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Ethnopharmacological Relevance: The herbal composition Gyeongshingangjeehwan 18 (GGEx18), composed of Rheum palmatum L. (Polygonaceae), Laminaria japonica Aresch (Laminariaceae), and Ephedra sinica Stapf (Ephedraceae), is used as an antiobesity drug in Korean clinics. The constituents of GGEx18 have traditionally been reported to inhibit obesity and related metabolic diseases such as insulin resistance and dyslipidemia., Objective: This study investigated the effects of GGEx18 on nonalcoholic fatty liver disease (NAFLD) in mice fed a high-fat diet (HFD) and the underlying cellular and molecular mechanisms involved., Methods: C57BL/6 J mice were fed either a low-fat diet (LFD), an HFD, or an HFD supplemented with GGEx18 (125, 250, or 500 mg/kg of body weight/day). After 13 weeks, blood analyses, histology, immunohistochemistry, and real-time PCR were performed to assess NAFLD development in these mice., Results: Mice fed an HFD had increases in body weight, epididymal adipose tissue mass, adipocyte size, and adipose expression of inflammation-related genes compared with those fed an LFD. These increases were ameliorated in mice treated with 500 mg/kg/day GGEx18 without affecting food consumption profiles. GGEx18 not only decreased serum levels of triglycerides, free fatty acids, and alanine aminotransferase, but also decreased hepatic lipid accumulation, numbers of mast cells and α-smooth muscle actin-positive cells, and collagen levels induced by an HFD. Consistent with the histological data, the hepatic expression of lipogenesis-, inflammation-, and fibrosis-related genes was lower, while hepatic fatty acid β-oxidation-related gene expression was higher, in mice receiving GGEx18 compared to mice fed only the HFD., Discussion and Conclusion: These results indicate that GGEx18 attenuates visceral obesity and NAFLD, in part by altering the expression of genes involved in hepatic steatosis and fibroinflammation in HFD-induced obese mice. These findings suggest that GGEx18 may be effective for preventing and treating NAFLD associated with visceral obesity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Obesity is the third most risk factors of death in the middle-income and high-income countries. Whether DNA polymorphisms in CORIN and NPPA genes were associated with obesity, and if these associations could be modified by smoking in the Chinese Han population were unknown, hence a group of 1507 participants were recruited and genotyped for 12 tag single-nucleotide polymorphisms (SNPs) of CORIN and NPPA genes. Regression models were used to test the associations of SNPs with obesity. The potential SNP-smoking interactions were detected in regression models. NPPA SNPs rs5063 and rs198358 were associated with the body mass index (BMI) ( P = 0.0053 and 0.0037, respectively). Rs198358 was associated with obesity in both univariate- and multivariable-adjusted analyses ( P = 0.0138 and 0.0173, respectively). Rs5063 was associated with central obesity in both univariate- and multivariable-adjusted analyses ( P = 0.0454 and 0.0361, respectively). Significant interactions between cigarette smoking and rs5063 and rs198358 were detected ( P = 0.0019 and 0.0006, respectively). In subgroup analyses, rs5063 and rs198358 were associated with central obesity in smokers ( P = 0.0081 and 0.0037, respectively). The results of our study demonstrated that the effect of NPPA SNPs rs5063 and rs198358 on central obesity might be modified by smoking in the Chinese Han population. Further studies are needed to confirm the associations and elucidate the underlying mechanisms.

The relationship of the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor γ (PPARγ) gene with obesity and its modulation by dietary fat has been proposed, but the few studies addressing this issue have yielded controversial results. In a Mexican population characterized by high-fat consumption, we hypothesized that the Pro12Ala PPARγ genotype is related to obesity and this relationship is modulated by intake of saturated fatty acids (SFAs) and trans-fatty acids (TFAs). We recruited 69 adults for this cross-sectional study. The Pro12Ala PPARγ polymorphism was determined from blood genomic DNA by using real-time polymerase chain reaction. Univariate and multivariate logistic regression analyses were performed. Pro12Ala showed a positive association with central obesity (adjusted odds ratio, 7.38; 95% confidence interval, 1.19-45.77; P = .032) and percentage of body fat (%BF; adjusted odds ratio, 1.08; 95% confidence interval, 1.00-1.17; P = .048), suggesting that Pro12Ala carriers are more likely to have central obesity and a higher %BF than Pro12Pro carriers. A modifying effect was observed for the SFAs strata: we found a significant association between the Pro12Ala polymorphism and %BF in the high-SFA-intake stratum (P < .04), but not in the low-intake stratum (P > .7). No modifying effect was observed for the TFAs strata. In addition, the impact of total energy intake on obesity in Pro12Ala carriers seemed to be stronger than that in the wild-type genotype carriers. As hypothesized, our data demonstrated a relationship between the Pro12Ala PPARγ polymorphism and the presence of obesity, which is modulated by SFA intake but not TFA intake., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Fatty acid (FA) status is associated with the risk of several diet-related diseases. Since postmenopausal women are at increased risk of cardiometabolic disturbances, determinants of FA metabolism should be fully understood in this group. We hypothesize that FA metabolism in postmenopausal Polish women may depend on current macronutrient intake and on fatty acid desaturase ( FADS ) gene polymorphism. One-hundred-and-twenty-eight postmenopausal women with central obesity were recruited to the study and their dietary intake, FA composition in red blood cells (RBC), and rs174556, rs174561, rs174547, and rs3834458 polymorphism of the FADS gene were analyzed. Higher levels of 18:2n-6t level in RBC were associated with higher protein or fat intake or with lower carbohydrate intake. The minor allele carriers of rs174561 of the fatty acid desaturase 1 ( FADS1 ) gene had 9.7% lower concentration of 20:4n⁻6 in RBC ( p < 0.05), but there were no other associations between other FA in RBC levels and FADS1 or fatty acid desaturase 2 ( FADS2 ) polymorphisms. The mean D5D value was 15.3⁻17.9% lower in the minor allele carriers of each SNPs. We concluded that protein and carbohydrate intake may be associated with FA concentrations in RBC in centrally obese postmenopausal Polish women. The D5D value may be affected by FADS1 or FADS2 polymorphism.

Background: Observational studies have illustrated that maternal central obesity is associated with birth size, including of birth weight, birth length and head circumference, but the causal nature of these associations remains unclear. Our study aimed to test the causal effect of maternal central obesity on birth size and puberty height growth using a Mendelian randomization (MR) analysis., Methods: We performed two-sample MR using summary-level genome-wide public data. Thirty-five single nucleotide polymorphisms (SNPs), 25 SNPs and 41 SNPs were selected as instrumental variables for waist-to-hip ratio adjusted for BMI, waist circumference adjusted for BMI and hip circumference adjusted for BMI, respectively to test the causal effects of maternal central obesity on birth size and puberty height using an inverse-variance-weighted approach., Results: In this MR analysis, we found no evidence of a causal association between waist circumference or waist-to-hip ratio and the outcomes. However, we observed that one standard deviation (SD) increase in hip circumference (HIP) was associated with a 0.392 SD increase in birth length (p = 1.1 × 10 - 6 ) and a 0.168 SD increase in birth weight (p = 7.1 × 10 - 5 ), respectively at the Bonferroni-adjusted level of significance. In addition, higher genetically predicted maternal HIP was strongly associated with the puberty heights (0.835 SD, p = 8.4 × 10 - 10 ). However, HIP was not associated with head circumference (p = 0.172)., Conclusions: A genetic predisposition to higher maternal HIP was causally associated with larger offspring birth size independent of maternal BMI. However, we found no evidence of a causal association between maternal waist circumference, waist-to-hip ratio and birth size.

Aims/hypothesis: Angiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4 -/- mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity., Methods: We chronically fed wild-type (WT) and Angptl4 -/- mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests., Results: Mice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4 -/- mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4 -/- mice., Conclusions/interpretation: Despite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism.

Background: The aim of this study was to quantify the association of Val109Asp polymorphism of intelectin 1 (ITLN1) gene with the abdominal obesity (AO) in Kyrgyz population., Methods: Patients admitted to annual screening at a local outpatient facility were enrolled or this study. We genotyped 297 nonrelated adults of Kyrgyz ethnicity, of whom 127 were AO patients, including 46 men and 81 women with the mean age 53.2 ± 7.1 years, and 170 non-obese controls, including 61 men and 109 women with the mean age 52.0 ± 9.0 years. AO was defined as having waist circumferences ≥ 102 cm in men and ≥ 88 cm in women. We used PCR-RFLP method to define Val109Asp polymorphism of ITLN1 gene., Results: Asp109Asp, Asp109Val and Val109Val genotypes were found in 48%, 40%, and 12% of AO patients respectively, and in 53%, 43%, and 4% of controls, whereas Val109Val homozygous genotype of ITLN1 gene Val109Asp polymorphic marker was significantly more prevalent in AO patients. In Kyrgyz population, Val109Val genotype of ITLN1 gene increased the risk of AO (odds ratio (OR) 3.12, 95% CI 1.23-7.90). Asp109Asp homozygous genotype, on opposite, was not associated with this condition (OR 0.82, 95% CI 0.53-1.30). Finally, the allelic variants of Val109Asp polymorphism of ITLN1 gene were not associated with AO., Conclusion: Significant increase in the frequency of Val109Val genotype of ITLN1 gene in AO patients may be indicative of some potential role of ITLN1 gene in molding genetic predisposition to AO in the Kyrgyz. This requires further elaboration in the future studies.

Objective: Given the rising prevalence of central obesity and the discovery that beige cells appear within white adipose tissue, strategies to enhance these energy-expending adipocytes or "browning" within white adipose depots have become of therapeutic interest to combat obesity and its associated disorders. This study focused on, the role of microRNA (miRNA)-27b-3p in human visceral adipose tissue (VAT) browning., Methods: Expression of miR-27b-3p and UCP1 in VAT and serum of humans was measured. MiR-27b-3p was overexpressed or suppressed in human visceral stromal fraction cells to analyze the potential role of miR-27b-3p., Results: UCP1 expression in human VAT decreased with elevated BMI and waist-hip ratio, whereas expression of miR-27b-3p was found to correlate positively with BMI and waist-hip ratio. High expression of miR-27b-3p was associated with reduced browning ability of human visceral adipocytes. Antagonism of miR-27b-3p led to the enhancement of browning ability in human visceral adipocytes., Conclusions: These findings highlight the decreased browning ability of VAT from humans with obesity and the role of miR-27b-3p in regulating browning of human visceral adipocytes. They suggest that miR-27b-3p should be further explored as a potential target for the treatment of central obesity., (© 2017 The Obesity Society.)

Deficiency of primary cilia formation by knockout kinesin family member 3A (Kif3a) in mature osteoblasts led to osteopenia and enhanced adipogenesis. Adipogenesis plays an important role in adipose tissue expansion by High-fat-diet (HFD) induced obesity. Whether primary cilia participate in high-fat-diet induced adiposity remains unclear. In this study, we found that the number and length of primary cilia and expression levels of KIF3A and intraflagellar transport 88 homolog (IFT88) mRNA and proteins reached peak on the day 3 of adipogenesis, followed by a decrease to reach low basal expression levels at day 9 when differentiated to lipid accumulating adipocytes in VAT-SVFs derived from lean mice. The number of primary cilia was reduced by shRNA and chemical methods, leading to elevated transcripts of Pparγ, Cebp-α, Srebp-1, and Fasn and protein levels of PPARγ and FASN. Similar to the proadipogenic effect by the inhibition of primary cilia formation in control VAT-SVFs, HFD caused severe reduction of primary cilia formation and enhancement of adipogenesis in VAT-SVFs cultures. Flow cytometry analysis revealed percentage of G2/M phase cells and the protein expression of Cyclin A2 and CDK2 increased in control VAT-SVFs by knockdown of primary cilia with shRNA or chemical methods and HFD induced obese VAT-SVFs. In conclusion, the expression of primary cilia was in reverse correlation with adipogenic differentiation. HFD caused severe defects of primary cilia in VAT-SVFs, leading to adipose tissue expansion by enhancement of adipogenesis through promoting cell cycle re-entry at the early stage of adipogenesis., (© 2017 Wiley Periodicals, Inc.)

The alpha2A-adrenoceptors (α2A-ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally inhibit insulin secretion and lipolysis. We have earlier shown that α2A-/- mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α2A-/- mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α2A-ARs protects from diet-induced obesity and type 2 diabetes (T2D). In addition, a high-caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α2A-/- mice accumulated less visceral fat than the wild-type controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α2A-ARs is associated with an increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α2A-/- mice displayed enhanced lipolytic responses to Epi, and increased faecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α2A-/- mice, and brown fat showed an increased response to NE. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α2A-AR signalling promoted weight loss more efficiently than exercise with normal α2A-AR function. These results suggest that blockade of α2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion., (© 2018 S. Karger AG, Basel.)

The Native American Pima population has the highest incidence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) of any reported population, but the pathophysiologic mechanism is unknown. Genetic studies in Pima Indians have linked acyl-CoA dehydrogenase 10 (ACAD10) gene polymorphisms, among others, to this predisposition. The gene codes for a protein with a C-terminus region that is structurally similar to members of a family of flavoenzymes-the acyl-CoA dehydrogenases (ACADs)-that catalyze α,β-dehydrogenation reactions, including the first step in mitochondrial FAO (FAO), and intermediary reactions in amino acids catabolism. Dysregulation of FAO and an increase in plasma acylcarnitines are recognized as important in the pathophysiology of IR and T2DM. To investigate the deficiency of ACAD10 as a monogenic risk factor for T2DM in human, an Acad-deficient mouse was generated and characterized. The deficient mice exhibit an abnormal glucose tolerance test and elevated insulin levels. Blood acylcarnitine analysis shows an increase in long-chain species in the older mice. Nonspecific variable pattern of elevated short-terminal branch-chain acylcarnitines in a variety of tissues was also observed. Acad10 mice accumulate excess abdominal adipose tissue, develop an early inflammatory liver process, exhibit fasting rhabdomyolysis, and have abnormal skeletal muscle mitochondria. Our results identify Acad10 as a genetic determinant of T2DM in mice and provide a model to further investigate genetic determinants for insulin resistance in humans.

Abdominal obesity is a risk factor for cardiovascular disease and diabetes mellitus and has been associated with vitamin D deficiency. Some studies have suggested an association between obesity and adipokine levels as well as low serum 25-hydroxyvitamin D (25(OH)D) level but the underlying mechanisms of the interlink between vitamin D status and serum leptin and adiponectin concentrations are still disputed. We included 435 residents (132 males) from St. Petersburg, Russia into this study. All subjects had physical examination and demographics noted. Blood was collected after an overnight fast and plasma glucose, insulin, serum lipids, 25(OH)D and adipokines (adiponectin and leptin) concentrations were determined at baseline in all participants. Abdominal obesity was diagnosed in 310 (71.3%) subjects (251 females and 59 males). Vitamin D insufficiency and deficiency were found in 314 (72.2%) subjects. Mean (95% CI) age, body mass index (BMI) and serum 25(OH)D for the cohort were 47.6±11.3years; 28.7±0.2kg/m 2 and 62.5±24.3nmol/l respectively. Serum 25(OH)D level inversely correlated with body weight, waist circumference (WC) and BMI in females but not in males, was lower in diabetic than non-diabetic subjects, and was not significantly different in subjects with and without MetS. WC was positively correlated with leptin and negatively correlated with adiponectin. We found correlation between leptin and serum 25(OH)D level (r=-0.15, p=0.01) but this finding was a characteristic seen only in women. Our study showed a high prevalence of abdominal obesity, vitamin D deficiency and insufficiency in residents from North-West region of Russia, close association between adipokine (leptin, adiponectin) concentrations as well as vitamin D status and body composition (WC, BMI). However in our study the interlink between leptin level and 25(OH)D was found only in females. Further investigations are required to study the relationship between serum 25(OH)D level, obesity and serum adipokine levels., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

There is increasing interest of which dietary patterns can modify the association of fat mass and obesity associated (FTO) variants with obesity. This study was aimed at investigating the interaction of the Mediterranean dietary pattern (Med Diet) with FTO polymorphisms in relation to obesity phenotypes. Subjects of this nested case-control study were selected from the Tehran Lipid and Glucose Study participants. Each case was individually matched with a normal weight control ( n = 1254). Selected polymorphisms (rs1421085, rs1121980, rs17817449, rs8050136, rs9939973, and rs3751812) were genotyped. Genetic risk score (GRS) were calculated using the weighted method. The Mediterranean dietary score (MDS) was computed. Individuals with minor allele carriers of rs9939973, rs8050136, rs1781749, and rs3751812 had lower risk of obesity when they had higher MDS, compared to wild-type homozygote genotype carriers. The obesity risk was decreased across quartiles of MDS in participants with high GRS (OR: 1, 0.8, 0.79, 0.67) compared to individuals with low GRS (OR: 1.33, 1.06, 0.97, 1.12) (Pinteraction < 0.05). No significant interaction between the GRS and MDS on abdominal obesity was found. A higher Med Diet adherence was associated with lower obesity risk in subjects with more genetic predisposition to obesity, compared to those with lower adherence to the Med Diet and lower GRS., Competing Interests: The authors declare no conflict of interest.

Background: Epigenome-wide association studies (EWAS) have identified DNA methylation loci involved in adiposity. However, EWAS on adiposity in sub-Saharan Africans are lacking despite the high burden of adiposity among African populations. We undertook an EWAS for anthropometric indices of adiposity among Ghanaians aiming to identify DNA methylation loci that are significantly associated., Methods: The Illumina 450k DNA methylation array was used to profile DNA methylation in whole blood samples of 547 Ghanaians from the Research on Obesity and Diabetes among African Migrants (RODAM) study. Differentially methylated positions (DMPs) and differentially methylation regions (DMRs) were identified for BMI and obesity (BMI ≥ 30 kg/m 2 ), as well as for waist circumference (WC) and abdominal obesity (WC ≥ 102 cm in men, ≥88 cm in women). All analyses were adjusted for age, sex, blood cell distribution estimates, technical covariates, recruitment site and population stratification. We also did a replication study of previously reported EWAS loci for anthropometric indices in other populations., Results: We identified 18 DMPs for BMI and 23 for WC. For obesity and abdominal obesity, we identified three and one DMP, respectively. Fourteen DMPs overlapped between BMI and WC. DMP cg00574958 annotated to gene CPT1A was the only DMP associated with all outcomes analysed, attributing to 6.1 and 5.6% of variance in obesity and abdominal obesity, respectively. DMP cg07839457 ( NLRC5 ) and cg20399616 ( BCAT1 ) were significantly associated with BMI, obesity and with WC and had not been reported by previous EWAS on adiposity., Conclusions: This first EWAS for adiposity in Africans identified three epigenome-wide significant loci ( CPT1A , NLRC5 and BCAT1 ) for both general adiposity and abdominal adiposity. The findings are a first step in understanding the role of DNA methylation in adiposity among sub-Saharan Africans. Studies on other sub-Saharan African populations as well as translational studies are needed to determine the role of these DNA methylation variants in the high burden of adiposity among sub-Saharan Africans.

Background: Central obesity (CO) is an inflammatory disease. Because immune cells and adipocytes are catecholamines(CA)-producing cells, we studied the expression of adrenoceptors (AR) in peripheral blood mononuclear cells (PBMCs) hypothesizing a distinct adrenergic pattern in inflammatory obesity. Methods: AR expression was assessed in blood donors categorized by waist circumference (WC) (CO: WC≥0.80 m in women and ≥0.94 m in men). Following a pilot study for all AR subtypes, we measured β 2 AR expression in fifty-seven individuals and correlated this result with anthropometric, metabolic and inflammatory parameters. A ratio (R) between AR mRNA of CO and non-CO<0.5 was considered under and >2.0 over expression. Results: The pilot study revealed no differences between groups, except for β 2 AR mRNA. CO individuals showed underexpression of β 2 AR relatively to those without CO (R=0.08; p=0.009). β 2 AR expression inversely correlated with triacylglycerol (r=-0.271; p=0.041), very low-density lipoprotein-cholesterol (r=-0.313; p=0.018) and leptin (r=-0.392; p=0.012) and positively with high-density lipoprotein-cholesterol (r=0.310: p=0.045) plasma levels. Multiple logistic regression analysis showed a protective effect of β 2 AR expression (≥2x10-6) [odds ratio (OR) 0.177 with respective confidence interval of 95% (95% CI) (0.040- 0.796)] for the occurrence of CO. A higher association was found for women as compared to men (Ξ9:1) [OR 8.972 (95% CI) (1.679-47.949)]. Conclusion: PBMCs β 2 AR, underexpressed in centrally obese, are associated with a better metabolic profile and showed a protective role for the development of CO. The discovery of β 2 AR as a new molecular marker of obesity subphenotypes in PBMCs might contribute to clarify the adrenergic immunomodulation of inflammatory obesity., Competing Interests: Competing interest: The authors declare that they have no competing interests.

Objective: To investigate possible effect of 6 obesity-associated SNPs in contribution to central obesity and examine whether there is an interaction in the 6 SNPs in the cause of central obesity in school-aged children in China. Methods: A total of 3 502 school-aged children who were included in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) Study were selected, and based on the age and sex specific waist circumference (WC) standards in the BCAMS study, 1 196 central obese cases and 2 306 controls were identified. Genomic DNA was extracted from peripheral blood white cells using the salt fractionation method. A total of 6 single nucleotide polymorphisms ( FTO rs9939609, MC4R rs17782313, BDNF rs6265, PCSK1 rs6235, SH2B1 rs4788102, and CSK rs1378942) were genotyped by TaqMan allelic discrimination assays with the GeneAmp 7900 sequence detection system (Applied Biosystems, Foster City, CA, USA). Logistic regression model was used to investigate the association between 6 SNPs and central obesity. Gene-gene interactions among 6 polymorphic loci were analyzed by using the Generalized Multifactor Dimensionality Reduction (GMDR) method, and then logistic regression model was constructed to confirm the best combination of loci identified in the GMDR. Results: After adjusting gender, age, Tanner stage, physical activity and family history of obesity, the FTO rs9939609-A, MC4R rs17782313-C and BDNF rs6265-G alleles were associated with central obesity under additive genetic model ( OR =1.24, 95 %CI : 1.06-1.45, P =0.008; OR =1.26, 95 %CI : 1.11-1.43, P =2.98×10(-4); OR =1.18, 95 % CI : 1.06-1.32, P =0.003). GMDR analysis showed a significant gene-gene interaction between MC4R rs17782313 and BDNF rs6265 ( P =0.001). The best two-locus combination showed the cross-validation consistency of 10/10 and testing accuracy of 0.539. This interaction showed the maximum consistency and minimum prediction error among all gene-gene interaction models evaluated. Moreover, the combination of MC4R rs17782313-C and BDNF rs6265-G was associated with an increased risk of central obesity after adjustment for gender, age, Tanner stage, physical activity and family history of obesity. Conclusions: Our study showed that FTO rs9939609-A, MC4R rs17782313-C and BDNF rs6265-G alleles were associated with central obesity, and statistical interaction between MC4R rs17782313-C and BDNF rs6265-G increased risk of central obesity in school-aged children in China.

A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites. The genome-wide association study conducted to identify the SNPs (meQTL) associated with methylation levels at variable CpG sites revealed 2292 significant associations (P < 2.22 × 10 -11 ) involving 2182 unique meQTLs regulating the methylation levels of 174 variable CpG sites. Two meQTLs disrupting CpG sites located within the collagen-encoding COL11A2 gene were tested for associations with MetS and its components in a cohort of 3021 obese individuals. Rare alleles of these meQTLs showed association with plasma fasting glucose levels. Further analysis conducted on these meQTL suggested a biological impact mediated through the disruption of transcription factor (TF)-binding sites based on the prediction of TF-binding affinities. The current study identified meQTL in the VAT of severely obese men and revealed associations of two COL11A2 meQTL with fasting glucose levels., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Obesity is a heritable trait that contributes to substantial global morbidity and mortality. Here, we summarize findings from the past decade of genetic and epigenetic research focused on unravelling the underpinnings of adiposity. More than 140 genetic regions now are known to influence adiposity traits. The genetics of general adiposity, as measured by body mass index, and that of abdominal obesity, as measured by waist-to-hip ratio, have distinct biological backgrounds. Gene expression associated with general adiposity is enriched in the nervous system. In contrast, genes associated with abdominal adiposity function in adipose tissue. Recent population-based epigenetic analyses have highlighted additional distinct loci. We discuss how associated genetic variants can lead to understanding causal mechanisms, and to disentangling reverse causation in epigenetic analyses. Discoveries emerging from population genomics are identifying new disease markers and potential novel drug targets to better define and combat obesity and related diseases., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Obesity is a major risk factor for chronic diseases and arises from the interactions between environmental factors and multiple genes. Psychosocial stress may affect the risk for obesity, modifying food intake and choice. A recent study suggested regulator of G-protein signaling 6 (RGS6) as a novel candidate gene for obesity in terms of reward-related feeding under stress. In this study, we tried to verify the unidentified connection between RGS6 and human obesity with psychosocial stress in a Korean population. A total of 1,462 adult subjects, who participated in the Korean Association Resource cohort project, were included for this analysis. Obesity-related traits including waist circumference, body mass index, and visceral adipose tissue were recorded. A total of 4 intronic SNPs for the RGS6 gene were used for this study. We found that interactions between SNP rs2239219 and psychosocial stress are significantly associated with abdominal obesity (p = 0.007). As risk allele of this SNP increased, prevalence of abdominal obesity under high-stress conditions gradually increased (p = 0.013). However, we found no SNPs-by-stress interaction effect on other adiposity phenotypes. This study suggests that RGS6 is closely linked to stress-induced abdominal obesity in Korean adults.

Background: The renin-angiotensin system has a pivotal role in the pathophysiology of visceral obesity. Angiotensin II type 1 receptor (AT1R) is a major player in the signal transduction of the renin-angiotensin system, and the overactivation of this signaling contributes to the progression of visceral obesity. We have shown that the AT1R-associated protein (ATRAP) promotes AT1R internalization from the cell surface into cytoplasm along with the suppression of overactivation of tissue AT1R signaling. In this study, we examined whether the enhancement of adipose ATRAP expression could efficiently prevent diet-induced visceral obesity and insulin resistance., Methods and Results: We generated adipocyte-specific ATRAP transgenic mice using a 5.4-kb adiponectin promoter, and transgenic mice and littermate control mice were fed either a low- or high-fat diet for 10 weeks. Although the physiological phenotypes of the transgenic and control mice fed a low-fat diet were comparable, the transgenic mice exhibited significant protection against high-fat diet-induced adiposity, adipocyte hypertrophy, and insulin resistance concomitant with an attenuation of adipose inflammation, macrophage infiltration, and adipokine dysregulation. In addition, when mice were fed a high-fat diet, the adipose expression of glucose transporter type 4 was significantly elevated and the level of adipose phospho-p38 mitogen-activated protein kinase was significantly attenuated in the transgenic mice compared with control mice., Conclusions: Results presented in this study suggested that the enhancement in adipose ATRAP plays a protective role against the development of diet-induced visceral obesity and insulin resistance through improvement of adipose inflammation and function via the suppression of overactivation of adipose AT1R signaling. Consequently, adipose tissue ATRAP is suggested to be an effective therapeutic target for the treatment of visceral obesity., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: The mechanism leading to the development of metabolic complications in obese individuals is not fully understood. Thus, the objective of this study was to examine differences in insulin resistance, inflammation, cytokine and adipokine levels, and expression of selected genes across obese individuals with different number of metabolic syndrome (MetS) components., Methods: Forty obese individuals who underwent bariatric surgery, divided in three groups based on the number of components of MetS, in addition to abdominal obesity (0, 1, and 2-3 additional components), were studied. Levels of inflammatory proteins, insulin resistance, cytokines, adipokines, and gene expression in subcutaneous (SAT) and visceral adipose tissue (VAT) were compared., Results: There was a significantly higher expression of MYD88 in SAT among those with more components of MetS (P = 0.008). In SAT, but not in VAT, MYD88 expression was significantly correlated with toll-like receptor 4 expression (r = 0.7, P < 0.05). Expression of adipsin in SAT was also associated with the presence of more components of MetS, but with borderline statistical significance (P = 0.05). There were no significant differences in insulin resistance, inflammation, and cytokine and adipokine levels by the number of components of MetS., Conclusions: Our study suggests that MYD88 expression in SAT of obese subjects could be associated with the development of components of MetS.

Introduction: Waist-to-height ratio (WHtR) can be effective for the diagnosis of abdominal obesity and the risk of type 2 diabetes. The role of genetic factors in the development of obesity has been broadly recognized. Adiponectin's level is inversely correlated with body fat percentage and is reduced in obesity and type 2 diabetes. The aim of this study is to investigate the association between WHtR and adiponectin gene polymorphisms in Iranian population., Methods: This study was conducted on 610 subjects from two Iranian populations. Anthropometric characteristics were measured by routine methods. Blood samples were collected in tubes (3-5 mL) containing EDTA and were stored at 20 °C. After DNA extraction, genotyping was performed using PCR-RFLP technique., Results: There were statistically significant differences in genotype frequencies of -11391 G/A in centrally obese (WHtR >0.5) and noncentrally obese (WHtR ≤0.5) subjects (P value <0.044). In the former, the frequencies of GG and GA + AA genotypes were 89.4 and 10.6 %, respectively, while the frequencies of GG and GA + AA genotypes were 95.9 and 4.1 %, respectively, in noncentrally obese subjects., Conclusions: The frequency of GG genotype was significantly increased in subjects with WHtR >0.5 compared to the other group. After adjustment for diabetes, abdominal obesity was significantly associated with the -11391 G/A polymorphism.

Importance: In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain., Objective: To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes., Design, Setting, and Participants: A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank., Exposures: Genetic predisposition to increased WHR adjusted for BMI., Main Outcomes and Measures: Type 2 diabetes and CHD., Results: Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1-mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440)., Conclusions and Relevance: A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes.

Background and Aims: Whether EPA and DHA exert similar anti-inflammatory effects through modulation of gene expression in immune cells remains unclear. The aim of the study was to compare the impact of EPA and DHA supplementation on inflammatory gene expression in subjects at risk for cardiometabolic diseases., Methods: In this randomized double-blind crossover trial, 154 men and women with abdominal obesity and low-grade inflammation were subjected to three 10-wk supplementation phases: 1) EPA (2.7 g/d); 2) DHA (2.7 g/d); 3) corn oil (3 g/d), separated by a 9-wk washout. Pro- and anti-inflammatory gene expression was assessed in whole blood cells by RT-qPCR after each treatment in a representative sample of 44 participants., Results: No significant difference was observed between EPA and DHA in the expression of any of the genes investigated. Compared with control, EPA enhanced TRAF3 and PPARA expression and lowered CD14 expression (p < 0.01) whereas DHA increased expression of PPARA and TNFA and decreased CD14 expression (p < 0.05). Variations in gene expression after EPA and after DHA were strongly correlated for PPARA (r = 0.73, p < 0.0001) and TRAF3 (r = 0.66, p < 0.0001) and less for TNFA (r = 0.46, p < 0.005) and CD14 (r = 0.16, p = 0.30)., Conclusions: High-dose supplementation with either EPA or DHA has similar effects on the expression of many inflammation-related genes in immune cells of men and women at risk for cardiometabolic diseases. The effects of EPA and of DHA on anti-inflammatory gene expression may be more consistent than their effects on expression of pro-inflammatory genes in whole blood cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background/objectives: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition., Subjects/methods: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants., Results: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses., Conclusions: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci., Competing Interests: Authors declare no conflict of interest

Aim: The effect of interleukin 33 (IL-33) in the inflammatory process generates significant interest in the potential significance of IL-33 as a biomarker for coronary artery disease (CAD). Here, our objective was to analyze whether IL-33 gene polymorphisms are associated with premature CAD in a case-control association study., Methods: Four IL-33 polymorphisms (rs7848215, rs16924144, rs16924159 and rs7044343) were genotyped by 5' exonuclease TaqMan assays in 1095 patients with premature CAD and 1118 controls., Results: The rs7044343 T allele was significantly associated with a diminished risk of premature CAD (OR = 0.81, 95% CI: 0.69-0.97, Pdom = 0.020; OR = 0.85, 95% CI: 0.75-0.96, Padd = 0.019) and central obesity (OR = 0.74, 95% CI: 0.58-0.93, Pdom = 0.0007), respectively. When patients were divided into groups with and without type 2 diabetes mellitus (T2DM), the rs7044343 T allele was associated with a reduced risk of premature CAD in patients without (OR = 0.85, 95% CI: 0.73-0.99, Padd = 0.038) and with T2DM (OR = 0.61, 95% CI: 0.38-0.97, Pdom = 0.039; OR = 0.69, 95% CI: 0.49-0.97, Padd = 0.035). In order to establish the functional effect of the rs7044343 polymorphism, the production of IL-33 was determined in monocytes of selected individuals. Monocytes from individuals with rs7044343 CC genotype produced higher levels of IL-33 than monocytes from individuals with other genotypes., Conclusion: The results suggest that the IL-33 rs7044343 T allele could be a susceptibility marker for premature CAD and central obesity. The rs7044343 polymorphism could be involved in regulating the production of IL-33., Competing Interests: The authors have declared that no competing interests exist.

Increasing evidence suggests a close interrelationship between disrupted circadian rhythms and obesity and metabolic disturbances. In particular, abdominal obesity, which contributes to the pathogenesis of metabolic disease, is associated with disrupted clock gene expression. However, little is known about the relationship between clock gene expression and accurate computed tomography (CT)-based measurements of visceral adiposity. Therefore, we examined the relationship between expression of clock genes in peripheral blood mononuclear cells (PBMCs) with visceral and subcutaneous adiposity in 75 healthy overweight or obese individuals. PBMCs were obtained from blood samples collected at 8 AM, and gene expression was analyzed by real-time reverse transcription polymerase chain reaction. Visceral and subcutaneous adiposity were measured by CT. Our results showed that visceral fat area was significantly positively correlated with BMAL1 and CRY1 mRNA levels and significantly negatively correlated with CLOCK, PER2, PER3 and CRY2 mRNA levels. In contrast, subcutaneous fat area was not correlated with the expression of any of the clock genes analyzed. After adjusting for multiple variables, visceral fat area was significantly associated with the expression of BMAL1, PER2 and CRY1. Taken together, our results indicate that visceral adiposity, but not subcutaneous adiposity, correlates with expression of clock genes in PBMCs.

Objective: To determine the relationship of the gain-of-function variant A750T in leucine-rich repeat containing G protein-coupled receptor 4 (LGR4) with central obesity and related metabolic phenotypes., Methods: The LGR4 A750T (c.2248 G > A) variant was detected by Sanger sequencing in a discovery young population and a validation community-based population with obesity from eastern China. Fat indices determined by anthropometry and computed tomography scans and clinical biochemical measurements were collected for association analysis., Results: LGR4 A750T was significantly correlated with waist circumference (P = 0.030) and waist-to-height ratio (P < 0.001) in the young cohort (N = 594) and with waist-to-hip ratio (P = 0.013) in the community population (N = 1067). Combined analysis showed a significant correlation of the variant with waist circumference (P < 0.001) and waist-to-hip ratio (P = 0.021). Moreover, the variant had a remarkable correlation with abdominal visceral fat area (P = 0.004) and was associated with 2-h plasma insulin (P = 0.009) and the Matsuda index (P = 0.027) after an oral glucose tolerance test in young subjects with obesity., Conclusions: The LGR4 A750T variant may contribute to central obesity characterized by abdominal visceral fat accumulation., (© 2016 The Obesity Society.)

Introduction . Increase in body weight is a gradual process that usually begins in childhood and in adolescence as a result of multiple interactions among environmental and genetic factors. This study aimed to analyze the relationship between copy number variants (CNVs) in five genes and four intergenic regions with obesity in Mexican children. Methods . We studied 1423 children aged 6-12 years. Anthropometric measurements and blood levels of biochemical parameters were obtained. Identification of CNVs was performed by real-time PCR. The effect of CNVs on obesity or body composition was assessed using regression models adjusted for age, gender, and family history of obesity. Results . Gains in copy numbers of LEPR and NEGR1 were associated with decreased body mass index (BMI), waist circumference (WC), and risk of abdominal obesity, whereas gain in ARHGEF4 and CPXCR1 and the intergenic regions 12q15c, 15q21.1a, and 22q11.21d and losses in INS were associated with increased BMI and WC. Conclusion . Our results indicate a possible contribution of CNVs in LEPR , NEGR1 , ARHGEF4 , and CPXCR1 and the intergenic regions 12q15c, 15q21.1a, and 22q11.21d to the development of obesity, particularly abdominal obesity in Mexican children., Competing Interests: The authors declare that they have no conflict of interests.

Background: Several studies have focused on the association between peroxisome proliferators-activated receptor gamma (PPARG) polymorphism and diabetic nephropathy (DN); however, the results of these studies were inconsistent, and until now, no population-based study has focused on the impact of PPARG gene-abdominal obesity interaction on DN risk. The aim of this study was to investigate the impact of PPARG polymorphisms and its interaction with abdominal obesity on DN risk in the Chinese Han population., Methods: A total of 848 patients with type 2 diabetes mellitus, including 420 DN patients and 428 controls were recruited. Generalized multifactor dimensionality reduction (GMDR) and logistic regression model were used to examine the association and interaction between single nucleotide polymorphism and abdominal obesity on DN; OR and 95% CI were calculated., Results: We found a significant association between CG or GG in rs1805192 and increased DN risk. DN risk was higher in the carriers of CG or GG genotype of rs1805192 than those with CC genotype; OR (95% CI) was 1.31 (1.11-1.58). GMDR analysis suggested a significant 2-locus model (p = 0.0107) involving rs1805192 and abdominal obesity, indicating a potential gene-environment interaction between rs1805192 and abdominal obesity. Overall, the 2-locus models had a cross-validation consistency of 10 of 10, and the testing accuracy of 62.17%., Conclusions: Our results support an important association between rs1805192 minor allele (G allele) of PPARG and increased DN risk; the interaction analysis showed a combined effect of interaction between rs1805192 and abdominal obesity on DN risk. The results obtained from this study are meaningful for studies on individualized PPARG agonist in treating DN for different persons, such as abdominal obese or non-abdominal obese subject., (© 2016 S. Karger AG, Basel.)

Context/objective: Acute pharmacological inhibition of 11β-hydroxysteroid-dehydrogenase 1 (11β-HSD1), which converts cortisone into the much more potent cortisol in peripheral tissues, results in reduction of total, visceral, and liver fat but not insulin resistance. We now investigated whether lifelong alterations of 11β-HSD1 activity similarly affect these cardiometabolic risk parameters by studying single-nucleotide polymorphisms (SNPs) in the 11β-HSD1-coding gene (HSD11B1)., Design/methods: Liver fat content was measured by 1 H-magnetic resonance spectroscopy and total and visceral fat mass by 1 H-magnetic resonance tomography in 327 subjects. Insulin sensitivity (IS) was estimated during an oral glucose tolerance test and the euglycemic, hyperinsulinemic clamp (n = 219). Nine SNPs covering the whole HSD11B1 gene were genotyped., Results: After correction for multiple testing, liver fat content strongly correlated with three SNPs, rs2235543, rs12565406, and rs4844880 (P = .0002, P = .001, and P = .0009, respectively), independently of gender and age. There was a nominal association of these SNPs with hepatic IS but only of rs4844880 with whole-body IS. Subjects homozygous for the major allele had an adjusted odds ratio of 2.16 (95% confidence interval [CI] 1.23-3.90) for rs2235543, 2.06 (95% CI 1.08-4.13) for rs12565406, and 1.95 (95% CI 1.13-3.49) for rs4844880 for having nonalcoholic fatty liver disease compared with carriers of the minor allele. Less strong associations of these SNPs with visceral fat mass were observed. In liver biopsies, carriers of the minor alleles of rs2235543 and rs12565406 had significantly lower HSD11B1 mRNA expression (n = 105, P = .034 and P = .0086, respectively)., Conclusions: 11β-HSD1 may be an important enzyme in the pathogenesis of fatty liver and visceral obesity and a promising target for their treatment.

Objective: Fibroblast growth factor 21 (FGF21) is involved in the regulation of energy balance and adipose metabolism. Our previous genome-wide association study identified genetic variants in the FGF21 region associated with macronutrient intake preference. We investigated whether the FGF21 genotype modified effects of weight-loss diets varying in macronutrient intake on changes in adiposity in a 2-year randomized diet intervention trial., Research Design and Methods: We genotyped FGF21 rs838147 in 715 overweight or obese individuals who were assigned to one of four diets varying in macronutrient contents. A DEXA scan was performed to evaluate body composition., Results: We observed a significant interaction between the FGF21 genotype and carbohydrate/fat intake on 2-year changes in waist circumference (WC), percentage of total fat mass, and percentage of trunk fat (P = 0.049, P = 0.001, and P = 0.003 for interaction, respectively). In response to the low-carbohydrate/high-fat diet, carrying the carbohydrate intake-decreasing C allele of rs838147 was marginally associated with less reduction in WC (P = 0.08) and significantly associated with less reduction of total fat mass (P = 0.01) and trunk fat (P = 0.02). Opposite genetic associations with these outcomes were observed among the high-carbohydrate/low-fat diet group; carrying the C allele was associated with a greater reduction of WC, total body fat mass, and trunk fat., Conclusions: Our data suggest that FGF21 genotypes may interact with dietary carbohydrate/fat intake on changes in central adiposity and body fat composition. A low-calorie, high-carbohydrate/low-fat diet was beneficial for overweight or obese individuals carrying the carbohydrate intake-decreasing allele of the FGF21 variant to improve body composition and abdominal obesity., (© 2016 by the American Diabetes Association.)

Objectives: To investigate the association between the fat mass and obesity related (FTO) gene rs9939609 and near melanocortin-4-receptor (MC4R) gene rs17782313 polymorphisms with obesity measures and metabolic parameters in urban and rural dwelling Sri Lankans., Methods: 535 subjects (60.9% female) from the general adult population (ages 18-70 years) representative of both urban (28.4%) and rural areas of residence were recruited by multi-stage random sampling. Body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) was obtained by standard methods. DNA extracted from whole blood was genotyped using real-time PCR., Results: The FTO risk genotypes (AA+AT) were associated with higher BMI (p=0.03) and WC (p=0.05) measures as well as categorical obesity (BMI ≥27.5kgm -2 definition) (OR 1.69 95% CI 1.11-2.56, p=0.01). The near MC4R risk genotypes (CC+CT) were associated with greater BMI (p=0.03) as well as categorical obesity (BMI ≥25kgm -2 definition) (OR 1.57 95% CI 1.11-2.22, p=0.01). In addition the MC4R risk genotype carriers (CC+CT) had significantly higher fasting blood sugar (FBS) levels compared to the 'TT' genotype carriers independent of BMI (p=0.05). Urban living was associated with significantly greater BMI values for FTO risk genotypes compared to rural living (p=0.02)., Conclusions: FTO and near MC4R variants are associated with obesity measures in Sri Lankan populations whilst urban living accentuates the obesogenic effect of the FTO polymorphism., (Copyright © 2016 Asia Oceania Association for the Study of Obesity. All rights reserved.)

Objective: Circadian rhythm, which is controlled by circadian genes, regulates metabolic balance including the circulating levels of glucose, fatty acids, triglycerides, various hormones and so on. The study aimed to investigate the impact of potential polymorphisms in circadian genes on abdominal obesity among Chinese Han adults., Methods: A total of 260 cases with abdominal obesity and 260 controls were recruited by individual matching. Demographic characteristics and lifestyle information were collected by a validated questionnaire, and anthropometric parameters was measured by physical examination. Twenty-three single nucleotide polymorphisms (SNPs) in three circadian genes, CLOCK, CRY1 and CRY2, were genotyped by MassArray technique., Results: Five SNPs significantly deviated from Hardy-Weinberg equilibrium (HWE) among controls, so eighteen SNPs were taken into logistic regression analysis. Independently, CLOCK rs10002541 (CC genotype vs. TT genotype: OR: 0.45, 95% CI: 0.23-0.86), CLOCK rs6850524 (CC genotype vs. GG genotype: OR: 0.50, 95% CI: 0.25-0.99) and CRY1 rs10861688 (TT genotype vs. CC genotype: OR: 0.50, 95% CI: 0.25-0.97) were negatively associated with the risk of abdominal obesity. Haplotype analysis showed that the haplotypes of CG and TG for CLOCK rs10002541 and rs4864546 had significant associations with abdominal obesity. Compared with the carriers of TA, those of CG were observed to have a lower risk (OR: 0.74, 95% CI: 0.56-0.99) of abdominal obesity, and those of TG presented a higher risk (OR: 1.70, 95% CI: 1.03-2.81)., Conclusions: Our findings suggest that CLOCK and CRY1 polymorphisms might be involved in individual susceptibility to abdominal obesity in Chinese Han population., (Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Background: Increased adiposity in visceral depots is a crucial feature associated with glucocorticoid (GC) excess. The action of GCs in a target tissue is regulated by GC receptor (GR) and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6pdh). Glycogen synthase kinase-3β (GSK3β) is known to be a crucial mediator of ligand-dependent gene transcription. We hypothesized that the major effects of corticosteroids on adipose fat accumulation are in part mediated by changes in GSK3β and H6pdh., Methods: We characterized the alterations of GSK3β and GC metabolic enzymes, and determined the impact of GR antagonist mifepristone on obesity-related genes and the expression of H6pdh and 11ß-HSD1 in adipose tissue of mice exposed to excess GC as well as in in vitro studies using 3T3-L1 adipocytes treated with GCs., Results: Corticosterone (CORT) exposure increased abdominal fat mass and induced expression of lipid synthase acetyl-CoA carboxylase and ATP-citrate lyase with activation of GSK3β phosphorylation in abdominal adipose tissue of C57BL/6J mice. Increased pSer(9) GSK3β was correlated with the induction of H6pdh and 11ß-HSD1. In addition, mifepristone treatment reversed the production of H6pdh and attenuated CORT-mediated production of 11ß-HSD1 and lipogenic gene expression with reduction of pSer(9) GSK3β, thereby leading to improvement of phenotype of adiposity within adipose tissue in mice treated with excess GCs. Suppression of pSer(9) GSK3β by mifepristone was accompanied by activation of pThr(308) Akt and blockade of CORT-induced adipogenic transcriptor C/EBPα and PPARγ. In addition, mifepristone also attenuated CORT-mediated activation of IRE1α/XBP1. In addition, reduction of H6pdh by shRNA showed comparable effects to mifepristone on attenuating CORT-induced expression of GC metabolic enzymes and improved lipid accumulation in vitro in 3T3-L1 adipocytes., Conclusion: These findings suggest that elevated adipose GSK3β and H6pdh expression contribute to 11ß-HSD1 mediating hypercortisolism associated with visceral adiposity.

South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10-6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.

Objectives: Numerous genetic loci have been associated with measures of central fat accumulation, such as waist-to-hip ratio adjusted for body mass index (WHRadjBMI). However the mechanisms by which genetic variations influence obesity remain largely elusive. Lipolysis is a key process for regulation of lipid storage in adipocytes, thus is implicated in obesity and its metabolic complications. Here, genetic variants at 36 WHRadjBMI-associated loci were examined for their influence on abdominal subcutaneous adipocyte lipolysis., Subjects and Methods: Fasting subcutaneous adipose tissue biopsies were collected from 789 volunteers (587 women and 202 men, body mass index (BMI) range 17.7-62.3 kg/m2). We quantified subcutaneous adipocyte lipolysis, both spontaneous and stimulated by the catecholamine isoprenaline or a cyclic AMP analogue. DNA was extracted from peripheral blood mononuclear cells and genotyping of SNPs associated with WHRadjBMI conducted. The effects on adipocyte lipolysis measures were assessed for SNPs individually and combined in a SNP score., Results: The WHRadjBMI-associated loci CMIP, PLXND1, VEGFA and ZNRF3-KREMEN1 demonstrated nominal associations with spontaneous and/or stimulated lipolysis. Candidate genes in these loci have been reported to influence NFκB-signaling, fat cell size and Wnt signalling, all of which may influence lipolysis., Significance: This report provides evidence for specific WHRadjBMI-associated loci as candidates to modulate adipocyte lipolysis. Additionally, our data suggests that genetically increased central fat accumulation is unlikely to be a major cause of altered lipolysis in abdominal adipocytes.

Fatty acid ethanolamides (FAE), a group of lipid mediators derived from long-chain fatty acids (FA), mediate biological activities including activation of cannabinoid receptors, stimulation of fat oxidation and regulation of satiety. However, how circulating FAE levels are influenced by FA intake in humans remains unclear. The objective of the present study was to investigate the response of six major circulating FAE to various dietary oil treatments in a five-period, cross-over, randomised, double-blind, clinical study in volunteers with abdominal obesity. The treatment oils (60 g/12 552 kJ per d (60 g/3000 kcal per d)) provided for 30 d were as follows: conventional canola oil, high oleic canola oil, high oleic canola oil enriched with DHA, flax/safflower oil blend and corn/safflower oil blend. Two SNP associated with FAE degradation and synthesis were studied. Post-treatment results showed overall that plasma FAE levels were modulated by dietary FA and were positively correlated with corresponding plasma FA levels; minor allele (A) carriers of SNP rs324420 in gene fatty acid amide hydrolase produced higher circulating oleoylethanolamide (OEA) (P=0·0209) and docosahexaenoylethanolamide (DHEA) levels (P=0·0002). In addition, elevated plasma DHEA levels in response to DHA intake tended to be associated with lower plasma OEA levels and an increased gynoid fat mass. In summary, data suggest that the metabolic and physiological responses to dietary FA may be influenced via circulating FAE. Genetic analysis of rs324420 might help identify a sub-population that appears to benefit from increased consumption of DHA and oleic acid.

Late-onset hypogonadism (i.e. androgen deficiency) raises the risk for abdominal obesity in men. The mechanism for this obesity is unclear. Here, we demonstrated that hypogonadism after castration caused abdominal obesity in high-fat diet (HFD)-fed, but not in standard diet (SD)-fed, C57BL/6J mice. Furthermore, the phenotype was not induced in mice treated with antibiotics that disrupt the intestinal microflora. In HFD-fed mice, castration increased feed efficiency and decreased fecal weight per food intake. Castration also induced in an increase of visceral fat mass only in the absence of antibiotics in HFD-fed mice, whereas subcutaneous fat mass was increased by castration irrespective of antibiotics. Castration reduced the expression in the mesenteric fat of both adipose triglyceride lipase and hormone-sensitive lipase in HFD-fed mice, which was not observed in the presence of antibiotics. Castration decreased thigh muscle (i.e. quadriceps and hamstrings) mass, elevated fasting blood glucose levels, and increased liver triglyceride levels in a HFD-dependent manner, whereas these changes were not observed in castrated mice treated with antibiotics. The Firmicutes/Bacteroidetes ratio and Lactobacillus species increased in the feces of HFD-fed castrated mice. These results show that androgen (e.g. testosterone) deficiency can alter the intestinal microbiome and induce abdominal obesity in a diet-dependent manner.

Objective: To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors., Subjects and Methods: Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (rg) and environmental (re) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs (intrapair BMI difference ≥3 kg/m(2))., Results: Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (rg=0.40), glycoprotein (rg=0.37), serum triglycerides (rg=0.36), BCAAs (rg=0.30-0.40), HDL particle diameter (rg=-0.33) and HDL cholesterol (rg=-0.30). The effect of acquired obesity within the discordant MZ pairs was particularly strong for atherogenic lipoproteins., Conclusions: A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To identify stop-codon variants associated with blood pressure (BP)., Methods: Illumina exome chip was genotyped in 5453 individuals of the population-based Malmö Diet and Cancer Study. We compared BP levels between carriers and noncarriers of all stop-codon variants found in at least 10 individuals and characterized these further based on literature evidence of functionality. Next, the association to ischemic stroke was evaluated in 2278 cases of ischemic stroke and 5969 controls., Results: We identified 19 stop-codon variants with nominally significant BP associations (P < 0.05). One of these, located in the phosphodiesterase 11A (PDE11A) gene (R307X), has previously been reported to cause loss of PDE11A function and Cushing's syndrome in female carriers. In the Malmö Diet and Cancer Study, 1% of the population carried R307X and had age and sex-adjusted (mean, 95% confidence interval) 5.0, 0.29-9.7 (P = 0.038), and 3.3, 0.83-5.7 (P = 0.009) mmHg higher SBP and DBP than noncarriers and also significantly higher waist circumference and BMI. Among females, carriers of the R307X had age adjusted 8.3, 2.3-14 (P = 0.006) and 4.7, 1.7-7.7 (P = 0.002) mmHg higher SBP and DBP, 4.3, 0.84-7.8 (P = 0.015)  cm higher waist circumference and 1.7, 0.30-3.1 (P = 0.018)  kg/m higher BMI. In addition, carriers of the R307X mutation had an odds ratio of ischemic stroke of 1.73 (95% confidence interval 1.06-2.82); P = 0.028., Conclusion: One percent of the Swedish population carries a PDE11A loss-of-function mutation associated with elevated BP, abdominal obesity, and risk of ischemic stroke.

Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases, alkylglycerol monooxygenase, and nitric oxide synthases (NOS). Inborn errors of BH4 metabolism lead to severe insufficiency of brain monoamine neurotransmitters while augmentation of BH4 by supplementation or stimulation of its biosynthesis is thought to ameliorate endothelial NOS (eNOS) dysfunction, to protect from (cardio-) vascular disease and/or prevent obesity and development of the metabolic syndrome. We have previously reported that homozygous knock-out mice for the 6-pyruvolytetrahydropterin synthase (PTPS; Pts-ko/ko) mice with no BH4 biosynthesis die after birth. Here we generated a Pts-knock-in (Pts-ki) allele expressing the murine PTPS-p.Arg15Cys with low residual activity (15% of wild-type in vitro) and investigated homozygous (Pts-ki/ki) and compound heterozygous (Pts-ki/ko) mutants. All mice showed normal viability and depending on the severity of the Pts alleles exhibited up to 90% reduction of PTPS activity concomitant with neopterin elevation and mild reduction of total biopterin while blood L-phenylalanine and brain monoamine neurotransmitters were unaffected. Yet, adult mutant mice with compromised PTPS activity (i.e., Pts-ki/ko, Pts-ki/ki or Pts-ko/wt) had increased body weight and elevated intra-abdominal fat. Comprehensive phenotyping of Pts-ki/ki mice revealed alterations in energy metabolism with proportionally higher fat content but lower lean mass, and increased blood glucose and cholesterol. Transcriptome analysis indicated changes in glucose and lipid metabolism. Furthermore, differentially expressed genes associated with obesity, weight loss, hepatic steatosis, and insulin sensitivity were consistent with the observed phenotypic alterations. We conclude that reduced PTPS activity concomitant with mildly compromised BH4-biosynthesis leads to abnormal body fat distribution and abdominal obesity at least in mice. This study associates a novel single gene mutation with monogenic forms of obesity.

Background: Peroxisome proliferator-activated receptor (PPAR) gene plays an important role in obesity and PPAR δ protein is a potent inhibitor; however, few previous studies have focused on this gene., Aim: To investigate the association of haplotypes of PPAR δ gene rs2016520 and rs9794 with abnormal weight (BMI ≥ 24 kg/m(2)) and abdominal obesity (WC ≥ 90 cm for males and ≥ 80 cm for females) in a Chinese Han population., Subjects and Methods: In total, 820 subjects (270 men, 550 women) were randomly selected from the PMMJS cohort population and no individuals were related. rs2016520 and rs9794 were detected by TaqMan fluorescence probe. Hardy-Weinberg equilibrium (HWE) was used to detect genotype typing errors by Fisher's exact test. Linkage disequilibrium (LD) between polymorphisms was estimated by using SHEsis. Two PPAR δ SNPs (rs2016520 and rs9794) were analysed by using the logistic regression model., Results: After adjustment for covariates, the haplotype containing the rs1026520-C and rs9794-C alleles was associated with a statistically significant decreased risk of obesity (OR = 0.64; 95% CI = 0.48-0.84, p = 0.0015). Coincidentally, the haplotype containing the rs1026520-C and rs9794-C alleles was also associated with a statistically decreased risk of abdominal obesity after covariate adjustment (OR = 0.59, 95% CI = 0.45-0.77, p < 0.001)., Conclusion: C-C haplotype, constructed from rs2016520 and rs9794 alleles, showed a significant protective effect for both abnormal weight and abdominal obesity.

Objective: Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if the genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM., Design: Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991-1996., Methods: Four tag single nucleotide polymorphisms (SNPs: rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort)., Results: In MDC-CC, the major allele of rs35810727 was associated with elevated BMI (β-coefficient ± s.e.m.; 0.30 ± 0.14, P=0.03) and waist (0.78 ± 0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21 ± 0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00-1.20), P=0.04)., Conclusions: Genetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between the disturbance of the pharmacologically modifiable AVP system and the body weight regulation., (© 2016 The authors.)

Aims: To test the potential association of cytosine-phosphate-guanine dinucleotides (CpG)-single-nucleotide polymorphisms (SNPs) located within actin-related protein 2/3 complex subunit 3 (ARPC3), a gene recently linked to adipogenesis and lipid accumulation, with metabolic syndrome (MetS) features in severely obese patients., Methods: Prioritized SNPs within the ARPC3 locus were genotyped and tested for associations with MetS features in a cohort of 1,749 obese patients with and without MetS. Association testing with CpG methylation levels was performed in a methylation sub-cohort of 16 obese men., Results: A significant association was found between the CpG-SNP rs3759384 (C>T) and plasma triglyceride (TG) levels (false discovery rate-corrected p = 3.5 × 10-2), with 0.6% of the phenotypic variance explained by the CpG-SNP, and with TT homozygotes showing the highest plasma TG levels (1.89 mmol/l). The carriers of the rs3759384 T allele also showed a significant decrease in methylation levels of the ARPC3 promoter-associated CpG site cg10738648 in both visceral adipose tissue and blood. ARPC3 expression levels showed a strong correlation with plasma TG levels (r = 0.70; p = 0.02)., Conclusions: The increased plasma TG levels found in homozygous rs3759384 T allele carriers argue for a relevant role of this CpG-SNP in lipid management among obese individuals, which may be driven by an epigenetic-mediated mechanism., (© 2016 S. Karger AG, Basel.)

Background. Obesity study in the context of scavenger receptors has been linked to atherosclerosis. CD36 and LOX-1 are important, since they have been associated with atherogenic and metabolic disease but not fat redistribution. The aim of our study was to determinate the association between CD36 and LOX-1 in presence of age and abdominal obesity. Methods. This is a cross-sectional study that included 151 healthy individuals, clinically and anthropometrically classified into two groups by age (<30 and ≥30 years old) and abdominal obesity (according to World Health Organization guidelines). We excluded individuals with any chronic and metabolic illness, use of medication, or smoking. Fasting blood samples were taken to perform determination of CD36 mRNA expression by real-time PCR, lipid profile and metabolic and low grade inflammation markers by routine methods, and soluble scavenger receptors (CD36 and LOX-1) by ELISA. Results. Individuals ≥30 years old with abdominal obesity presented high atherogenic index, lower soluble scavenger receptor levels, and subexpression of CD36 mRNA (54% less). On the other hand, individuals <30 years old with abdominal adiposity presented higher levels in the same parameters, except LOX-1 soluble levels. Conclusion. In this study, individuals over 30 years of age presented low soluble scavenger receptors levels pattern and CD36 gene subexpression, which suggest the chronic metabolic dysregulation in abdominal obesity.

Objective: To study whether matrix metalloproteinases-9 (MMP) -1562C/T (rs3918242) and MMP-2-1306C/T (rs243865) were associated with the susceptibility on nonalcoholic fatty liver disease (NAFLD) and the interactions between the two factors and central obesity., Methods: Genotypes of 545 patients and 636 subjects with NAFLD under control were examined by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Unconditional logistic regression (ULR) was performed to assess the NAFLD risk. The gene-environment interactions on the risk of NAFLD were explored by generalized multifactor dimensionality reduction (GMDR) and ULR methods., Results: Results from the case-control analysis indicated that there was an increased risk of developing NAFLD for MMP-9 rs3918242 (TT/CT) genotype carriers, when compared with the non-carriers (CC) , with OR=1.67, 95%CI: 1.32-2.12, P=0.001; Adjusted OR=1.65, 95% CI: 1.31-2.01 (P=0.008). However, risk reduction of NAFLD was found when MMP-2 rs243865 (TT/CT) genotype carriers compared with the non-carriers (CC) , with OR=0.68, 95% CI: 0.53-0.86, P=0.001; with adjusted OR=0.66, 95% CI: 0.49-0.90 (P=0.007). Data from the GMDR showed that gene-environment interaction among rs3918242 and central obesity on the risk of NAFLD might be significant (P=0.001). By using the ULR method, subjects as central obesity-positive but with genotype CT/TT, appeared having 4.50 (95% CI: 2.78-7.17, P= 0.007) times risk of NAFLD, when compared to the central obesity-negative subjects with genotype CC after adjusting for the covariates., Conclusion: MMP-9 rs3918242, MMP-2 rs243865 were associated with risk of NAFLD while both rs3918242 and central obesity showing synergistic effects on the risk of the NAFLD.

Background & Aims: The I148M variant because of the substitution of C to G in PNPLA3 (rs738409) is associated with the increased risk of nonalcoholic fatty liver disease (NAFLD). In liver, I148M variant reduces hydrolytic function of PNPLA3, which results in hepatic steatosis; however, its association with the other clinical phenotype such as adiposity and metabolic diseases is not well established., Methods: To identify the impact of I148M variant on clinical risk factors of NAFLD, we recruited 1363 generally healthy Korean males after excluding alcoholic and secondary causes of hepatic steatosis. Central adiposity was assessed by computed tomography, and hepatic steatosis was evaluated by abdominal ultrasonography., Results: The participants were predominantly middle-aged (49.0 ± 7.1 years; range 30-60 years), and the frequency of NAFLD was 44.2%. The rs738409-G allele carriers had a 1.19-fold increased risk for NAFLD (minor allele frequency 0.43; allelic odds ratio 1.38; P = 4.3 × 10(-5) ). Interestingly, the rs738409 GG carriers showed significantly lower levels of visceral and subcutaneous adiposity (P < 0.001 and = 0.015, respectively), BMI (P < 0.001), triglycerides (P < 0.001) and insulin resistance (P = 0.002) compared to CC carriers. These negative associations between clinical risk factors and rs738409-G dosage were more prominent in non-NAFLD group compared to those in NAFLD group., Conclusions: The I148M variant, although increasing the risk of NAFLD, was associated with reduced levels of central adiposity, BMI, serum triglycerides and insulin resistance, suggesting differential roles in fat storage and distribution according to cell types and metabolic status., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study aimed to investigate the effects of daily intake of vitamin D-fortified yogurt drink (doogh) on central obesity indicators in subjects with type 2 diabetes (T2D) and the possible modulation of this effect by vitamin D receptor (VDR) Cdx-2 genotypes. A total of sixty T2D subjects were randomly allocated to two groups to receive either plain doogh (PD; n 29, containing 170 mg Ca and no vitamin D/250 ml) or vitamin D3-fortified doogh (FD; n 31, containing 170 mg Ca and 12·5 μg/250 ml) twice a day for 12 weeks. 25-hydroxyvitamin D (25(OH)D), glycaemic as well as adiposity indicators were evaluated before and after the intervention. VDR-Cdx-2 genotypes in extended number of T2D subjects in the FD group (n 60) were determined as AA, GA and GG. After 12 weeks, in FD compared with PD, serum 25(OH)D increased (+35·4 v. -4·8 nmol/l; P<0·001) and mean changes of waist circumference (WC; -1·3 v. +1·6 cm; P=0·02), body fat mass (FM; -1·9 v. +0·60 %; P=0·008), truncal fat (TF; -1·1 v. 0·13 %; P=0·003) and visceral adipose tissue (-0·80 v. +0·37 AU; P<0·001) decreased significantly. Circulating 25(OH)D was raised only in the AA group (34·8 nmo/l in AA group v. -6·4 nmol/l in AG and -1·6 nmol/l in GG groups; P<0·001), which was accompanied by a significant decrease in changes of WC (P=0·004), FM% (P=0·01) and TF% (P<0·001) in the AA genotype. Daily intake of vitamin D-FD for 12 weeks improved the central obesity indices in T2D subjects, and the improvement was more pronounced in the carriers of the AA genotype of VDR-Cdx-2.

Central adiposity, rather than body mass index (BMI), is a key pathophysiological feature of the development of obesity-related diseases. Although genetic studies by anthropometric measures such as waist circumference have been widely conducted, genetic studies for abdominal fat deposition measured by computed tomography (CT) have been rarely performed. A total of 1,243 participants who were recruited from two health check-up centers were included in this study. We selected four and three single-nucleotide polymorphisms (SNPs) in NGEF and RGS6, respectively, and analyzed the associations between the seven SNPs and central adiposity measured by CT using an additive, dominant, or recessive model. The participants were generally healthy middle-aged men (50.7 ± 5.3 years). In the additive model, the rs11678490 A allele of NGEF was significantly associated with total adipose tissue, visceral adipose tissue (VAT), and subcutaneous adipose tissue (all P < 0.05). The AA genotype of this SNP in the recessive model showed a more significant association with all adiposity traits, and its association with VAT remained significant even after adjustment for BMI (P = 0.005). In the overall or visceral obesity group analysis, the AA genotype of rs11678490 showed no association with overall obesity (P = 0.148), whereas it was significantly associated with visceral obesity both before (P = 0.010) and after (P = 0.029) adjustment for BMI. In particular, an AA genotype effect was conspicuous between lower and upper groups with 5% extreme VAT phenotypes (OR = 9.59, 95% CI = 1.50-61.31). However, we found no significant association between SNPs of RGS6 and central adiposity. We identified a visceral-fat-associated SNP, rs11678490 of NGEF, in Korean men. This study suggests that the genetic background of central adiposity and BMI is different, and that additional efforts should be made to find the unique genetic architecture of intra-abdominal fat accumulation.