Sporadic mutations in melanocortin receptor 3 in morbid obese individuals.

Several mutations in the melanocortin receptor 4 gene have been identified in humans and account for 3-6% of morbid obesity. In contrast, strong evidence of a causative role for melanocortin receptor 3 (MC3R) mutations are still lacking. In MC3R knockout mice, high feed efficiency rather than hyperphagia seems to contribute to increased fat mass. On the basis of this evidence, the objective of the present study was to investigate the presence of MC3R mutations in a group of 290 obese subjects (mean BMI 44.2+/-5.9 kg/m2). As a control, a group of 215 normal-weight subjects (mean BMI 22.4+/-2.7 kg/m2) was also screened. Three novel mutations in the MC3R gene (A293T, I335S and X361S) were identified among the obese patients. The mutations segregated with obesity in the members of the families studied. In vitro expression studies of each mutation demonstrated a loss of function of the I335S-mutated receptor. These findings suggest that, in humans, MC3R mutations may be a cause of a dominantly inherited form of obesity. However, this association as well as the specific phenotypic characteristics resulting from these mutations need to be further evaluated in larger series of obese subjects.

The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure.

Ghrelin is a gastric hormone that exerts a stimulatory effect on appetite and fat accumulation. Ser(3) octanoylation is regarded as a prerequisite for ghrelin biological activity, although des-octanoylated forms may retain biological functions in vitro. Circulating ghrelin levels are usually low in obesity and in states of positive energy balance. Hence, the aim of our study was to analyze plasma active and serum total ghrelin levels in 20 obese (ages, 22-42 yr; body mass index, 41.3 +/- 1.1 kg/m(2)) and 20 lean subjects (ages, 22-43 yr; body mass index, 22.4 +/- 0.6 kg/m(2)) as well as their relationship to measures of glucose homeostasis, body fat, and resting energy expenditure (REE). The measured/predicted REE percentage ratio was calculated to subdivide groups into those with positive (> or = 100% ) and negative (<100%) ratio values. In obese patients, plasma active (180 +/- 18 vs. 411 +/- 57 pg/ml; P < 0.001) and serum total ghrelin levels (3650 +/- 408 vs. 5263 +/- 643 pg/ml; P < 0.05) were significantly lower when compared with lean subjects. Hence, ghrelin activity, defined as the proportion of active over total ghrelin levels, was similarly reduced in the obese state (6.1 +/- 0.9% vs. 8.4 +/- 1%; P < 0.05). There was a significant correlation between active and total ghrelin (r = 0.62; P < 0.001), and between total ghrelin and insulin (r = -0.53; P < 0.001) or insulin resistance using the homeostatis model of assessment-insulin resistance (r = -0.49; P < 0.001) approach. Significantly higher active ghrelin levels (214 +/- 22 vs. 159 +/- 30 pg/ml; P < 0.05) and ghrelin activity (8 +/- 1.7% vs. 4.9 +/- 0.9%; P < 0.05) were observed in patients with positive compared with negative measured/predicted REE ratio values. Our study shows that obesity is associated with an impairment of the entire ghrelin system. The observation that ghrelin is further decreased in cases of abnormal energy profit adds new evidence to the relationship between ghrelin activity and energy balance in obesity.

The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients.

OBJECTIVE: We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low-dose dexamethasone (0.25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a BclI restriction site polymorphism in a group of Italian patients with severe obesity. DESIGN: Two hundred and seventy-nine patients (mean BMI 45.9 +/- 0.9 kg/m2) were genotyped using both PCR-restriction fragment length polymorphism analysis and Taqman Sequence Detection System. Determination of several metabolic and antropometric parameters was also performed in order to correlate them to the genotype. RESULTS: In this group of obese patients, 13 subjects (eight female, five males) were heterozygous for the N363S variant (allelic frequency 2.3%) and had significantly higher BMI (P < 0.04), resting energy expenditure (P < 0.03) and food intake (P < 0.01) when compared to wild-type homozygotes. When the data were analysed according to sex, female heterozygotes for the N363S allele had significantly higher BMI (P = 0.04), resting energy expenditure (P = 0.03) and food intake (P = 0.008) than obese women with the wild-type 363 GR gene. Male carriers of this variant also had higher values for these variables although the differences did not reach statistical significance. A case-control study with homozygous wild-type obese subjects which were age-, sex- and BMI-matched, revealed no difference in resting energy expenditure and food intake. The allele frequency of the BclI variant was 27% (89 females and 41 males out of 269 subjects). No differences in anthropometric and metabolic parameters were found between subjects heterozygous or homozygous for this variant GR in this obese population. However, when we studied the effect of the presence of the BclI polymorphism and the N363S variant in the same individual, we found that the subjects who carried both polymorphisms had a tendency towards higher systolic and diastolic blood pressure and significantly higher total and LDL-cholesterol levels (P = 0.005 and P = 0.05, respectively). DISCUSSION: Taking the results of this study and those obtained in the Dutch population, we speculate that heterozygous carriers of the N363S variant who develop obesity, may become even more obese, possibly because they have a hypersensitive insulin response and thus, via activation of lipogenesis, store fat more efficiently. Furthermore, these data suggest that N363S carriers who carry the BclI polymorphism as well, tend to have a slightly unfavourable cardiovascular profile.