Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21

OBJECTIVE—Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) –dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPAR, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS—The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPAR activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS—Oleate and linoleate increased FGF-21 expression and secretion in a PPAR-dependent fashion, as demonstrated by small-interfering RNA–induced PPAR knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS—The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity

Peptide YY, Cholecystokinin, Insulin and Ghrelin Response to Meal did not Change, but Mean Serum Levels of Insulin is Reduced in Children with Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a contiguous gene syndrome characterized by uncontrollable eating or hyperphagia. Several studies have confirmed that plasma ghrelin levels are markedly elevated in PWS adults and children. The study of anorexigenic hormones is of interest because of their regulation of appetite by negative signals. To study the pattern and response of the anorexigenic hormones such as cholecystokinin (CCK) and peptide YY (PYY) to a meal in PWS, we measured the plasma CCK, PYY, ghrelin and serum insulin levels in PWS patients (n=4) and in controls (n=4) hourly for a day, and analyzed hormone levels and hormonal responses to meals. Repeated measures of ANOVA of hormone levels demonstrated that only insulin levels decreased (p=0.013) and CCK (p=0.005) and ghrelin (p=0.0007) increased in PWS over 24 hr. However, no significant group x time interactions (ghrelin: p=0.89, CCK: p=0.93, PYY: p=0.68 and insulin: p=0.85) were observed; in addition, there were no differences in an assessment of a three-hour area under the curve after breakfast. These results suggest that the response pattern of hormones to meals in PWS patients parallels that of normal controls. In addition, the decrease of insulin levels over 24 hr, in spite of obesity and elevated ghrelin levels, suggests that the baseline insulin level, not the insulin response to meals, may be abnormal in patients with PWS

Marked Suppression of Ghrelin Concentration by Insulin in Prader-Willi Syndrome

The plasma ghrelin has been reported to be elevated in Prader-Willi syndrome (PWS) and modulated by insulin. It was hypothesized that insulin might have a more pronounced effect on reducing plasma ghrelin in PWS patients, which would influence appetite. This study investigated the degree of ghrelin suppression using an euglycemic hyperinsulinemic clamp in children with PWS (n=6) and normal children (n=6). After a 90-min infusion of insulin, the plasma ghrelin level decreased from a basal value of 0.86±0.15 to 0.58±0.12 ng/mL in the controls, and from 2.38±0.76 to 1.12±0.29 ng/mL in children with PWS (p=0.011). The area under the curve below the baseline level over the 90 min insulin infusion was larger in children with PWS than in controls (-92.82±44.4 vs. -10.41±2.87 ng/mL/90 min) (p=0.011). The insulin sensitivity measured as the glucose infusion rate at steady state was similar in the two groups (p=0.088). The decrease in the ghrelin levels in response to insulin was more pronounced in the children with PWS than in the controls. However, the level of ghrelin was always higher in the children with PWS during the clamp study. This suggests that even though insulin sensitivity to ghrelin is well maintained, an increase in the baseline ghrelin levels is characteristic of PWS

Acetylcholine regulates ghrelin secretion in humans

Ghrelin secretion has been reportedly increased by fasting and energy restriction but decreased by food intake, glucose, insulin, and somatostatin. However, its regulation is still far from clarified. The cholinergic system mediates some ghrelin actions, e.g. stimulation of gastric contractility and acid secretion and its orexigenic activity. To clarify whether ghrelin secretion undergoes cholinergic control in humans, we studied the effects of pirenzepine [PZ, 100 mg per os (by mouth)], a muscarinic antagonist, or pyridostigmine (PD, 120 mg per os), an indirect cholinergic agonist, on ghrelin, GH, insulin, and glucose levels in six normal subjects. PD increased (P < 0.05) GH (change in area under curves, mean +/- SEM, 790.9 +/- 229.3 microg(*)min/liter) but did not modify insulin and glucose levels. PZ did not significantly modify GH, insulin, and glucose levels. Circulating ghrelin levels were increased by PD (11290.5 +/- 6688.7 pg(*)min/ml; P < 0.05) and reduced by PZ (-23205.0 +/- 8959.5 pg(*)min/ml; P < 0.01). The PD-induced ghrelin peak did not precede that of GH. In conclusion, circulating ghrelin levels in humans are increased and reduced by cholinergic agonists and antagonists, respectively. Thus, ghrelin secretion is under cholinergic, namely muscarinic, control in humans. The variations in circulating ghrelin levels induced by PD and PZ are unlikely to mediate the cholinergic influence on GH secretion

Role of Androgen Receptor CAG Repeat Polymorphism and X-Inactivation in the Manifestation of Recurrent Spontaneous Abortions in Indian Women

The aim of the present study was to investigate the role of CAG repeat polymorphism and X-chromosome Inactivation (XCI) pattern in Recurrent Spontaneous Abortions among Indian women which has not been hitherto explored. 117 RSA cases and 224 Controls were included in the study. Cases were recruited from two different hospitals - Lakshmi Fertility Clinic, Nellore and Fernandez Maternity Hospital, Hyderabad. Controls were roughly matched for age, ethnicity and socioeconomic status. The CAG repeats of the Androgen Receptor gene were genotyped using a PCR-based assay and were analysed using the GeneMapper software to determine the CAG repeat length. XCI analysis was also carried out to assess the inactivation percentages. RSA cases had a significantly greater frequency of allele sizes in the polymorphic range above 19 repeats (p = 0.006), which is the median value of the controls, and in the biallelic mean range above 21 repeats (p = 0.002). We found no evidence of abnormal incidence of skewed X-inactivation. We conclude that longer CAG repeat lengths are associated with increased odds for RSA with statistical power estimated to be ∼90%