A common polymorphism of uncoupling protein 2 gene is associated with hypertension

OBJECTIVES: The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the -866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus. METHODS: A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The -866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P=0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P<0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes. CONCLUSION: These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.     

Variants of uncoupling protein-2 gene and obesity: interaction with peroxisome proliferator-activated receptorgamma2

OBJECTIVE: To analyse the association of the UCP2 gene, alone or in combination with the PPARgamma2 gene, with obesity. DESIGN: Cross-sectional, case-control study. STUDY POPULATION: From a working population of 4500 Italian Caucasian employees of the Italian telephone company participating in a firm-sponsored health screening programme, we selected all those with obesity [n = 122; body mass index (BMI) > or = 30 kg/m2]. For each case, three nonobese age- and sex-matched individuals were selected as controls from the same population (n = 374). Included in the study were also 76 severely obese (BMI > or = 40 kg/m2) patients consecutively admitted to the obesity clinic of the department. Diabetic individuals were excluded. MEASUREMENTS: The -866G/A UCP2 and the Pro12Ala PPARgamma2 polymorphisms were determined on genomic DNA of the studied individuals. Several metabolic and anthropometric measures were also obtained, like plasma glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol and BMI. RESULTS: BMI, plasma glucose, insulin, triglycerides, total and HDL cholesterol were not significantly different in carriers and noncarriers of the -866G/A variant. No significant association was observed between the -866G/A UCP2 gene polymorphism and moderate or severe obesity. This was also observed when the UCP2 polymorphism was analysed in combination with the PPARgamma2 polymorphisms. CONCLUSIONS: The -866G/A variants of the UCP2 gene are not associated with either obesity or other features of the metabolic syndrome in the studied groups of the Italian population. This negative finding is not modified after a combined analysis of the UCP2 polymorphism and the Pro12Ala polymorphism of PPARgamma2.     

解偶联蛋白2-866G/A多态性与肥胖关系的研究

目的研究中国自然人群解偶联蛋白2-866G/A多态性与肥胖的关系。方法调查对象为山西省盂县和北京石景山2组人群共3735人,采用标准方法测量身高、体重、腰围,计算体重指数,同时调查其他心血管病危险因素。分别采用DNA MassARRAY技术和PCR-RFLP方法检测2人群UCP2-866G/A位点多态性。以资料完整且排除癌症,心肌梗塞,脑卒中和糖尿病后的2817人为研究对象。使用t检验、χ2检验、一般线性模型(generalized linear model,GLM)和Logistic回归模型分析研究对象解偶联蛋白2-866G/A各基因型及等位基因与肥胖相关指标的关系。结果研究人群UCP2-866G/A基因型频率为AA0.221、AG0.496、GG0.284,基因型分布符合Hardy-Weinberg平衡(P>0.05),石景山和盂县人群基因型频率差异无统计学意义(P=0.508),性别组间基因型频率差异有统计学意义(P=0.032)。男性肥胖组和对照组的基因型分布频率有显著性差异(χ2=8.046,P=0.018),但等位基因频率差异没有统计学意义(χ2=2.945,P=0.086)。GLM分析调整地区,...     

解偶联蛋白2基因-866G／A多态性与2型糖尿病代谢表型相关性的核心家系研究

目的探讨解偶联蛋白2（UCP2）基因-866G／A多态性与2型糖尿病及相关代谢异常性状的关系。方法2005年5月至2007年9月,通过先证者引荐法在北京市房山区农村社区共募集287个2型糖尿病家系。应用聚合酶链反应结合限制性片段长度多态性方法进行UCP2基因-866（3／A多态性鉴定。采用非参数同胞对连锁分析和以家庭为基础的关联分析进行基因多态性与表型的相关性检验。结果2型糖尿病家系人群中UCP2基因-866G／A多态性AA、GA和GG三种基因型频率分别为19．7％、52．9％和27．4％,A、G等位基因频率分别为0．461和0．539;非参数连锁分析未发现阳性结果;以家庭为基础的关联分析发现G等位基因具有传递优势,与代谢综合征和中心性肥胖两表型相关（Z=2．28、2．01,均P〈0．05）,AA基因型也与上述两表型相关（Z=-2．22、-2．01,均P〈0．05）。结论UCP2基因-866G／A多态性与2型糖尿病家系人群的代谢综合征和中心性肥胖相关,与2型糖尿病及血脂异常无关。     

The common -866G/A polymorphism in the promoter region of the UCP-2 gene is associated with reduced risk of type 2 diabetes in Caucasians from Italy

Uncoupling protein-2 (UCP2) regulates insulin secretion and may play an important role in linking obesity to type 2 diabetes (T2D). Previous studies of the role of the UCP2 promoter -866G/A single nucleotide polymorphisms (SNP) in T2D have given opposite results. We tested the distribution of the -866G/A SNP in 746 T2D patients and 327 healthy unrelated Caucasians from Italy. We also tested for an effect of the P12A variant of the peroxisomal proliferator-activated receptor-gamma 2 (PPAR gamma 2) gene on diabetes risk given by the UCP2 SNP. Compared with -866G/G carriers, a progressively reduced (P = 0.01) risk of T2D was observed in -866G/A and -866A/A subjects, with the latter showing an approximately 50% risk reduction [odd ratio (OR), 0.51; 95% confidence interval (CI), 0.3-0.8; P = 0.003]. Conversely, the -866G/G genotype was associated with increased risk (OR, 1.31; 95% CI, 1.01-1.71). Overall, the population risk attributable to the UCP2 -866G/G genotype was about 12%. After stratifying for the PPAR gamma 2 polymorphism, the increased risk conferred by the UCP2 G/G genotype was still evident among P12/P12 homozygous subjects (n = 801; OR, 1.38; 95% CI, 1.04-1.83), but seemed to disappear among the X12/A12 subjects (i.e. P12/A12 heterozygous or A12/A12 homozygous subjects; n = 137; OR, 0.87; 95% CI, 0.40-1.91). Whether this apparent difference is entirely due to the different number of carriers of the two PPAR gamma 2 genotypes is a likely possibility that deserves deeper investigation. In conclusion, in our population, the -866G/A SNP is associated with T2D. Additional studies in larger samples are needed to investigate the possibility of a concomitant effect of modifier genes such as PPAR gamma 2.     

Phenotypic characterization of the beta3-adrenergic receptor mutation and the uncoupling protein 1 polymorphism in Japanese men.

The Trp64Arg mutation of the beta3-adrenergic receptor (beta3AR) gene and A to G polymorphism of the uncoupling protein 1 (UCP1) gene are reported to be associated with weight gain, and both have been shown to have an additive effect on weight gain in Caucasians. Racial differences have also been noted in the beta3AR mutation; however, the effect of UCP1 polymorphism on body weight is not obvious in the Japanese. Thus, we investigated the association of genetic variations in beta3AR and UCP1 genes and the additive effects of these two genes in 214 Japanese men. The frequency of the Trp64Arg allele was 0.19, and serum triglyceride was significantly higher in Arg64 homozygotes versus Trp64 homozygotes. The frequency of the G allele was 0.51, and the body mass index (BMI) was significantly higher in subjects with the G allele (GG homozygotes and AG heterozygotes) versus those without it (AA homozygotes). The beta3AR mutation and UCP1 polymorphism were not found to have additive effects, and they were not related to glucose tolerance patterns and insulin resistance. Our results suggest that the beta3AR mutation is associated with hypertriglyceridemia and the UCP1 polymorphism may be a weak contributing factor to obesity in Japanese men.     

Overweight Japanese with body mass indexes of 23.0-24.9 have higher risks for obesity-associated disorders: a comparison of Japanese and Mongolians

OBJECTIVE: The degree of obesity of Asians is less than that of Caucasians. It has been suggested that Japanese, categorized as having normal weight (BMI<25.0), as defined by WHO (2000), have a tendency toward increased incidences of dyslipidemia and diabetes. Our objective was to analyze parameters constituting obesity-associated disorders in overweight Japanese and Mongolians with a body mass index (BMI) of 23.0-24.9, and to assess the suitability for Asians of the Regional Office for Western Pacific Region of WHO criteria pertaining to obesity (WPRO criteria, 2000). DESIGN: Cross-sectional study in a workplace setting. SUBJECTS: A total of 386 Japanese men and 363 Japanese women, and 102 Mongolian men and 155 Mongolian women. MEASUREMENTS: Anthropometric measurements (weight, height, waist circumference, hip circumference and blood pressure) and metabolic measurements (plasma levels of total cholesterol, HDL cholesterol, triglyceride, glucose and insulin). RESULTS: Graded increases in BMI of Japanese and Mongolians were positively associated with body fat percent, waist circumference, hip circumference and waist/hip ratio. The Japanese were categorized as 22% overweight, 22% obese I, 3% obese II; the Mongolians rated as 18% overweight, 34% obese I, 19% obese II, based on the WPRO BMI criteria. The Mongolians had a higher prevalence of obesity and a higher body fat percent, but a lesser gradation of dyslipidemia, than did the BMI-matched Japanese groups. Overweight Japanese (BMI 23.0-24.9), in comparison to normal Japanese (BMI 18.5-22.9), had significant differences in systolic blood pressure, HDL-cholesterol and triglyceride in men, and in systolic and diastolic blood pressure, HDL-cholesterol, triglyceride, insulin and Homoeostasis model assessment-insulin resistance in women. In contrast, the Mongolians showed no significant differences in metabolic parameters between overweight and normal subjects, except for diastolic blood pressure. CONCLUSION: Since the relationship between abdominal fat mass and BMI is ethnic-specific, a universal BMI cutoff point is inappropriate for Asian populations such as the Japanese and Mongolians. The present investigation suggests that, while the WPRO criteria are suitable for Japanese, the WHO criteria are more appropriate for Mongolians.     

Synergistic effect of polymorphisms of uncoupling protein 1 and beta3-adrenergic receptor genes on autonomic nervous system activity.

OBJECTIVE: To investigate the association of the promoter region -3826 A to G polymorphism of the uncoupling protein 1 (UCP1) gene with autonomic nervous system (ANS) activity and the interaction of the polymorphism with the Trp64Arg polymorphism of the beta3 adrenergic receptor (beta3AR). SUBJECTS: Three-hundred and forty-nine young (mean age 20.4+/-2.1 y old), healthy Japanese males. MEASUREMENTS: DNA was extracted from whole blood and genotyped by polymerase chain reaction restriction fragment length polymorphism. Plasma glucose, plasma insulin and body mass index (BMI) were measured. Frequency of family history of diabetes or obesity was determined by interview. Subjects randomly chosen from each genotype were examined for ANS activity during supine rest and standing by electrocardiogram power spectral analysis of heart rate variability. RESULTS: UCP1 or beta3AR polymorphism was not associated with BMI, plasma glucose, plasma insulin and frequency of family history of diabetes or obesity. The inhibitory effect of UCP1 polymorphism on ANS activity was observed only with occurrence of the variant of beta3AR. The very low frequency component associated with thermoregulation in the sympathetic nervous system of homozygotes of UCP1 (GG) at supine rest was significantly lower than normal (AA, 203.2+/-50.3 vs 462.2+/-83.6 ms(2); mean+/-s.e., P=0.021). A higher response to postural change to standing was also observed in both sympathetic and parasympathetic nervous activities of AA than of GG. CONCLUSION: While UCP1 polymorphism alone does not affect ANS activity, it has a synergistic effect with beta3AR polymorphism in decreasing sympathetic nervous system activity.     

Waist circumference correlates with hepatic fat accumulation in male Japanese patients with non-alcoholic fatty liver disease, but not in females

Background and Aim:  Abdominal obesity, a component of metabolic syndrome, is a major risk factor for non-alcoholic fatty liver disease (NAFLD). In recent worldwide definitions of metabolic syndrome, waist measurement has been proposed as a simple and useful estimate of abdominal obesity, taking into account gender differences in waist circumference. The present cross-sectional study investigated the correlation of hepatic fat accumulation and waist circumference in Japanese NAFLD patients to determine if there are gender differences in this relationship.
Methods:  Consecutive patients ( n  = 2111) who had at least one of two criteria for liver disease (alanine aminotransferase [ALT] level >30 IU/mL and aspartate aminotransferase [AST]/ALT ratio <1) underwent abdominal ultrasonography. Patients positive for hepatitis B virus, hepatitis C virus or autoimmune antibodies and whose alcohol intake was >20 g/day were excluded. Patients with NAFLD underwent abdominal computed tomography. Hepatic fat accumulation was estimated by liver/spleen attenuation ratio (L/S ratio) and visceral adipose accumulation was measured as visceral fat area (VFA) at the umbilical level.
Results:  Of the 221 NAFLD patients, 103 were females. In males, the relationship between L/S ratio and waist circumference was negative ( r  =−0.356, P  < 0.01), and there was no correlation in the female group. The relationship between L/S ratio and VFA was negative in both groups (males: r  = −0.269, P  < 0.01; females: r  = −0.319, P  < 0.01). Subcutaneous fat area/total fat area ratio at the umbilical level was larger in females than in males ( P  < 0.01).
Conclusions:  In NAFLD patients, waist measurement is more susceptible to gender differences than VFA.     

A Val227Ala substitution in the peroxisome proliferator activated receptor alpha (PPAR alpha) gene associated with non-alcoholic fatty liver disease and decreased waist circumference and waist-to-hip ratio

Background and Aim:  This study analyzes the effect of the val227ala variant of the peroxisome proliferators-activated receptor-alpha (PPAR-α) on non-alcoholic fatty liver disease.
Methods:  79 patients with NAFLD and 63 healthy counterparts were included in the study. Body mass index (BMI), hip, waist, waist-to-hip ratio (WHR), blood pressure (BP), the percentage of body fat, total protein, albumin, ALT, triglyceride, cholesterol, HDL and fasting blood glucose were assessed. The genotypes were analyzed using oligonucleotide microarray. Logistic model was used to perform the multi-factors synthetical analysis on the data obtained to screen the risk factors closely associated with Val227Ala polymorphism of PPAR-α gene.
Results:  There were 6.33% (5/79) subjects with CC/CT genotype (ala227ala and val227ala) and 93.67% (74/79) subjects with TT genotype (val227val) in patients with NAFLD, and there were 20.63% (13/63) with CC/CT genotype and 79.37% (50/63) subjects with TT genotype. The distribution of PPAR-α val227ala polymorphism between NAFLD and healty subjects was significant (p = 0.011). The level of weight, body mass index, hip circumference, waist circumference, waist-hip ratio, percentage of body fat, abdominal wall fat thickness in subjects with Val227Ala variant were significantly lower than that in Val227wide type. The results showed that waist circumference and WHR were related with the PPAR-α val227ala polymorphism.
Conclusion:  PPAR-α val227ala polymorphism may be involved in the pathogenesis of NAFLD and play a protective role in obesity.     

Tumor necrosis factor-alpha--308 G/A polymorphism in obese Caucasians

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) is expressed primarily in adipocytes, and elevated levels of this cytokine have been linked to obesity and insulin resistance. Recently, the A allele of a polymorphism in the 5'-flanking region of the TNF-alpha gene (G-308A) has been reported to be more frequent in obese than in lean subjects and has also been associated with increased expression of this cytokine in fat tissue and influences fat mass and insulin resistance. We, therefore, examined the relationship between this variant and obesity in a German Caucasian population. SUBJECTS AND METHODS: We genotyped 176 index subjects recruited within the framework of the BErG (Berlin Ern?hrung Geschwister)- Study for the TNF-alpha-G-308A polymorphism. Subjects were characterized for weight, height, waist and hip circumference, body mass index (BMI), body composition, glucose tolerance, leptin and angiotensinogen levels. RESULTS: The frequency of the -308A allele (0.18) was similar to that reported previously and genotype distribution was in Hardy-Weinberg equilibrium (GG, n=118; GA, n=53; AA, n=5). There was a significant difference in allele frequencies of the polymorphism by BMI quartiles (I,<27.3 kg/m2; II, 27.3-31.9 kg/m2; III, 31.9-36.5 kg/m2; IV,>36.5 kg/m2, in each quartile n=44) with -308A allele carriers having a higher BMI than G allele carriers (P=0.013). Despite previous smaller studies that have related insulin resistance to the G-308A polymorphism, we found no relationship between glucose and insulin response during an oral glucose tolerance test (OGTT) and the polymorphism. Furthermore, none of the plasma parameters were related to the polymorphism. CONCLUSION: Our findings support the hypothesis that the G-308A polymophism of the TNF-alpha gene is associated with BMI. The G-308A polymorphism may, therefore, represent a genetic marker for increased susceptibility for obesity in Caucasians.     

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

Aims/hypothesis Uncoupling protein-2 (UCP2) is thought to play a role in insulin secretion and the development of obesity. In this study, we investigated the effects of genetic variation in UCP2 on type 2 diabetes and obesity, as well as on metabolic phenotypes related to these diseases, in Pima Indians.Methods The coding and untranslated regions of UCP2, and approximately 1 kb of the 5 upstream region, were sequenced in DNA samples taken from 83 extremely obese Pima Indians who were not first-degree relatives.Results Five variants were identified: (1) a –866G/A in the 5 upstream region; (2) a G/A in exon 2; (3) a C/T resulting in an Ala55Val substitution in exon 4; and (4, 5) two insertion/deletions (ins/del; 45-bp and 3-bp) in the 3 untranslated region. Among the 83 subjects whose DNA was sequenced, the –866G/A was in complete genotypic concordance with the Ala55Val and the 3-bp ins/del polymorphism. The G/A polymorphism in exon 2 was extremely rare. To capture the common variation in this gene for association analyses, the –866G/A variant (as a representative of Ala55Val and the 3-bp ins/del polymorphism) and the 45-bp ins/del were also genotyped for 864 full-blooded Pima Indians. Neither of these variants was associated with type 2 diabetes or body mass index. However, in a subgroup of 185 subjects who had undergone detailed metabolic measurements, these variants were associated with 24-h energy expenditure as measured in a human metabolic chamber (p=0.007 for the 45-bp ins/del and p=0.03 for the –866G/A after adjusting for age, sex, family membership, fat-free mass and fat mass).Conclusions/interpretation Our data indicate that variation in UCP2 may play a role in energy metabolism, but this gene does not contribute significantly to the aetiology of type 2 diabetes and/or obesity in Pima Indians.     

Fasting serum adiponectin concentration is reduced in Indo-Asian subjects and is related to HDL cholesterol

Aims: Adiponectin is a 30-kDa protein secreted by adipose tissue. The aim of the present study was to compare serum adiponectin in male Indo-Asian and Caucasian subjects and examine its association with fat topography and metabolic parameters.
Methods: Diabetic and non-diabetic male subjects (n = 48) were studied. A single observer carried out blood pressure and anthropometric measurements. Serum glucose, insulin, lipid profile and adiponectin (measured by RIA) were measured on a fasting sample.
Results: There was no statistically significant difference in serum adiponectin between diabetic and BMI-matched non-diabetic subjects. However, serum adiponectin was lower in Indo-Asians compared with BMI-matched Caucasians, [median adiponectin (interquartile range) 3.3 (2.1–3.9) vs. 4.9 (3.5–6.6) μg/ml respectively (p = 0.016)]. Univariate analysis showed serum adiponectin to be positively associated with HDL in diabetic (p = 0.039) and non-diabetic subjects (p = 0.0098). Waist circumference (p = 0.02), saggital diameter (p = 0.04) were negatively correlated with serum adiponectin in diabetic subjects. Multiple regression analysis including waist, HDL, fasting insulin, age, diabetes and ethnicity in all subjects showed HDL to be the best predictor of serum adiponectin.
Conclusions: Serum adiponectin is associated with HDL cholesterol and central obesity. Caucasians have higher serum adiponectin levels compared with Indo-Asians. Further studies are needed to explore basis for the association of adiponectin with HDL cholesterol and the reason for lower levels in Indo-Asians.     

Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2.

BACKGROUND: Oxidative stress reduces total antioxidant status (TAOS) and is implicated in atherogenesis. Mitochondrial uncoupling protein 2 (UCP2) negatively regulates reactive oxygen species generation. The UCP2 gene demonstrates a common functional promoter variant (-866G>A). METHODS AND RESULTS: Amongst 465 diabetic men (age 61.7 +/- 13.3 years), an association of the UCP2-866A allele with significantly lower TAOS in those without CHD was even more pronounced in those with CHD (TAOS 30.1 +/- 16.1% vs. 41.6 +/- 12.4% for AA vs. GG; P=0.016). In a sample of 20 diabetic men selected for homozygosity for the UCP2-866G>A variant, matched for baseline characteristics, plasma markers of oxidative stress in those with CHD were significantly higher in AA genotype men (TAOS 31.7 +/- 7.3% vs. 52.6 +/- 6.3%; P=0.001 and F2-isoprostanes 220.6 +/- 37.2 pg ml(-1) vs. 109.9 +/- 51.1 pg ml(-1); P=0.005 for AA vs. GG). Amongst 2695 healthy men (age 56.1 +/- 3.5 years) prospectively studied for a median 10.2 years, AA homozygotes had a highly significant doubling in CHD risk after adjustment for established risk factors (HR 1.99 [1.37-2.90]; P=0.002). Risk associated with this genotype was substantially increased by the presence of other risk factors (obesity, hypertension and diabetes). CONCLUSIONS: This study provides the first in vivo evidence of a role for UCP2 in modifying oxidative stress and CHD risk in humans.     

Association between accumulation of visceral fat and the combination of β3 adrenergic receptor Trp64Arg, β2 adrenergic receptor Arg16Gly and uncoupling protein 1 -3826A>G polymorphisms detected by Smart Amplification Process 2

β2 and β3 adrenergic receptors (β2AR, β3AR) and uncoupling protein 1 (UCP1) have been considered as candidate genes for obesity. Although each polymorphism of β3AR Trp64Arg, β2AR Arg16Gly and UCP1 -3826A>G is known to be associated with obesity, the interaction among these polymorphisms is not fully understood. We analyzed β3AR Trp64Arg, β2AR Arg16Gly and UCP1 -3826A>G polymorphisms by the Smart Amplification Process 2 in 222 Japanese subjects without the medication of hypertension, dyslipidemia or diabetes, and investigated the association between the physical and metabolic characteristics and the combination of these polymorphisms. In analysis of the genotypes combination, only the carriers of both β2AR Arg/Arg and UCP1 G/G genotypes had significantly higher waist to hip ratio (p=0.014). In analysis of the alleles combination, a significant difference was observed in waist to hip ratio among the groups stratified by the carrying number of the alleles of β3AR Arg, β2AR Arg and UCP1 G (p=0.026), and the waist to hip ratio was significantly higher in the carriers of four and five risk alleles than in the carriers from zero to three risk alleles (p=0.005). The present study demonstrated the interaction among β3AR Trp64Arg, β2AR Arg16Gly and UCP1 -3826A>G for the accumulation of visceral fat.     

Associates of change in liver fat content in the morbidly obese after laparoscopic gastric banding surgery

Aim:  Hepatic steatosis affects up to 30% of the population. After weight loss, monitoring of the change in hepatic steatosis is not routinely performed. This study aimed to define the closest associates of change in liver fat content in a population of obese females following laparoscopic gastric banding surgery.
Methods:  Before and 3 months after surgery, proton magnetic resonance spectroscopy and magnetic resonance imaging were used to estimate the amount of lipid contained within the liver and abdominal subcutaneous and visceral compartments of 29 obese [mean body mass index (BMI) 39 ± 5 kg/m²], non-diabetic women aged between 20 and 62 years. Liver enzymes, fasting plasma glucose and insulin were also measured as well as body weight, BMI and waist circumference. Insulin sensitivity was estimated using homeostasis model assessment insulin resistance index.
Results:  Significant reductions occurred in body weight (p < 0.001), abdominal fat volumes (p < 0.001) and liver fat (p = 0.037) 3 months after surgery. Change in liver fat content more closely associated with change in serum gamma-glutamyl transferase (GGT; r = 0.71, p < 0.001) than with changes in weight (r = 0.10, p = 0.612) and waist circumference (r = 0.15, p = 0.468).
Conclusions:  Our findings suggest that obese non-diabetic female patients who have undergone significant weight loss over 3 months can be better assessed for the regression of excess liver fat content by monitoring changes in serum GGT levels rather than changes in simple anthropometry.     

Studies of the synergistic effect of the Trp/Arg64 polymorphism of the beta3-adrenergic receptor gene and the -3826 A-->G variant of the uncoupling protein-1 gene on features of obesity and insulin resistance in a population-based sample of 379 young Danish subjects

This study examined whether the simultaneous presence of the previously identified Trp/Arg64 polymorphism of the beta3-adrenergic receptor (BAR) gene and the -3826 A-->G nucleotide variant of the uncoupling protein-1 (UCP1) gene are associated with obesity, insulin resistance, or alterations in size at birth in a Danish study population comprising 379 unrelated young Caucasian subjects. All study participants underwent an iv glucose tolerance test with addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the 2 polymorphisms by applying PCR-restriction fragment length polymorphism. The subjects were divided into 4 groups according to their BAR and UCP1 genotype: wild-type carriers (n = 184), only Trp/Arg64 carriers (n = 29), only A-->G UCP1 carriers (n = 146), and carriers of both genetic variants (n = 20). There were no differences across the genotype groups with respect to body mass index, fat mass, waist to hip ratio, birth weight or length, ponderal index, or weight gain during childhood or adolescence, nor was the combined genotype related to alterations in fasting serum levels of lipids, insulin, or C peptide or the insulin sensitivity index. In conclusion, the present study failed to demonstrate an additive or synergistic effect of the Trp/Arg64 variant of the BAR gene and the -3826 A-->G variant of the UCP1 gene on the development of obesity and insulin resistance among randomly recruited Danish Caucasian subjects.     

Association of ENPP1 (PC-1) K121Q polymorphism with obesity-related parameters in subjects with metabolic syndrome

Background The metabolic syndrome (MS), a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), originally described as a plasma cell allo‐antigen and named plasma cell membrane glycoprotein (PC‐1), is an inhibitor of insulin‐induced activation of the insulin receptor. The single nucleotide polymorphism (SNP) K121Q in the ENPP1 gene has been studied in relation to obesity, insulin resistance and other features of MS in several populations with conflicting results. We therefore investigate the role of the K121Q SNP in the ENPP1 gene in MS in Caucasians from the province of Segovia in Central Spain (Castille). Design and methods We recruited 794 unrelated persons (46·5% males and 53·5% females), ages 35–74 years from a cross‐sectional population‐based epidemiological survey in the province of Segovia in Central Spain (Castille). Obesity‐related anthropometric measurements included BMI, waist circumference, blood pressure and lipid profile. MS was defined by International Diabetes Federation (IDF) guidelines. K121Q PC‐1 genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP). Results The 121Q allele was associated with an increased BMI and waist circumference among subjects fulfilling the criteria for MS. These differences remained statistically significant even after the adjustment for sex, age and degree of glucose tolerance (β = 1·347, P = 0·017 and β = 2·824, P = 0·046; for BMI and waist circumference, respectively). Moreover, among type 2 diabetic patients those carrying the 121Q allele had higher BMI and higher leptin levels than subjects carrying the K121K genotype. Conclusions Our results suggest that the ENPP1121Q allele might contribute to the genetic susceptibility to abdominal obesity among subjects with MS.     

Mutational analysis of the coding region of the uncoupling protein 2 gene in obese NIDDM patients: Impact of a common amino acid polymorphism on juvenile and maturity onset forms of obesity and insulin resistance

Summary Recently, a gene encoding a novel human uncoupling protein, designated UCP2, was discovered. The murine UCP2 was mapped to a region on mouse chromosome 7 which in several models has been shown to be linked to obesity and hyperinsulinaemia. Single strand conformation polymorphism (SSCP) analysis and direct sequencing of the coding region of the UCP2 gene in 35 obese Caucasian NIDDM patients of Danish ancestry revealed one nucleotide substitution, replacing an alanine with a valine at codon 55. The amino acid polymorphism was present in 24 of the 35 (69 %) examined subjects. The allelic frequency of the A/V55 variant was 48.3 % (95 % CI: 42.5–54.1 %) among 144 subjects with juvenile onset obesity, 45.6 % (40.5–50.7 %) among 182 subjects randomly selected at the draft board examination, and 45.5 % (37.1–53.9 %) among lean control subjects selected from the same study cohort. Within these cohorts there were no differences in BMI values at different ages among wild-type carriers and A/V55 carriers. In a population-based sample of 369 young healthy Caucasians the variant showed no association with alterations in BMI, waist-to-hip ratio, fat mass or weight gain during childhood or adolescence. The A/V55 polymorphism was not related to alterations in fasting values of serum insulin and C-peptide or to an impaired insulin sensitivity index. We conclude that genetic variability in the human UCP2 gene is not a common factor contributing to NIDDM in obese Danish Caucasian subjects and the common A/V55 amino acid polymorphism of the gene is not implicated in the pathogenesis of juvenile or maturity onset obesity or insulin resistance in Caucasians. [Diabetologia (1997) 40: 1227–1230] Received: 20 June 1997     

Association of polymorphisms in the estrogen receptor alpha gene with body fat distribution

OBJECTIVE: To examine whether polymorphisms of the estrogen receptor (ER) alpha gene are associated with body fat distribution. DESIGN: Cross-sectional, epidemiological study of two single-nucleotide polymorphisms, a T --> C (PvuII) and an A --> G (XbaI), in the first intron of the ERalpha gene. SUBJECTS: A total of 2238 community-dwelling middle-aged and elderly Japanese population (age: 40-79 y). MEASUREMENTS: The ERalpha genotypes (by automated fluorescent allele-specific DNA primer assay system), anthropometric variables, fat mass (FM) and percentage FM (%FM) (by dual-energy X-ray absorptiometry). RESULTS: FM and waist were inversely associated with age (r=-0.630 and -0.504, respectively) in women with the GG genotype. On the other hand, waist circumference of the AA genotype was positively correlated with age (r=0.231). Thus, for middle-aged women (40-59 y) with the AG or GG genotype body mass index (BMI), %FM, FM, waist, hip and waist-to-hip ratio (WHR) were larger than those with the AA genotype. In particular, FM and waist were greater by 20% and 9%, respectively, for the GG genotype, compared to the AA genotype. Alternatively, FM and waist were smaller by 18% and 6%, respectively, in older women with the GG genotype, compared to the AA genotype. No effect was found among the A --> G polymorphisms for men. For both genders, no difference was found in any variables among the TT, TC and CC genotypes with the exception of BMI of older men (60-79 y). CONCLUSION: No association was found between the ERalpha gene polymorphisms and body fat distribution in men. For women, the A --> G polymorphism, in particular the GG genotype, may contribute to the development of upper-body obesity in middle-aged individuals, but may serve to decrease the whole-body and abdominal fat tissue of older individuals.