Serum fibroblast growth factor 21 in human obesity: regulation by insulin infusion and relationship with glucose and lipid oxidation.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) reduces plasma glucose and triglycerides, and increases free fatty acid oxidation in animal models of diabetes. The aim of the present study was to assess the relationships of serum FGF21 with glucose oxidation (GOx) and lipid oxidation (LOx) in the baseline and insulin-stimulated conditions in lean and obese subjects. DESIGN: Cross-sectional study. SUBJECTS: Eighty-four subjects with normal glucose tolerance, 42 lean (body mass index (BMI) <25 kg m(-2)) and 42 overweight or obese (BMI between 25 and 40 kg m(-2)). MEASUREMENTS: Euglycemic hyperinsulinemic clamp and indirect calorimetry in the baseline state and during last 30 min of the clamp. The change in respiratory quotient (ΔRQ) in response to insulin was used as a measure of metabolic flexibility. Serum FGF21 was determined in the baseline state and after the clamp. RESULTS: Obese subjects had higher LOx in the baseline and insulin-stimulated conditions, lower insulin-stimulated GOx and ΔRQ (all P<0.05). Fasting serum FGF21 did not differ between the groups. Insulin infusion resulted in an increase in serum FGF21 in the obese (P=0.0001), but not in the lean group (P=0.76). Postclamp serum FGF21 was higher in the obese subjects (P=0.0007). In this group, postclamp FGF21 was related to LOx during the clamp (r=0.32, P=0.044), change in GOx and LOx in response to insulin (r=-0.44, P=0.005; r=0.47, P=0.002; respectively) and ΔRQ (r=-0.50, P=0.001). CONCLUSIONS: An increase in serum FGF21 in response to insulin in obese subjects might represent inappropriate response, possibly associated with metabolic inflexibility in obesity and insulin resistance.

Relationships between serum adiponectin and soluble TNF-α receptors and glucose and lipid oxidation in lean and obese subjects.

Insulin resistance might be associated with an impaired ability of insulin to stimulate glucose oxidation and inhibit lipid oxidation. Insulin action is also inversely associated with TNF-α system and positively related to adiponectin. The aim of the present study was to analyze the associations between serum adiponectin, soluble TNF-α receptors concentrations and the whole-body insulin sensitivity, lipid and glucose oxidation, non-oxidative glucose metabolism (NOGM) and metabolic flexibility in lean and obese subjects. We examined 53 subjects: 25 lean (BMI < 25 kg × m(-2)) and 28 with overweight or obesity (BMI > 25 kg × m(-2)) with normal glucose tolerance. Hyperinsulinemic euglycemic clamp and indirect calorimetry were performed. An increase in respiratory exchange ratio in response to insulin was used as a measure of metabolic flexibility. Obese subjects had lower insulin sensitivity, adiponectin and higher sTNFR1 (all P < 0.001) and sTNFR2 (P = 0.001). Insulin sensitivity was positively related to adiponectin (r = 0.49, P < 0.001) and negatively related to sTNFR1 (r = -0.40, P = 0.004) and sTNFR2 (r = -0.52, P < 0.001). Adiponectin was related to the rate of glucose (r = 0.47, P < 0.001) and lipid (r = -0.40, P = 0.003) oxidation during the clamp, NOGM (r = 0.41, P = 0.002) and metabolic flexibility (r = 0.36, P = 0.007). Serum sTNFR1 and sTNFR2 were associated with the rate of glucose (r = -0.45, P = 0.001; r = -0.51, P < 0.001, respectively) and lipid (r = 0.52, P < 0.001; r = 0.46, P = 0.001, respectively) oxidation during hyperinsulinemia, NOGM (r = -0.31, P = 0.02; r = -0.43, P = 0.002, respectively) and metabolic flexibility (r = -0.47 and r = -0.51, respectively, both P < 0.001) in an opposite manner than adiponectin. Our data suggest that soluble TNF-α receptors and adiponectin have multiple effects on glucose and lipid metabolism in obesity.

The FTO gene modifies weight, fat mass and insulin sensitivity in women with polycystic ovary syndrome, where its role may be larger than in other phenotypes.

AIM: Genome-wide association studies have shown that variation in the FTO gene predisposes to obesity and related traits that are common features of polycystic ovary syndrome (PCOS). The aim of the present study was to assess the effect of FTO variation on obesity, insulin sensitivity, and metabolic and hormonal profiles in PCOS. METHODS: We examined 136 PCOS women (mean body mass index [BMI]: 28.28+/-6.95kg/m(2), mean age: 25.36+/-5.48 years). Anthropometric measurement, euglycaemic-hyperinsulinaemic clamp and oral glucose tolerance tests and sex hormone assessments were performed. The study group was genotyped for the FTO rs9939609 polymorphism. RESULTS: BMI (29.0+/-6.9kg/m(2) vs 26.1+/-6.8kg/m(2); P=0.023), body weight (80.1+/-20.7kg vs 72.6+/-20.2kg; P=0.048), fat mass (29.7+/-1 6.6kg vs 24.6+/-17.7kg; P=0.045) and waist circumference (89.8+/-16.7cm vs 83.2+/-17.1cm; P=0.028) were higher in carriers of at least one copy of the A allele. Differences in these parameters were more significant when comparing AA and TT homozygotes. Women with the AA genotype also had decreased insulin sensitivity (P=0.025) and follicle-stimulating hormone (P=0.036). In logistic-regression analyses, the association of the FTO gene polymorphism with insulin sensitivity was no longer significant when BMI was included in the model. CONCLUSION: Variation in the FTO gene modifies weight, adiposity and other measures of obesity and insulin sensitivity in PCOS. The examined FTO gene variant appears to have a greater impact on obesity and related traits in PCOS than in other phenotypes. The effect on insulin sensitivity appears to be secondary to its influence on obesity and body fat.