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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.