title: FGF21 Improves the Adipocyte Dysfunction Related to Seipin Deficiency.
abstract: Fibroblast growth factor 21 (FGF21) was shown to improve metabolic homeostasis, at least partly by controlling white adipocyte profile and adiponectin secretion. Here, we studied its effect on adipocyte dysfunction in the context of Berardinelli-Seip congenital lipodystrophy (BSCL) linked to seipin deficiency. Bscl2-/-mice displayed a progressive adipose tissue loss with aging as evidenced by the altered profile of residual fat pads and the decrease in adiponectin plasma levels in 12- vs. 4-week-old animals. Aiming to prevent this impairment, we treated 6-week-old Bscl2-/-mice with an FGF21 analog (LY2405319) for a period of 28 days. FGF21 treatment increased adiponectin plasma levels and normalized insulin sensitivity in Bscl2-/-mice by improving the white adipose tissue gene expression pattern. To further decipher the molecular pathways altered by seipin deficiency in mature adipocytes, we developed a unique inducible seipin knockdown cell line (SKD). SKD showed chronic activation of the p38 MAPK pathway associated with apoptotic cell death. Interestingly, FGF21 treatment exerted an antistress effect on SKD cells, reducing p38 MAPK phosphorylation and limiting mature adipocyte loss. Our data demonstrate that FGF21 treatment improves the metabolic profile of Bscl2-/-lipodystrophic mice, partly by improving mature adipocyte maintenance through suppression of cellular stress via inhibition of p38 MAPK activity.
authors.affiliation: INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Dollet
authors.affiliation: INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France.
authors.forename: Clara
authors.initials: C
authors.lastname: Levrel
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN.
authors.forename: Tamer
authors.initials: T
authors.lastname: Coskun
authors.affiliation: Stress Oxydant et Pathologies Métaboliques, INSERM UMR 1063, Université d'Angers, Angers, France.
authors.forename: Soazig
authors.initials: S
authors.lastname: Le Lay
authors.affiliation: INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Le May
authors.affiliation: INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Ayer
authors.affiliation: INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Venara
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Gimeno
authors.affiliation: INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Magré
authors.affiliation: INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France.|Department of Endocrinology, l'Institut du Thorax, CHU de Nantes, Nantes, France.|Université de Nantes, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.affiliation: INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France xavier.prieur@univ-nantes.fr.|Université de Nantes, Nantes, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Prieur
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000187:drug effects / Q000378:metabolism*; D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000494:pharmacology*; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D052242:Adiponectin; C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; C585266:LY2405319; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D020962:Heterotrimeric GTP-Binding Proteins