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

Abstract

Abbreviations: FGF21, fibroblast growth factor 21; NEFA, non-esterified fatty acid; OFTT, oral fructose tolerance test. Summary ObjectiveFibroblast 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. MethodsThirty-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. ResultsWomen 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. ConclusionsDaily 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.

FGF21 response to sucrose is associated with BMI and dorsal striatal signaling in humans

“…FGF21 response to sucrose was calculated as the total (AUC) 120 over the 120-minute testing period. We calculated total area under the curve at 35 minutes (AUC) 35 for plasma FGF21 and (AUC) 35 CBF in each ROI to quantify the FGF21 and neural responses to sucrose ingestion when both neuroimaging and blood sampling were simultaneously performed.…”

Impact of liver-specific GLUT8 silencing on fructose-induced inflammation and omega oxidation

“…Interestingly, despite females being at lower risk of NAFLD development when comparing with males (Balakrishnan et al, 2020;Lonardo et al, 2019), rodent data support the idea that this risk can increase when liver damage is mediated by fructose intake (Choi et al, 2017;Hyer et al, 2019;Spruss et al, 2012). Accordingly, human studies also revealed that women could be more affected than men by the ingestion of higher amounts of fructose than men and a fructose-rich diet sustained over time may lead to changes in hepatic fatty acid (FA) portioning and eventually to increased liver fat content (DiStefano, 2020a;Kang and Kim, 2017;Low et al, 2018;Rodgers et al, 2019). In line with this, studies in rats indicate that these sex differences were related to the fact that the liver enzyme fructokinase, which controlls fructose metabolism in the liver, was markedly induced by fructose liquid ingestion in females but not in males (Vila et al, 2011).…”

Sex Modifies the Association of Fibroblast Growth Factor 21 With Subclinical Carotid Atherosclerosis

“…It could be related to estrogen status, as it has been seen that activation of hepatic estrogen receptor-α increases energy expenditure by stimulating the production of FGF21 in female mice ( 15 ). In one study, baseline FGF21 levels were higher in females, and the levels decreased from baseline levels after increased fructose consumption in women only, suggestive of a possible difference in both secretion and sensitivity between the sex groups ( 16 ). A higher concentration of FGF21 has also been reported in female Danish children and adolescents, which was attributed to higher concentrations of triglycerides in females ( 17 ).…”