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.

Fibroblast growth factor 21 and fructose dynamics in humans.

Objective: Fructose 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. Methods: Lean, 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. Results: Fibroblast 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. Conclusions: The 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 Implications: By 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.

Divergent effects of leptin in mice susceptible or resistant to obesity.

Consumption of a high-fat diet decreases hypothalamic neuropeptide Y (NPY) and increases proopiomelanocortin (POMC) and brown adipose uncoupling protein (UCP)-1 mRNA in obesity-resistant SWR/J but not obesity-prone C57Bl/6J mice. Although leptin was elevated in both strains in response to a high-fat diet, its role in the development of diet-induced obesity has remained unclear since insulin and other factors that affect similar tissue targets are altered. Thus, we administered recombinant leptin by subcutaneous infusion to chow-fed mice to mimic the changes in plasma leptin across its broad physiologic range. We observed strain differences in responsiveness to reduced and elevated leptin levels. A reduction in leptin during fasting evoked a greater response in C57Bl/6J mice by decreasing energy expenditure and thyroxin, increasing corticosterone and stimulating food intake and weight gain during refeeding. However, C57Bl/6J mice were less responsive to an increase in leptin in the fed state. Conversely, the leptin-mediated response to fasting was blunted in SWR/J mice, whereas an increase in leptin profoundly reduced food intake and body weight in SWR/J mice fed ad libitum. Sensitivity to fasting in C57Bl/6J mice was associated with higher hypothalamic NPY mRNA and reduced POMC and UCP-1 mRNA expression, while the robust response to high leptin levels in SWR/J mice was associated with suppression of NPY mRNA. These results indicate that differences in leptin responsiveness between strains might occur centrally or peripherally, leading to alteration in the patterns of food intake, thermogenesis and energy storage.

Leptin accelerates the onset of puberty in normal female mice.

The fat-derived hormone, leptin, is proposed to serve as an adipostatic signal to the brain to reduce food intake and body weight. In addition to its effects on body weight, chronic leptin treatment restores puberty and fertility to ob/ob mice with total leptin deficiency, and acute treatment substantially corrects hypogonadism in mice starved for 2 d without affecting body weight. Leptin may therefore be a critical signal, linking adiposity and reproduction. Since body weight and adiposity appear to play a critical role in the timing of puberty in humans and rodents, and leptin levels rise with increasing adiposity, we studied the effects of once daily injections of recombinant leptin on the onset of puberty in female mice weaned on day 21 and fed ad libitum. There was a linear increase in body weight during the study period, which was not altered by the dose of leptin used. Mice injected with leptin had an earlier onset of three classic pubertal parameters (i.e., vaginal opening, estrus, and cycling) compared with saline-injected controls. Leptin is the first peripheral molecule demonstrated to accelerate the maturation of the reproductive axis in normal rodents. We propose that leptin is the signal that informs the brain that energy stores are sufficient to support the high energy demands of reproduction, and may be a major determinant of the timing of puberty.

Peripheral blood mononuclear cell dihydropyrimidine dehydrogenase activity in volunteers with and without diabetes mellitus.

It has been reported that cancer patients with diabetes mellitus receiving a continuous infusion of 5-fluorouracil (5-FU) have more toxicity and higher plasma 5-FU levels that patients without diabetes mellitus. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. DPD activity in peripheral blood mononuclear cells has been reported to correlate inversely with 5-FU plasma levels in patients. We therefore undertook a study to compare the activity of DPD in peripheral blood mononuclear cells of human subjects with and without diabetes mellitus. The study groups comprised 43 volunteers with and 39 without diabetes mellitus, and peripheral blood mononuclear cell DPD activity was assayed on samples obtained between 8 a.m. and 11 a.m. DPD activity was not decreased in diabetic subjects. There was no relationship between DPD activity and gender body mass index, or race. There was a modest correlation between DPD activity and age (r=0.19, P =0.08). We conclude that increases in 5-FU-related toxicities in diabetics must be related to factors other than peripheral blood mononuclear cell DPD activity.