Fructose ingestion acutely stimulates circulating FGF21 levels in humans

Abstract

Objective: Fibroblast growth factor 21 (FGF21) is a hormone with pleiotropic metabolic activities which, in rodents, is robustly regulated by fasting and ketogenic diets. In contrast, similar dietary interventions have either no or minimal effects on circulating FGF21 in humans. Moreover, no intervention or dietary challenge has been shown to acutely stimulate circulating FGF21 in either humans or animals. Recent animal data suggest that the transcription factor Carbohydrate Responsive-Element Binding Protein (ChREBP) stimulates hepatic FGF21 expression and that fructose may activate hepatic ChREBP more robustly than glucose. Here, we examined whether fructose ingestion can acutely stimulate FGF21 in humans.

Methods: We measured serum FGF21, glucose, insulin, and triglyceride levels in ten lean, healthy adults and eleven adults with the metabolic syndrome following oral ingestion of 75 g of glucose, fructose, or a combination of the two sugars.

Results: FGF21 levels rose rapidly following fructose ingestion, achieved a mean 3.4-fold increase at two hours (P < 0.01), and returned to baseline levels within five hours. In contrast, FGF21 did not increase in the first two hours following ingestion of a glucose load, although more modest increases were observed after three to four hours. Both baseline and fructose-stimulated FGF21 levels were 2-3 fold elevated in subjects with metabolic syndrome.

Conclusions: Fructose ingestion acutely and robustly increases serum FGF21 levels in humans in a pattern consistent with a hormonal response. While FGF21 appears to be critical for the adaptive response to fasting or starvation in rodents, these findings suggest that in humans, FGF21 may play an important role in fructose metabolism.

Keywords: ChREBP; FGF21; Fructose; Metabolic syndrome.

Figures

Figure 1

The serum FGF21 response to fructose ingestion in healthy adults. Panel A shows the average serum FGF21 level following oral ingestion of 75 g of fructose in 10 lean, healthy individuals. Panel B shows the serum FGF21 level for each of the individual subjects in Panel A. *P < 0.05 compared to baseline.

Figure 2

Hormone and metabolite responses to fructose or glucose ingestion. Effects of the ingestion of 75 g of fructose on serum FGF21 (Panels A), insulin (Panels B), glucose (Panels C), and triglyceride (Panels D) in lean healthy subjects (closed circle, black line) or patients with the metabolic syndrome (open circle, gray line). Effects of the ingestion of 75 g of glucose on serum FGF21 (Panels E), insulin (Panels F), glucose (Panels G), and triglyceride (Panels H). *P < 0.05 compared to baseline within group. #P < 0.05 at given time point between groups.

Figure 3

The serum FGF21 response to a mixture of fructose and glucose. Panel A shows the average serum FGF21 level following ingestion of a mixture of 37.5 g of glucose and 37.5 g of fructose in lean healthy subjects (closed circle, black line) and subjects with the metabolic syndrome (open circle, gray line). *P < 0.05 compared to baseline within group. #P < 0.05 at given time point between groups. Panel B shows the correlation between the FGF21 AUC in response to fructose alone versus the mixture of fructose and glucose. Each point represents an individual subject. Closed circles represent lean subjects. Open circles represent metabolic syndrome subjects.

Figure 4

The FGF21 response to fructose ingestion correlates with indices of glucose intolerance and insulin resistance. Panels A and B show the correlations between the FGF21 AUC in response to fructose and the serum glucose AUC (Panel A) or serum insulin AUC (Panel B) following glucose. Each point represents an individual subject. Open circles represent lean subjects. Closed circles represent metabolic syndrome subjects.