Fibroblast growth factor 21 and fructose dynamics in humans

Abstract

SummaryObjectiveFructose consumption is a risk factor for metabolic disease. We recently demonstrated that fibroblast growth factor 21 (FGF21), a metabolic hormone involved in lipid and glucose metabolism, is acutely stimulated in humans by 75 g oral fructose, with peak levels occurring 2 h after consumption. This study reports on the dose dependency and reproducibility of the FGF21 response to fructose.MethodsLean, healthy adults drank either five different doses of fructose dissolved in water, each separated by 2 weeks, or the same dose on three occasions, each separated by 1 week.ResultsFibroblast growth factor 21 levels peaked at 2 h in a dose‐dependent manner. No significant increase in FGF21 was seen after consumption of 10 g fructose, while robust increases were seen after drinking solutions containing 30, 50 and 75 g. At 2 h, the minimal fold change of FGF21 was highest following a 75 g fructose drink, and all subjects demonstrated at least a doubling of FGF21 levels following consumption of this dose.ConclusionsThe increase in FGF21 following an oral fructose challenge is dose dependent, with levels peaking at 2 h independent of dose. The FGF21 response to 75 g fructose is also highly reproducible within individuals.Clinical ImplicationsBy demonstrating that the FGF21 response to fructose is dose dependent and reproducible, this study deepens current understanding of FGF21 fructose dynamics and physiology in humans. This is an important area of clinical interest given associations between fructose intake and a wide variety of metabolic derangements.

Circulating FGF21 Levels in Human Health and Metabolic Disease

“…Fructose ingestions raise FGF21 within 2 hours 3-to 4-fold in humans and a recent study showed a dose-dependent effect of fructose on FGF21 levels, with the highest fructose dose of 75g resulting in at least 100 % increase (2-fold) in all individuals that were studied [196]. This provides evidence for a negative feedback loop regulating sugar consumption, in coherence with mouse data showing that sugar ingestion suppresses FGF21 levels [45,46].…”

Age‐related bone loss is associated with FGF21 but not IGFBP1 in healthy adults

“…The participants were instructed to consume a light meal, such as bread or porridge, >2 h before their scheduled trials. Given that postprandial FGF21 concentrations were affected by fructose consumption in a dose‐dependent manner (Migdal et al., 2018), differences in dietary intake could have affected the FGF21 response in the present study. Future studies on the FGF21 response should standardize or account for dietary intake.…”

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

“…Several population studies have shown that individuals with obesity, type 2 diabetes and metabolic syndrome have higher circulating FGF21 levels , suggesting a state of FGF21 resistance similar to insulin and leptin resistance; this physiological state would therefore be associated with increased risk for the development or worsening of dysmetabolism. Further complicating the study of FGF21 physiology in humans is the wide variability of FGF21 levels within and between individuals, with the precise biological factors contributing to the variability of this hormone remaining unknown .…”

“…Measurement of total FGF21 level includes both the cleaved and uncleaved forms of the hormone, while the intact level includes only the uncleaved, active form. The ratio of intact‐to‐total FGF21 remains unchanged over the course of a 75 g of OFTT , but it is not known whether the ratio of intact‐to‐total FGF21 changes in response to ongoing high‐fructose exposure. The present study demonstrates that the baseline ratio of intact‐to‐total FGF21 remains stable after 2 weeks of high‐fructose consumption, while the stimulated ratio trends towards an increase; larger studies are required to determine whether this change is significant.…”

“…In humans, FGF21 levels respond acutely to an oral fructose load, with peak levels occurring 2 h following ingestion of a pure fructose beverage . There is also an FGF21 dose–response to acute fructose consumption, with higher doses of fructose resulting in higher peak FGF21 levels .…”