FGF21 promotes metabolic homeostasis via white adipose and leptin in mice

• Published in: PloS one 2012-07, Vol.7 (7), p.e40164
• Main Authors: Véniant, Murielle M, Hale, Clarence, Helmering, Joan, Chen, Michelle M, Stanislaus, Shanaka, Busby, Jim, Vonderfecht, Steven, Xu, Jing, Lloyd, David J
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipose tissue; Adipose Tissue, White - drug effects; Adipose Tissue, White - metabolism; Adipose Tissue, White - transplantation; Animals; Anticholesteremic agents; Biology; Body composition; Body fat; Body weight; Cholesterol; Congenital diseases; Diabetes; Diabetes mellitus; Disease Models, Animal; Female; Fibroblast growth factor; Fibroblast growth factor receptor 1; Fibroblast growth factors; Fibroblast Growth Factors - administration & dosage; Fibroblast Growth Factors - metabolism; Fibroblast Growth Factors - pharmacology; Fibroblasts; Gene expression; Gene Expression Regulation - drug effects; Genotype & phenotype; Glucose; Glucose - metabolism; Glucose tolerance; Growth factors; Homeostasis; Homeostasis - drug effects; Humans; Immunological tolerance; Insulin; Insulin resistance; Kinases; Leptin; Leptin - administration & dosage; Leptin - metabolism; Leptin - pharmacology; Lipids; Lipodystrophy; Lipodystrophy - genetics; Lipodystrophy - metabolism; Lipodystrophy - therapy; Liver; Liver transplants; Male; Medicine; Metabolic disorders; Mice; Mice, Transgenic; Obesity; Overexpression; Pharmacology; Phosphatase; PPAR gamma - genetics; PPAR gamma - metabolism; Protein binding; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Rodents; Signal Transduction; Signaling; Sterol regulatory element-binding protein; Transgenic animals; Transplantation; Triglycerides
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040164

Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator, and pharmacological administration elicits glucose and lipid lowering responses in mammals. To delineate if adipose tissue is the predominant organ responsible for anti-diabetic effects of FGF21, we treated mice with reduced body fat (lipodystrophy mice with adipose specific expression of active sterol regulatory element binding protein 1c; Tg) with recombinant murine FGF21 (rmuFGF21). Unlike wildtype (WT) mice, Tg mice were refractory to the beneficial effects of rmuFGF21 on body weight, adipose mass, plasma insulin and glucose tolerance. To determine if adipose mass was critical for these effects, we transplanted WT white adipose tissue (WAT) into Tg mice and treated the mice with rmuFGF21. After transplantation, FGF21 responsiveness was completely restored in WAT transplanted Tg mice compared to sham Tg mice. Further, leptin treatment alone was sufficient to restore the anti-diabetic effects of rmuFGF21 in Tg mice. Molecular analyses of Tg mice revealed normal adipose expression of Fgfr1, Klb and an 8-fold over-expression of Fgf21. Impaired FGF21-induced signaling indicated that residual adipose tissue of Tg mice was resistant to FGF21, whilst normal FGF21 signaling was observed in Tg livers. Together these data suggest that adipose tissue is required for the triglyceride and glucose, but not the cholesterol lowering efficacy of FGF21, and that leptin and FGF21 exert additive anti-diabetic effects in Tg mice.