The ß(2)-adrenergic receptor (ADRB2) influences regulation of energy balance by stimulating catecholamine-induced lipolysis in adipose tissue. The rare functional ADRB2rs1800888(Thr164Ile) polymorphism could therefore influence risk of obesity and subsequently diabetes.
We tested the hypothesis that the ADRB2rs1800888(Thr164Ile) polymorphism associates with risk of obesity and diabetes and compared effect sizes with those of FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238).
We conducted a population-based cohort study in Copenhagen, Denmark.
We genotyped more than 64,000 individuals from the Danish general population.
We evaluated body mass index (BMI), obesity (BMI =30 kg/m(2)), and diabetes.
Rare allele frequencies were 0.02 for T for ADRB2rs1800888(Thr164Ile), 0.40 for A for FTOrs9939609, 0.25 for C for MC4Rrs17782313, and 0.20 for T for TMEM18rs6548238. For rare vs. common homozygotes, odds ratio for obesity was 3.32 (95% confidence interval = 1.08-10.19) for ADRB2rs1800888(Thr164Ile), 1.42 (1.35-1.52) for FTOrs9939609, 1.18 (1.06-1.30) for MC4Rrs17782313, and 1.28 (1.10-1.50) for TMEM18rs6548238 (common vs. rare). Corresponding odds ratios for diabetes were 1.85 (0.24-14.29), 1.22 (1.07-1.39), 0.96 (0.80-1.16), and 1.61 (1.17-2.22), respectively. After adjustment for BMI, only TMEM18rs6548238 remained associated with diabetes. BMI was increased in rare vs. common homozygotes in FTOrs9939609, MC4Rrs17782313, and TMEM18rs6548238 (common vs. rare) but not in ADRB2rs1800888(Thr164Ile).
Our results suggest that ADRB2rs1800888(Thr164Ile) rare vs. common homozygotes are not significantly associated with an increase in BMI measured continuously but may be associated with an increased risk of obesity. Also, TMEM18rs6548238 associated with risk of diabetes after adjustment for BMI. These findings need confirmation in other studies.
Obesity is a chronic relapsing disease that leads to numerous ailments and requires lifelong treatment. Genetic predisposition is one of the mostly discussed aspects of obesity development, and genome-wide association studies have provided evidence that several variants of the FTO and MC4R genes are significantly associated with obesity. In this study the association of FTO (rs9939609, rs7202116, and rs9930506) and MC4R (rs12970134 and rs17782313) genes' SNPs with obesity in Tatar women has been analyzed. In the investigation 340 women with obesity (Body Mass Index (BMI) = 30 kg/m2) and 330 women from a control group (BMI up to 24.9 kg/m2) took part. The FTO rs9939609 (p = 0.0002) and rs9930506 (p = 0.0005) SNPs were shown to be associated with obesity risk following an additive model, while the MC4R rs12970134 (p = 0.0076) and rs1778231 (p = 0.021) SNPs were associated by a recessive model. We also showed an association of quantitative parameters (age, weight, and BMI) with two the FTO rs9939609 and rs9930506 SNPs and the association of age and the MC4R rs12970134 SNP. Our study demonstrates the role of genetic variability in FTO and MC4R genes in obesity development in Tatar women from Russia.
Norepinephrine (NE) released from the sympathetic nerves innervating white adipose tissue (WAT) is the principal initiator of lipolysis in mammals. Central WAT sympathetic outflow neurons express melanocortin 4-receptor (MC4-R) mRNA. Single central injection of melanotan II (MTII; MC3/4-R agonist) nonuniformly increases WAT NE turnover (NETO), increases interscapular brown adipose tissue (IBAT) NETO, and increases the circulating lipolytic products glycerol and free fatty acid. The WAT pads that contributed to this lipolysis were inferred from the increases in NETO. Because phosphorylation of perilipin A (p-perilipin A) and hormone-sensitive lipase are necessary for NE-triggered lipolysis, we tested whether MTII would increase these intracellular markers of lipolysis. Male Siberian hamsters received a single 3rd ventricular injection of MTII or saline. Trunk blood was collected at 0.5, 1.0, and 2.0 h postinjection from excised inguinal, retroperitoneal, and epididymal WAT (IWAT, RWAT, and EWAT, respectively) and IBAT pads. MTII increased circulating glycerol concentrations at 0.5 and 1.0 h, whereas free fatty acid concentrations were increased at 1.0 and 2.0 h. Western blot analysis showed that MTII specifically increased p-perilipin A and hormone-sensitive lipase only in fat pads that previously had MTII-induced increases in NETO. Phosphorylation increased in IWAT at all time points and IBAT at 0.5 h, but not RWAT or EWAT at any time point. These results show for the first time in rodents that p-perilipin A can serve as an in vivo, fat pad-specific indictor of lipolysis and extend our previous findings showing that central melanocortin stimulation increases WAT lipolysis.
Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20-24% of the populations), subjects with three or four risk alleles (7-10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (approximately 1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm(3) (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.
Common variants near melanocortin receptor 4 (MC4R) have been related to fatness and type 2 diabetes. We examined the associations of rs17782313 and rs17700633 in relation to body fat, body fat distribution, metabolic traits, weight development and energy expenditure.
Obese young men (n = 753, BMI > or = 31.0 kg m(-2)) and a randomly selected group (n = 874) identified from a population of 174 800 men were re-examined in three surveys at mean ages 35, 46 and 49 years (S-35, S-46 and S-49). Measurements were available at upto eight times from birth to adulthood. Logistic regression analysis was used to assess odds ratio (OR) for the presence of the carrier allele for a given difference in phenotypic values.
Rs17782313 minor C-allele was associated with overall, abdominal and peripheral fatness (range of OR = 1.06-1.14 per z-score units) at all three surveys, although only consistently significant at S-35 and S-46. Rs17700633 minor A-allele was also associated with the fatness measures, but significantly so only at S-49 for overall and abdominal fatness (range of OR = 1.03-1.15 per z-score units), and peripheral fatness (OR = 1.15-1.20 per z-score units). There were only few significant associations with metabolic traits. The rs17782313 C-allele and the rs17700633 A-allele were both associated with lower high-density lipoprotein cholesterol (range of OR = 0.64-0.84 per mol l(-1)), significantly at S-46. The rs17700633 A-allele was significantly associated with insulin (OR = 1.25 per 50 pmol l(-1)), leptin (OR = 1.42 per 10 ng microl(-1)) and insulin sensitivity (OR = 0.81 per model unit). The rs17782313 C-allele and the rs17700633 A-allele were both associated with BMI in childhood and adolescence (range of OR = 1.04-1.17 per z-score units), significant for the rs17782313 C-allele at the age of 13-19 years and for rs17700633 A-allele at age 7, 10, 13 and 19 years. No significant associations were found for energy expenditure.
Near MC4R variants appear to contribute to body fat, body fat distribution, some metabolic traits, weight development during childhood, but not to energy expenditure.
Elevated blood pressure increases the risk of experiencing cardiovascular events like myocardial infarction and stroke. Current observational data suggest that body mass index may have a causal role in the etiology of hypertension, but this may be influenced by confounding and reverse causation. Through the use of instrumental variable methods, we aim to estimate the strength of the unconfounded and unbiased association between body mass index/adiposity and blood pressure. We explore these issues in the Copenhagen General Population Study. We used instrumental variable methods to obtain estimates of the causal association between body mass index and blood pressure. This was performed using both rs9939609 (FTO) and rs17782313 (MC4R) genotypes as instruments for body mass index. Avoiding the epidemiological problems of confounding, bias, and reverse causation, we confirmed observational associations between body mass index and blood pressure. In analyses including those taking antihypertensive drugs, but for whom appropriate adjustment had been made, systolic blood pressure was seen to increase by 3.85 mm Hg (95% CI: 1.88 to 5.83 mm Hg) for each 10% increase in body mass index (P=0.0002), with diastolic blood pressure showing an increase of 1.79 mm Hg (95% CI: 0.68 to 2.90 mm Hg) for each 10% increase in body mass index (P=0.002). Observed associations are large and illustrate the considerable benefits in terms of reductions in blood pressure-related morbidity that could be achieved through a reduction in body mass index.
Elevated body mass index (BMI) is associated with an increased risk of gallstone disease. Whether this reflects a causal association is unknown. Using a Mendelian randomization approach, we studied 77,679 individuals from the general population. Of these, 4,106 developed symptomatic gallstone disease during up to 34 years of follow-up. Subjects were genotyped for three common variants known to associate with BMI: FTO(rs9939609); MC4R(rs17782313); and TMEM18(rs6548238). The number of BMI-increasing alleles was calculated for each participant. In observational analyses, mean baseline BMI was 55% (11.6 kg/m(2) ) increased in individuals in the fifth quintile versus the first quintile, similar in women and men. The corresponding multifactorially adjusted hazard ratio (HR) for symptomatic gallstone disease was 2.84 (95% confidence interval [CI]: 2.32-3.46) overall, 3.36 (95% CI: 2.62-4.31) in women, and 1.51 (95% CI: 1.09-2.11) in men (P trend: 0.001 to
Two Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to +70% before age 10) and 252 morbidly obese adults (body mass index, > or = 40 kg/m(2)), were screened for melanocortin-4 receptor (MC4R) mutations. We identified a pathogenic mutation (S127L) in one child, causing severe early-onset obesity. We describe the phenotype of this particular mutation for the first time. We also identified a novel (I226T) polymorphism in the coding and two new variations (-439delGC and 1059C>T) outside the coding region of the MC4R gene. Three previously described polymorphisms (V103I, T112M, and I125L) were identified. In vitro functional studies of variants T112M, S127L, and I226T supported a pathogenic role of the S127L mutation, because signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired. The S127L mutation did not affect receptor inhibition by the antagonist agouti-related protein. Localization of the three variant receptors was similar to that of wild type. In conclusion, a pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane.
We investigated the associations between a polymorphism in the melanocortin 4 receptor (MC4R) gene and changes in body size and composition from childhood to adulthood in the Québec Family Study. Ninety-one subjects (43 males) less than 18 years of age (mean age 13.5 +/- 2.4 years; range 8.4-17.8 years) at baseline were re-measured 11.2 years later on average. The anthropometric variables analyzed were height, weight, body mass index, percent body fat, sum of skinfolds, fat mass index, and fat free mass index (FFMI). All variables were adjusted for age and sex. The subjects were genotyped for the MC4R C-2745T polymorphism. Forty-five subjects were homozygotes for the common allele (C/C), 36 were heterozygotes (C/T) and 10 were homozygotes for the rare allele (T/T). The rare allele was associated with increased height at baseline as well as at the follow-up visit. Although FFMI tended to increase more in subjects carrying the rare allele, no significant differences were found for the changes over time for the other phenotypes. These results suggest that DNA sequence variation in the MC4R locus may contribute to the gain in body height from childhood to adulthood.
Recent studies suggest that meal frequencies influence the risk of obesity in children and adolescents. It has also been shown that multiple genetic loci predispose to obesity already in youth. However, it is unknown whether meal frequencies could modulate the association between single nucleotide polymorphisms (SNPs) and the risk of obesity. We examined the effect of two meal patterns on weekdays -5 meals including breakfast (regular) and = 4 meals with or without breakfast (meal skipping) - on the genetic susceptibility to increased body mass index (BMI) in Finnish adolescents. Eight variants representing 8 early-life obesity-susceptibility loci, including FTO and MC4R, were genotyped in 2215 boys and 2449 girls aged 16 years from the population-based Northern Finland Birth Cohort 1986. A genetic risk score (GRS) was calculated for each individual by summing the number of BMI-increasing alleles across the 8 loci. Weight and height were measured and dietary data were collected using self-administered questionnaires. Among meal skippers, the difference in BMI between high-GRS and low-GRS (