Physiological modulation of circulating FGF21: relevance of free fatty acids and insulin

Fibroblast growth factor 21 (FGF-21), a novel metabolic factor in obesity and fasting metabolism, has been shown to be regulated by supraphysiological levels of free fatty acids (FFAs) under hyperinsulinemic conditions. Interestingly, it is still unclear whether the observed effects of FFAs on FGF-21 are relevant under physiological conditions, and the relative functions of FFAs and insulin within this context also need to be determined. Fourteen healthy men were studied in a randomized controlled crossover trial (RCT) using lipid heparin infusion (LHI) at a dose inducing physiological elevations of FFAs vs. saline heparin infusion. In a second randomized controlled trial, FGF-21 was analyzed in 14 patients with type 1 diabetes (6 men, 8 women) during continuous insulin supply vs. discontinued insulin infusion and subsequently increased lipolysis and ketosis. Circulating FGF-21 increased during physiologically elevated FFAs induced by LHI, which was accompanied by mild hyperinsulinemia. Interestingly, a mild elevation of FFAs resulting from complete insulin deficiency also increased FGF-21 levels. These results from two independent human RCTs suggest that FFAs increase circulating FGF-21, while insulin is only of minor importance under physiological conditions. This mechanism might explain the apparent paradox of increased FGF-21 levels in obesity, insulin resistance, and starvation.