Influence of two polymorphisms of the tumoral necrosis factor-alpha gene on the obesity phenotype.

Several populational-based studies have suggested an association between tumoral necrosis factor-alpha (TNF-alpha) polymorphisms and obesity-related phenotypes. Therefore, this study aimed at assessing the situation (frequency and associated phenotype) of two TNF-alpha common polymorphisms in a Spanish population. In a case-control design study, a group of Spanish subjects (n=313) were genotyped for the TNF-alpha G/A -308 and -238 polymorphisms. Obese subjects (cases) were compared with lean individuals (controls) according to body mass index (BMI; cases: BMI >30 kg/m2, controls: BMI <25 kg/m2). Waist-to-hip ratio, body composition and some metabolic indicators were assessed. The frequency of the -308A allele (0.14) and -238A allele (0.09) was similar to those previously reported in other Caucasian populations. Interestingly, cases with the -308A allele of the TNF-alpha gene have significantly higher hip and waist circumferences (p<0.05), BMI (p<0.01) and body fat mass (p<0.05) values than obese individuals carrying the -308G allele, but not the waist-to-hip ratio. No apparent influence of the -308A polymorphism on other metabolic indicators (insulin and leptin levels) was found. We could not detect any association between the substitution at position -238 polymorphism of the TNF-alpha gene and obesity anthropometrical phenotypes in this Spanish population, despite some differences in plasma leptin. These results support the hypothesis that the G/A -308 polymorphism of the TNF-alpha gene is associated with a higher BMI as well as hip ad waist circumferences, particularly on female bearers, while no influence on such measurements was found for the G/A -238 TNF-alpha gene polymorphism, but only an effect on leptinaemia.

A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population.

BACKGROUND: In recent years, several groups have reported dominant inheritance of obesity conferred by missense, nonsense and frameshift mutations in the melanocortin 4 receptor gene (MC4R). Hence, MC4R is involved in the most common monogenic form of human obesity described so far. OBJECTIVES: In this context, we screened a Spanish population, composed of obese subjects and normal weight controls, for mutations in the MC4-R by single-strand conformational polymorphism (SSCP). SUBJECTS AND METHODS: Overall 313 individuals, 159 obese subjects (body mass index: BMI: 37.6 kg/m(2), 95% CI: 36.7-38.5 kg/m(2)) and 154 normal weight control subjects (BMI: 22.3 kg/m(2), 95% CI: 22.0-22.6 kg/m(2)) were screened for MC4-R mutations. RESULTS: We detected a novel nonsense mutation at codon 16 of the MC4-R in an obese female (BMI: 30.0 kg/m(2)) and a previously described missense mutation (Val-253-Ile) located within the sixth trans-membrane domain of the MC4-R in a normal weight individual (BMI: 19.0 kg/m(2)). The polymorphism Val-103-Ile was detected in one obese individual, while four subjects (two cases and two controls) with the polymorphism Ile-251-Leu were found. CONCLUSIONS: We have identified a novel nonsense mutation (Trp-16-Stop) that, based on previously described frameshift and nonsense mutations, most likely results in dominantly inherited obesity. Within this Spanish population, the frequency of the Ile-251-Leu polymorphism of the MC4R was similar in obese and control subjects (about 1.3%), while the polymorphism Val-103-Ile was only detected in an obese individual (0.6%).

TRP64ARG polymorphism of the beta 3-adrenergic receptor gene and obesity risk: effect modification by a sedentary lifestyle.

AIM: We performed a case-control study to assess the association between obesity risk and the Trp64Arg polymorphism of the beta 3-adrenergic receptor gene. METHODS: Obese subjects [n = 159; body mass index (BMI) > 30 kg/m2] and controls (n = 154; BMI < 25 kg/m2) were compared using multivariable logistic regression to control for potential confounders. RESULTS: A higher obesity risk (adjusted OR: 2.98; 95% CI: 1.00-8.56; p = 0.05) was associated with the Trp64Arg polymorphism among sedentary, but not among more active people. CONCLUSIONS: Our results suggest that the TRP64ARG polymorphism of the ADRB3 seems to be a risk factor for obesity that is dependent on a sedentary lifestyle.

The risk of obesity and the Trp64Arg polymorphism of the beta(3)-adrenergic receptor: effect modification by age.

AIM: To examine the association between the risk of obesity and the Trp64Arg polymorphism of the beta(3)-adrenergic receptor gene. METHODS: A case-control study was conducted. The case series encompassed 159 subjects with a body mass index >30 kg/m(2) (obesity) and no other major diseases except for type 2 diabetes, and the controls were 154 healthy subjects with a body mass index <25 kg/m(2). 313 Spanish subjects between 20 and 60 years of age were screened for the Trp64Arg mutation. RESULTS: The prevalence of the Trp64Arg mutation was similar among cases (19.5%) and control subjects (16.2%). The association between the risk of obesity and the Trp64Arg mutation was estimated using multivariate logistic regression. A higher odds ratio of 3.84 (95% CI 1.33-11.12) for the mutation was found among younger individuals (20-35 years), while no increased risk was apparent among older participants (35-60 years). Moreover, when the model was adjusted for gender, age, and leisure-time physical activity, the product-term for interaction (effect modification) between age and the presence of the Trp64Arg mutation was statistically significant (likelihood ratio test p = 0.035). CONCLUSION: Individuals aged 20-35 years who are Trp64Arg carriers had a substantially higher risk of developing obesity, independent of their sex or leisure-time physical activity.

Beta(2)-adrenergic receptor mutation and abdominal obesity risk: effect modification by gender and HDL-cholesterol.

OBJECTIVE AND DESIGN: A case-control study was conducted to examine the association between the 27Glu polymorphism of the beta(2)-adrenergic receptor gene (ADRB2) and the risk of abdominal obesity (defined by a waist/hip ratio: WHR higher than 0.85). METHODS: The case series encompassed 112 obese subjects with body mass index (BMI) > 30 kg/m(2) and WHR > 0.85 and no other major disease except for type 2 diabetes, while the controls were 127 healthy subjects, BMI < 25 kg/m(2) and WHR < 0.85. RESULTS: The association between the risk of abdominal obesity and the 27Glu polymorphism was estimated using multivariate logistic regression. A higher crude odds ratio (OR) of 4.08 (95 % confidence interval: 0.98-16.3) for the 27Glu allele was found among men, while no increased risk was apparent among female participants. Moreover, when the model was adjusted for age, male subjects carriers of the 27Glu allele had a significant ten-fold higher risk of abdominal obesity (OR = 10.31; 95 % CI: 1.4-76.8) and the product-term for the interaction (effect modification) between gender and the ADRB2 mutation was near to the limits of statistical significance (Likelihood ratio test p = 0.056). Interestingly, we also found an effect modification with higher OR among individuals with low HDL-cholesterol (< 1.5 mmol/l) after adjustment for age and gender (OR = 2.87 95 % CI 1.09-7.50) and the product-term for interaction between the 27Glu allele and HDL-cholesterol was statistically significant (Likelihood ratio test p = 0.003). CONCLUSIONS: Our results showed that the 27Glu allele of the ADRB2 gene appears to be a risk factor for abdominal obesity among male subjects, specially among those with lower HDL-cholesterol levels.

High-fat feeding reduced muscle uncoupling protein 3 expression in rats.

Uncoupling Protein 3 (UCP3), largely expressed in skeletal muscle, is modulated by cold, thyroid hormones, leptin, fasting-refeeding and exercise training among other factors in a tissue-specific manner. In brown adipose tissue, there is an increase in UCP3 levels after high-fat feeding and beta3-adrenergic agonist treatment. Controversial effects of these agents have been reported in skeletal muscle. The aim of this experimental trial was to evaluate the effect of high-fat feeding and beta3-adrenergic agent treatment on skeletal muscle UCP3 expression levels. Lean rats were fed a cafeteria diet for 30 days and found to have significantly higher fat stores and body weight than control rats at the end of the experimental period. When cafeteria-diet rats were daily i.p. injected with Tertatolol for 30 days; a decrease in total fat mass and body weight was found. Such an effect was not observed in fa/fa rats. Interestingly, gastrocnemius muscle UCP3 mRNA levels were significantly reduced in cafeteria-diet rats when compared to lean animals. Likewise, mitochondrial O2 consumption in gastrocnemius muscle was also significantly decreased (-31%) in cafeteria-diet rats as compared to the control group. It is suggested that the down-regulation of UCP3 gene expression together with the lower O2 consumption observed in high fat fed rats may be linked to lower fatty oxidation, which would promote triglyceride accumulation.