Upregulation of Skeletal Muscle FGF-21 Is Linked to Weight Loss following a Lifestyle Intervention in Humans with Obesity

Abstract

Skeletal muscle has emerged as an endocrine organ that is capable of secreting myokines that regulate metabolic function via interorgan crosstalk. Two of these myokines are fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF15). Both have been described as metabolic mediators that regulate energy homeostasis and insulin sensitivity, thus leading to increased weight loss in obese diabetic rodent models. We hypothesized that aerobic exercise would improve FGF-21 and GDF15 gene and protein expression in insulin resistant skeletal muscle. Older obese subjects (n=15; 66±1 years; 34±1 kg/m2) were recruited and participated in a 12-week supervised aerobic exercise training program (1h/d at ≈ 85% HRmax). Body composition, cardio-metabolic testing and vastus lateralis muscle biopsies were performed before and after the intervention; gene and protein expression were determined by quantitative-real time PCR and Western blot analysis, respectively. Lifestyle intervention increased clamp-derived insulin sensitivity, aerobic capacity (P<0.0001), and fat oxidation (P<0.05), and reduced body weight, BMI and fat mass (P≤0.0001). Exercise training increased expression of skeletal muscle myokines, FGF-21 (gene: P=0.05; protein: P=0.02) and GDF15 (gene: P=0.04). Changes in skeletal muscle FGF-21 were positively correlated with changes in GDF15 (r=0.61, P=0.02), as well as carnitine palmitoyl transferase 1B (r=0.54, P=0.03), and pyruvate dehydrogenase kinase 4 (r=0.52, P=0.05), enzymes important for lipid and glucose oxidation, respectively. The improvement in FGF-21 gene expression was negatively correlated with percent reduction in body weight (r=-0.63, P=0.009), BMI (r=-0.63, P=0.009) and fat mass (r=-0.61, P=0.02). We conclude that exercise training regulates FGF-21 and GDF15 myokine expression, and for FGF-21 this effect may contribute to loss of body fat, suggesting a novel role for FGF-21 in human adipose tissue metabolism. Disclosure A. Mulya: None. H. Zhang: None. J.P. Kirwan: None.