Serum fibroblast growth factor 21 in human obesity: regulation by insulin infusion and relationship with glucose and lipid oxidation

OBJECTIVE: Fibroblast growth factor 21 (FGF21) reduces plasma glucose and triglycerides, and increases free fatty acid oxidation in animal models of diabetes. The aim of the present study was to assess the relationships of serum FGF21 with glucose oxidation (GOx) and lipid oxidation (LOx) in the baseline and insulin-stimulated conditions in lean and obese subjects. DESIGN: Cross-sectional study. SUBJECTS: Eighty-four subjects with normal glucose tolerance, 42 lean (body mass index (BMI) <25 kg m(-2)) and 42 overweight or obese (BMI between 25 and 40 kg m(-2)). MEASUREMENTS: Euglycemic hyperinsulinemic clamp and indirect calorimetry in the baseline state and during last 30 min of the clamp. The change in respiratory quotient (Delta RQ) in response to insulin was used as a measure of metabolic flexibility. Serum FGF21 was determined in the baseline state and after the clamp. RESULTS: Obese subjects had higher LOx in the baseline and insulin-stimulated conditions, lower insulin-stimulated GOx and Delta RQ (all P<0.05). Fasting serum FGF21 did not differ between the groups. Insulin infusion resulted in an increase in serum FGF21 in the obese (P=0.0001), but not in the lean group (P=0.76). Postclamp serum FGF21 was higher in the obese subjects (P=0.0007). In this group, postclamp FGF21 was related to LOx during the clamp (r=0.32, P=0.044), change in GOx and LOx in response to insulin (r=-0.44, P=0.005; r=0.47, P=0.002; respectively) and Delta RQ (r=-0.50, P=0.001). CONCLUSIONS: An increase in serum FGF21 in response to insulin in obese subjects might represent inappropriate response, possibly associated with metabolic inflexibility in obesity and insulin resistance.