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Fructose ingestion acutely stimulates circulating FGF21 levels in humans.

ABSTRACT: 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.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.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.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.

SUBMITTER: Dushay JR

PROVIDER: S-EPMC4314524 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Fructose ingestion acutely stimulates circulating FGF21 levels in humans.

Dushay Jody R JR Toschi Elena E Mitten Emilie K EK Fisher Ffolliott M FM Herman Mark A MA Maratos-Flier Eleftheria E

Molecular metabolism 20141008 1

<h4>Objective</h4>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-El ...[more]

PMID: 25685689

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Project description:ObjectiveFibroblast-growth factor 21 (FGF21) is thought to be important in metabolic regulation. Recently, low protein diets have been shown to increase circulating FGF21 levels. However, when energy contribution from dietary protein is lowered, other macronutrients, such as carbohydrates, must be increased to meet eucaloric balance. This raises the possibility that intake of a diet rich in carbohydrates may induce an increase in plasma FGF21 levels per se. Here we studied the role of dietary carbohydrates on the levels of circulating FGF21 and concomitant physiologic effects by feeding healthy men a carbohydrate rich diet without reducing protein intake.MethodsA diet enriched in carbohydrates (80 E% carbohydrate; CHO) and a eucaloric control diet (CON) were provided to nine healthy men for three days. The energy intake during the CHO diet was increased (+75% energy) to ensure similar dietary protein intake in CHO and CON. To control for the effect of caloric surplus, we similarly overfed (+75% energy) the same subjects for three days with a fat-rich diet (78 E% fat; FAT), consisting of primarily unsaturated fatty acids. The three diets were provided in random order.ResultsAfter CHO, plasma FGF21 concentration increased 8-fold compared to CON (329 ± 99 vs. 39 ± 9 pg ml-1, p < 0.05). In contrast, after FAT only a non-significant tendency (p = 0.073) to an increase in plasma FGF21 concentration was found. The increase in FGF21 concentration after CHO correlated closely (r = 0.88, p < 0.01) with increased leg glucose uptake (62%, p < 0.05) and increased hepatic glucose production (17%, p < 0.01), indicating increased glucose turnover. Plasma fatty acid (FA) concentration was decreased by 68% (p < 0.01), supported by reduced subcutaneous adipose tissue HSL Ser660 phosphorylation (p < 0.01) and perilipin 1 protein content (p < 0.01), pointing to a suppression of adipose tissue lipolysis. Concomitantly, a 146% increase in the plasma marker of hepatic de novo lipogenesis C16:1 n-7 FA (p < 0.01) was observed together with 101% increased plasma TG concentration (p < 0.001) in association with CHO intake and increased plasma FGF21 concentration.ConclusionExcess dietary carbohydrate, but not fat, led to markedly increased FGF21 secretion in humans, notably without protein restriction, and affected glucose and lipid homeostais.

Project description: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.

Project description:ObjectiveIncreased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption.MethodsWe tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects.ResultsHepatic expression of ChREBP-? and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-? and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls.ConclusionsIn summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.

Project description:Background: Current sports nutrition guidelines recommend athletes ingest carbohydrates at 1.0-1.2 g·kg-1·h-1 to optimize repletion of muscle glycogen during short-term recovery from endurance exercise. However, they do not provide specific advice on monosaccharides (e.g., fructose or glucose) other than to ingest carbohydrates of moderate to high glycaemic index. Recent evidence suggests that combined ingestion of fructose and glucose in recovery leads to enhanced liver glycogen synthesis and that this translates into improvement of subsequent endurance capacity. Purpose: The purpose of the present study was to investigate whether consuming a combination of fructose and glucose as opposed to glucose alone during short-term recovery (i.e., 4 h) from exhaustive exercise would also improve subsequent pre-loaded cycle time trial (TT) performance. Methods: Eight participants (seven men, one woman; V? O2peak: 56.8 ± 5.0 mLO2·min-1·kg-1; Wmax: 352 ± 41 W) participated in this randomized double-blind study. Each experimental session involved a glycogen reducing exercise bout in the morning, a 4-h recovery period and 1-h of steady state (SS) exercise at 50% Wmax followed by a ~40-min simulated TT. During recovery carbohydrates were ingested at a rate of 1.2 g·kg-1·h-1 in the form of fructose and maltodextrin (FRU + MD) or dextrose and maltodextrin (GLU + MD) (both in 1:1.5 ratio). Substrate oxidation rates, including ingested carbohydrate oxidation, were determined during the steady state (SS). Blood samples were collected during recovery, during the SS exercise and at the end of the TT for determination of glucose and lactate concentrations. Results: There were no differences in TT performance [37.41 ± 3.45 (GLU + MD); 37.96 ± 5.20 min (FRU + MD), p = 0.547]. During the first 45-min of SS oxidation of ingested carbohydrates was greater in FRU + MD (1.86 ± 0.41 g-1·min-1 and 1.51 ± 0.37 g-1·min-1 for FRU + MD and GLU + MD, respectively; time x condition interaction p = 0.003) and there was a trend toward higher overall carbohydrate oxidation rates in FRU + MD (2.50 ± 0.36 g-1·min-1 and 2.31 ± 0.37 g-1·min-1 for FRU + MD and GLU + MD, respectively; p = 0.08). However, at 60-min of SS, differences in substrate oxidation disappeared. Conclusion: Ingestion of combined fructose and glucose compared to glucose only during recovery from an exhaustive exercise bout increased the ingested carbohydrate oxidation rate during subsequent exercise. Under the conditions studied, subsequent TT performance was not improved with fructose-glucose.

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Fructose ingestion acutely stimulates circulating FGF21 levels in humans.

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Fructose ingestion acutely stimulates circulating FGF21 levels in humans.

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