The Regulation of Circulating Hepatokines by Fructose Ingestion in Humans

Context: Fibroblast growth factor 21 (FGF21), follistatin, angiopoietin-like 4 (ANGPTL4), and growth differential factor 15 (GDF15) are regulated by energy metabolism. Recent findings in humans demonstrate that fructose ingestion increases circulating FGF21, with increased response in conditions of insulin resistance. Objective: This study examines the acute effect of fructose and somatostatin on circulating FGF21, follistatin, ANGPTL4, and GDF15 in humans. Methods: Plasma FGF21, follistatin, ANGPTL4, and GDF15 concentrations were measured in response to oral ingestion of 75 g of fructose in 10 young healthy males with and without a 15-minute infusion of somatostatin to block insulin secretion. A control infusion of somatostatin was also performed in the same subjects. Results: Following fructose ingestion, plasma FGF21 peaked at 3.7-fold higher than basal concentration (P < 0.05), and it increased 4.9-fold compared with basal concentration (P < 0.05) when somatostatin was infused. Plasma follistatin increased 1.8-fold after fructose ingestion (P < 0.05), but this increase was blunted by concomitant somatostatin infusion. For plasma ANGPTL4 and GDF15, no increases were obtained following fructose ingestion. Infusion of somatostatin alone slightly increased plasma FGF21 and follistatin. Conclusion: Here we show that in humans (1) the fructose-induced increase in plasma FGF21 was enhanced when somatostatin was infused, suggesting an inhibitory role of insulin on the fructose-induced FGF21 increase; (2) fructose ingestion also increased plasma follistatin, but somatostatin infusion blunted the increase; and (3) fructose ingestion had no stimulating effect on ANGPTL4 and GDF15 levels, demonstrating differences in the hepatokine response to fructose ingestion.