Increased fructose consumption has sex-specific effects on fibroblast growth factor 21 levels in humans

Fibroblast growth factor 21 (FGF21), a primarily hepatic hormone with pleotropic metabolic effects, is regulated by fructose in humans. Recent work has established that 75 g of oral fructose robustly stimulates FGF21 levels in humans with peak levels occurring 2 h following ingestion; this has been termed an oral fructose tolerance test (OFTT). It is unknown whether prolonged high-fructose consumption influences the FGF21 response to acute fructose or whether biological sex influences FGF21-fructose dynamics.

Thirty-nine healthy adults underwent baseline OFTT following an overnight fast. For the high-fructose exposure protocol, 20 subjects ingested 75 g of fructose daily for 14 ± 3 d, followed by repeat OFTT. For the control group, an OFTT was repeated following 14 ± 3 d of ad lib diet. For all subjects, FGF21 levels, glucose, insulin, non-esterified fatty acids and triglyceride levels were measured at baseline and 2 h following OFTT. All subjects maintained 3-d food logs prior to OFTT testing.

Women demonstrated significantly higher baseline and peak stimulated total and intact FGF21 levels compared with men both before and after high-fructose exposure. Baseline total and intact FGF21 levels decreased following ongoing fructose exposure, maintaining a stable ratio. This decrease was sex specific, with only women demonstrating decreased baseline FGF21 levels. There were no changes in metabolic or anthropometric parameters following the high-fructose exposure.

Daily ingestion of 75 g of fructose for 2 weeks results in a sex-specific decrease in baseline FGF21 levels without change in body weight or biochemical evidence of metabolic injury. There were also sex-specific differences in peak fructose-stimulated FGF21 levels, which do not change with high-fructose consumption. The role of FGF21 in the development of metabolic disease caused by fructose consumption may differ based on biological sex. Future long-term studies should consider sex differences in FGF21-fructose dynamics.