title: Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4) - a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity.
abstract: Fibroblast growth factor-1 (FGF-1) promotes differentiation of human preadipocytes into mature adipocytes via modulation of a BMP and Activin Membrane-Bound Inhibitor (BAMBI)/Peroxisome proliferator-activated receptor (PPARγ)-dependent network. Here, we combined transcriptomic and functional investigations to identify novel downstream effectors aligned with complementary analyses of gene expression in human adipose tissue to explore relationships with insulin sensitivity. RNA-Seq and qRT-PCR analysis revealed significant down-regulation of carboxypeptidase A4 (CPA4) following FGF-1 treatment or induction of differentiation of human preadipocytes in a BAMBI/PPARγ-independent manner. siRNA-mediated knockdown of CPA4 resulted in enhanced differentiation of human preadipocytes. Furthermore, expression of CPA4 in subcutaneous adipose tissue correlated negatively with indices of local and systemic (liver and muscle) insulin sensitivity. These results identify CPA4 as a negative regulator of adipogenesis that is down-regulated by FGF-1 and a putative deleterious modulator of local and systemic insulin sensitivity. Further investigations are required to define the molecular mechanism(s) involved and potential therapeutic opportunities.
authors.affiliation: a Laboratory of Animal Fat Deposition and Muscle Development , College of Animal Science and Technology, Northwest A&F University , Yangling , P.R. China.|b Mater Research Institute-University of Queensland, Translational Research Institute , Brisbane , Australia.
authors.forename: Jingjing
authors.initials: J
authors.lastname: He
authors.affiliation: c Garvan Institute of Medical Research , Sydney , Australia.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Chen
authors.affiliation: c Garvan Institute of Medical Research , Sydney , Australia.|d Faculty of Medicine , University of New South Wales , Randwick , Australia.
authors.forename: Dorit
authors.initials: D
authors.lastname: Samocha-Bonet
authors.affiliation: b Mater Research Institute-University of Queensland, Translational Research Institute , Brisbane , Australia.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Gillinder
authors.affiliation: b Mater Research Institute-University of Queensland, Translational Research Institute , Brisbane , Australia.
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Barclay
authors.affiliation: b Mater Research Institute-University of Queensland, Translational Research Institute , Brisbane , Australia.
authors.forename: Graham W
authors.initials: GW
authors.lastname: Magor
authors.affiliation: b Mater Research Institute-University of Queensland, Translational Research Institute , Brisbane , Australia.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Perkins
authors.affiliation: c Garvan Institute of Medical Research , Sydney , Australia.|d Faculty of Medicine , University of New South Wales , Randwick , Australia.|e Department of Endocrinology and Diabetes , St Vincent's Hospital , Sydney , Australia , and.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Greenfield
authors.affiliation: a Laboratory of Animal Fat Deposition and Muscle Development , College of Animal Science and Technology, Northwest A&F University , Yangling , P.R. China.
authors.forename: Gongshe
authors.initials: G
authors.lastname: Yang
authors.affiliation: b Mater Research Institute-University of Queensland, Translational Research Institute , Brisbane , Australia.|f School of Life Sciences , University of Lincoln , Lincolnshire , UK.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Whitehead
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis; D000328:Adult; D043422:Carboxypeptidases A / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism
chemical_list: C485671:BAMBI protein, human; D008565:Membrane Proteins; D047495:PPAR gamma; D016220:Fibroblast Growth Factor 1; C539656:CPA4, human; D043422:Carboxypeptidases A
keywords: FGF-1; carboxypeptidase; differentiation; obesity; preadipocyte