathways in mouse adipose tissues following acute in vivo administration of fibroblast growth factor 21.
abstract: FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation.
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey, United States of America.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Muise
authors.forename: Sandra
authors.initials: S
authors.lastname: Souza
authors.forename: An
authors.initials: A
authors.lastname: Chi
authors.forename: Yejun
authors.initials: Y
authors.lastname: Tan
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhao
authors.forename: Franklin
authors.initials: F
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Dallas-Yang
authors.forename: Margaret
authors.initials: M
authors.lastname: Wu
authors.forename: Tim
authors.initials: T
authors.lastname: Sarr
authors.forename: Lan
authors.initials: L
authors.lastname: Zhu
authors.forename: Hongbo
authors.initials: H
authors.lastname: Guo
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Wenyu
authors.initials: W
authors.lastname: Li
authors.forename: Weiwen
authors.initials: W
authors.lastname: Hu
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Jiang
authors.forename: Cloud P
authors.initials: CP
authors.lastname: Paweletz
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Hendrickson
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.forename: James
authors.initials: J
authors.lastname: Mu
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Huseyin
authors.initials: H
authors.lastname: Mehmet
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects; D016000:Cluster Analysis; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D020543:Proteome; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010750:Phosphoproteins; D020543:Proteome; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
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