C-B3-02: Association of FTO, INSIG2, MC4R, and PCSK1 Obesity SNPs With Binge Eating in Morbidly Obese Patients

PubMed Central

Gerhard, Glenn S; Still, Christopher D; Wood, G Craig; Chu, Xin; Erdman, Robert; Susek, Meghan; Gerst, Heather; Derr, Kim; AlAgha, Mouna; Hartman, Christina; Carey, David; Benotti, Peter

2010-01-01

Background/Aims: Obesity has a strong genetic component. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in or near over a dozen genes that are related to body mass index (BMI). Despite the association of these SNPs with BMI, the mechanism by which they influence the determination of body weight is not yet known. Recently, the fat- mass and obesity-associated (FTO) obesity SNP was related to energy intake and preference for foods of high caloric density in children. FTO genotype was not associated with resting energy expenditure. We have extended this type of analysis to eating behaviors in the morbidly obese. Methods: DNA was obtained from approximately 900 morbidly obese (BMI>40 kg/m2) patients and used to genotype obesity SNPs in or near the FTO, INSIG2, MC4R, and PCSK1 genes. Binge eating status (normal, episodic overeating, or any binge eating) was determined using the validated Questionnaire on Eating and Weight Patterns (QEWP). Binge eating status was correlated with each individual genotype, the combined obesity allele burden, and the combined homozygous obesity gene burden. Results: Binge eating data was obtained from 640 patients who had completed the QEWP. Of these 640, 116 (18%) were classified as manifesting binge eating behavior. No association was present between heterozygous or homozygous FTO (P=0.59), MC4R (P=0.30), or PSK1 (P=0.77) obesity SNPs. However, 29% of those who were homozygous for the INSIG2 obesity SNP were classified as binge eaters, versus 17% of heterozygous or homozygous normal patients (P=0.006). Association was also found with binge eating status and the presence of 2 or more homozygous obesity genotypes (28% versus 17%, P=0.041), likely due to the INSIG2 gene. Cumulative obesity allele burden (0–8 alleles for the 4 genes) was not associated with binge eating status (P=0.42). Conclusions: The INSIG2 obesity SNP appears to influence binge eating behavior in morbidly obese adults. The

Association of the FTO and ADRB2 genes with body composition and fat distribution in obese women.

PubMed

Rauhio, Anne; Uusi-Rasi, Kirsti; Nikkari, Seppo T; Kannus, Pekka; Sievänen, Harri; Kunnas, Tarja

2013-10-01

The aim of this study was to investigate whether the polymorphisms of the fat mass and obesity-associated gene (FTO, rs9939609:T>A) and the β2-adrenergic receptor gene (ADRB2, rs1042714:Gln>Glu) are associated with weight loss in dieting obese premenopausal women and the association of these SNPs with body weight, body composition and distribution of fat mass. 75 obese (BMI>30) premenopausal women participated in the intervention including a 3-month weight reduction period and a subsequent 9-month weight maintenance period. Weight and height were measured and BMI calculated. Body composition and fat mass distribution were assessed by dual energy X-ray absorptiometry. At baseline, the AA homozygotes of the FTO gene were 10.1 kg heavier (p=0.031), they had higher BMI (p=0.038), and greater waist and greater hip circumference (p=0.08 and p=0.067, respectively) compared to the TT homozygotes. Gln/Gln carriers of the ADRB2 gene had smaller gynoid fat-% compared with both the Gln/Glu and Glu/Glu carriers (p=0.050 and p=0.009, respectively). The Gln homozygotes had also smaller total body fat-% and higher total body lean mass-% than that of the Glu homozygotes (p=0.018 and p=0.019, respectively). FTO genotype was associated with body weight in general, whereas ADRB2 genotype was associated with fat distribution. However, all women in the study group lost weight similarly independently of their genotypes. Neither the FTO nor ADRB2 genotype had statistically significant effect on weight reduction or weight maintenance. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Statistical and biological gene-lifestyle interactions of MC4R and FTO with diet and physical activity on obesity: new effects on alcohol consumption

USDA-ARS?s Scientific Manuscript database

Fat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) and are relevant genes associated with obesity. This could be through food intake, but results are contradictory. Modulation by diet or other lifestyle factors is also not well understood. To investigate whether MC4R and FTO associations ...

Obesity-associated variants within FTO form long-range functional connections with IRX3.

PubMed

Smemo, Scott; Tena, Juan J; Kim, Kyoung-Han; Gamazon, Eric R; Sakabe, Noboru J; Gómez-Marín, Carlos; Aneas, Ivy; Credidio, Flavia L; Sobreira, Débora R; Wasserman, Nora F; Lee, Ju Hee; Puviindran, Vijitha; Tam, Davis; Shen, Michael; Son, Joe Eun; Vakili, Niki Alizadeh; Sung, Hoon-Ki; Naranjo, Silvia; Acemel, Rafael D; Manzanares, Miguel; Nagy, Andras; Cox, Nancy J; Hui, Chi-Chung; Gomez-Skarmeta, Jose Luis; Nóbrega, Marcelo A

2014-03-20

Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.

Common variants in the obesity-associated genes FTO and MC4R are not associated with risk of colorectal cancer.

PubMed

Yang, Baiyu; Thrift, Aaron P; Figueiredo, Jane C; Jenkins, Mark A; Schumacher, Fredrick R; Conti, David V; Lin, Yi; Win, Aung Ko; Limburg, Paul J; Berndt, Sonja I; Brenner, Hermann; Chan, Andrew T; Chang-Claude, Jenny; Hoffmeister, Michael; Hudson, Thomas J; Marchand, Loïc Le; Newcomb, Polly A; Slattery, Martha L; White, Emily; Peters, Ulrike; Casey, Graham; Campbell, Peter T

2016-10-01

Obesity is a convincing risk factor for colorectal cancer. Genetic variants in or near FTO and MC4R are consistently associated with body mass index and other body size measures, but whether they are also associated with colorectal cancer risk is unclear. In the discovery stage, we tested associations of 677 FTO and 323 MC4R single nucleotide polymorphisms (SNPs) 100kb upstream and 300kb downstream from each respective locus with risk of colorectal cancer in data from the Colon Cancer Family Registry (CCFR: 1960 cases; 1777 controls). Next, all SNPs that were nominally statistically significant (p<0.05) in the discovery stage were included in replication analyses in data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO: 9716 cases; 9844 controls). In the discovery stage, 43 FTO variants and 18 MC4R variants were associated with colorectal cancer risk (p<0.05). No SNPs remained statistically significant in the replication analysis after accounting for multiple comparisons. We found no evidence that individual variants in or near the obesity-related genes FTO and MC4R are associated with risk of colorectal cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

FTO Obesity Risk Variants Are Linked to Adipocyte IRX3 Expression and BMI of Children - Relevance of FTO Variants to Defend Body Weight in Lean Children?

PubMed Central

Landgraf, Kathrin; Scholz, Markus; Kovacs, Peter; Kiess, Wieland; Körner, Antje

2016-01-01

Background Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation. Aim We addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children. Results Expression of IRX3 was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of IRX3 and IRX5 with the presence of the FTO risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that IRX3 expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in UCP1-negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI, IRX3 expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children. Conclusion One interpretation of our observation of FTO risk variants linked to IRX3 expression and adipocyte size restricted to lean children, along with the decreased IRX3 expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children. PMID:27560134

Relation of fat-mass and obesity-associated gene polymorphism to fat mass content and body mass index in obese children.

PubMed

Pyrzak, Beata; Wisniewska, Alicja; Majcher, Anna; Tysarowski, Andrzej; Demkow, Urszula

2013-01-01

Fat mass content, fat distribution, and fat-mass and obesity associated (FTO) gene have been reported among a broad spectrum of genetic variation connected with body weight. The aim of our study was to investigate whether the T/A rs9939609 polymorphism of the FTO gene may influence obesity and metabolic indices in children. A 160 children were examined (136 obese and 24 non-obese). The anthropometric measurements and calculations included: height, weight, waist and hip circumference, sum of the thickness of 3 and 10 skin folds, % of fat content, % FAT- BIA , % LBM-BIA. BMI, SDS of BMI, WHR, and WHtR. Fasting plasma total cholesterol (TC), HDL and LDL-cholesterol, triglycerides (TG), oral glucose tolerance test (OGTT), and HOMA-IR were analyzed and the blood pressure were measured. The rs9939609 polymorphism of FTO gene was genotyped by allele-specific real-time polymerase chain- reaction (RT-PCR). We found that the mean concentrations of TC, TG, LDLC, and HOMA-IR were significantly higher, and HDL was lower in the obese than in non-obese children. The presence of TT, but not AA alleles, related to the percentage of fat content, BMI, and z-score of BMI. None of the other anthropometric indices did differ between the children with gene polymorphism and wild homozygous. In conclusion, rs9939609 polymorphism in the fat-mass and obesity-associated gene is associated with BMI and the percent of fat content in children.

A single FTO gene variant rs9939609 is associated with body weight evolution in a multiethnic extremely obese population that underwent bariatric surgery.

PubMed

Rodrigues, Gisele K; Resende, Cristina M M; Durso, Danielle F; Rodrigues, Lorena A A; Silva, José Luiz P; Reis, Rodrigo C; Pereira, Solange S; Ferreira, Daniela C; Franco, Gloria R; Alvarez-Leite, Jacqueline

2015-01-01

The rs9939609 single nucleotide polymorphism (SNP) in the fat mass and obesity-associated (FTO) gene is involved in obesity. Few studies have been conducted on patients who underwent bariatric surgery. The aim of this study was to evaluate the influence of FTO SNPs on body weight, body composition, and weight regain during a 60-mo follow-up period after bariatric surgery. The rs9939609 was genotyped in 146 individuals using a real-time polymerase chain reaction TaqMan assay. Data for lifestyle, comorbidities, body weight, body mass index (BMI), excess weight loss (EWL), and body composition were obtained before and 6, 12, 18, 24, 36, 48, and 60 mo after surgery. Data were analyzed by comparing two groups of patients according to rs9939609 FTO gene polymorphism. Mixed-regression models were constructed to evaluate the dynamics of body weight, BMI, and EWL over time in female patients. No differences were observed between the groups during the first 24 mo after surgery. After 36, 48, and 60 mo, body weight, fat mass, and BMI were higher, whereas fat-free mass and EWL were lower in the FTO-SNP patient group. Weight regain was more frequent and occurred sooner in the FTO-SNP group. There is a different evolution of weight loss in obese carriers of the FTO gene variant rs9939609 after bariatric surgery. However, this pattern was evident at only 2 y postbariatric surgery, inducing a lower proportion of surgery success and a greater and earlier weight regain. Copyright © 2015 Elsevier Inc. All rights reserved.

Common variants in the obesity-associated genes FTO and MC4R are not associated with risk of colorectal cancer

PubMed Central

Yang, Baiyu; Thrift, Aaron P.; Figueiredo, Jane C.; Jenkins, Mark A.; Schumacher, Fredrick R.; Conti, David V.; Lin, Yi; Win, Aung Ko; Limburg, Paul J.; Berndt, Sonja I.; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hoffmeister, Michael; Hudson, Thomas J.; Marchand, Loïc Le; Newcomb, Polly A.; Slattery, Martha L.; White, Emily; Peters, Ulrike; Casey, Graham; Campbell, Peter T.

2016-01-01

Background Obesity is a convincing risk factor for colorectal cancer. Genetic variants in or near FTO and MC4R are consistently associated with body mass index and other body size measures, but whether they are also associated with colorectal cancer risk is unclear. Methods In the discovery stage, we tested associations of 677 FTO and 323 MC4R single nucleotide polymorphisms (SNPs) 100kb upstream and 300kb downstream from each respective locus with risk of colorectal cancer in data from the Colon Cancer Family Registry (CCFR: 1,960 cases; 1,777 controls). Next, all SNPs that were nominally statistically signif icant (p<0.05) in the discovery stage were included in replication analyses in data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO: 9,716 cases; 9,844 controls). Results In the discovery stage, 43 FTO variants and 18 MC4R variants were associated with colorectal cancer risk (p<0.05). No SNPs remained statistically significant in the replication analysis after accounting for multiple comparisons. Conclusion We found no evidence that individual variants in or near the obesity-related genes FTO and MC4R are associated with risk of colorectal cancer. PMID:27449576

Establishing a genetic link between FTO and VDR gene polymorphisms and obesity in the Emirati population.

PubMed

Khan, Saad Mahmud; El Hajj Chehadeh, Sarah; Abdulrahman, Mehera; Osman, Wael; Al Safar, Habiba

2018-01-17

Obesity is a metabolic disease that is widely prevalent with approximately 600 million people classified as obese worldwide. Its etiology is multifactorial and involves a complex interplay between genes and the environment. Over the past few decades, obesity rates among the Emirati population have been increasing. The aim of this study was to investigate the association of candidate gene single nucleotide polymorphisms (SNPs), namely FTO (rs9939609) and VDR (rs1544410), with obesity in the UAE population. This is a case-control study in which genomic DNA was extracted from saliva samples of 201 obese, 115 overweight, and 98 normal subjects in the United Arab Emirates (UAE). Genotyping for the variants was performed using TaqMan assay. The mean Body Mass Index (BMI) ± SD for the obese, overweight, and normal subjects was 35.76 ± 4.54, 27.53 ± 1.45, and 22.69 ± 1.84 kg/m 2 , respectively. Increasing BMI values were associated with increase in values of HbA1c, systolic and diastolic blood pressure. There was a significant association observed between the FTO SNP rs9939609 and BMI (p = 0.028), with the minor allele A having a clear additive effect on BMI values. There was no significant association detected between BMI and rs1544410 of VDR. Moreover, significant interaction between the FTO rs9939609 and physical activity reduced the "AA" genotype effect on increase in BMI (p = 0.027). Our study findings indicate that the minor allele A of the rs9939609 has a significant association with increasing BMI values. Moreover, our findings support the fact that increasing BMI is associated with increasing risks of other comorbidities such as higher blood pressure, poorer glycemic control, and higher triglycerides. In addition, physical activity was found to attenuate the effect of the "AA" genotype on the predisposition to higher BMI values.

Differential distribution and association of FTO rs9939609 gene polymorphism with obesity: A cross-sectional study among two tribal populations of India with East-Asian ancestry.

PubMed

Ningombam, Somorjit Singh; Chhungi, Varhlun; Newmei, Masan Kambo; Rajkumari, Sunanda; Devi, Naorem Kiranmala; Mondal, Prakash Ranjan; Saraswathy, Kallur Nava

2018-03-20

The fat mass and obesity associated (FTO) rs9939609 gene polymorphism is most widely studied in terms of obesity in various populations. Recently, the prevalence of obesity has been reported to be very high among the North-Eastern State of India. The major aim of the present study is to understand the extent of FTO rs9939609 gene polymorphism and its association with obesity among the two North-East Indian tribal populations with similar East Asian ancestry. Somatometric data and fasting blood sample were collected from 521 tribal individuals (258 Liangmai and 263 Mizo) of Manipur after obtaining written informed consent. Genotyping of FTO rs9939609 single nucleotide polymorphism (SNP) was done using restriction fragment length polymorphism method for PCR-amplified fragments. Both the presently studied populations were not following Hardy-Weinberg law. The prevalence of obesity and minor allele frequency of FTO rs9939609 polymorphism was found to be significantly higher among the Mizo tribe compared to that of Liangmai. The selected polymorphism was found to be significantly associated with obesity (BMI) only among the Liangmai tribe (Odds ratio-3.0; 95% CI-1.4, 6.4; p-0.003), after adjusting for age and occupation. Age-cohort wise distribution and absolute fitness analysis indicated the lower fitness of minor allele in the higher age group among the Liangmai tribe. To the best of the author's knowledge this is the first study, associating FTO rs9939609 gene polymorphism and obesity in the North-eastern Indian tribal populations with East-Asian ancestry. This study revealed the FTO rs9939609 polymorphism is observed to be associated with obesity only among the Liangmai tribe not among the Mizo tribe. The differential distribution and association observed in the two selected tribes, inhabited in a similar geographical region, could be attributed to differences in their migratory histories in terms of both route and time of settlement. Copyright © 2018 Elsevier B

FTO Genetic Variation and Association With Obesity in West Africans and African Americans

PubMed Central

Adeyemo, Adebowale; Chen, Guanjie; Zhou, Jie; Shriner, Daniel; Doumatey, Ayo; Huang, Hanxia; Rotimi, Charles

2010-01-01

OBJECTIVE The FTO gene is one of the most consistently replicated loci for obesity. However, data from populations of African ancestry are limited. We evaluated genetic variation in the FTO gene and investigated associations with obesity in West Africans and African Americans. RESEARCH DESIGN AND METHODS The study samples comprised 968 African Americans (59% female, mean age 49 years, mean BMI 30.8 kg/m2) and 517 West Africans (58% female, mean age 54 years, mean BMI 25.5 kg/m2). FTO genetic variation was evaluated by genotyping 262 tag single nucleotide polymorphisms (SNPs) across the entire gene. Association of each SNP with BMI, waist circumference, and percent fat mass was investigated under an additive model. RESULTS As expected, both African-ancestry samples showed weaker linkage disequilibrium (LD) patterns compared with other continental (e.g., European) populations. Several intron 8 SNPs, in addition to intron 1 SNPs, showed significant associations in both study samples. The combined effect size for BMI for the top SNPs from meta-analysis was 0.77 kg/m2 (P = 0.009, rs9932411) and 0.70 kg/m2 (P = 0.006, rs7191513). Two previously reported associations with intron 1 SNPs (rs1121980 and rs7204609, r2 = 0.001) were replicated among the West Africans. CONCLUSIONS The FTO gene shows significant differences in allele frequency and LD patterns in populations of African ancestry compared with other continental populations. Despite these differences, we observed evidence of associations with obesity in African Americans and West Africans, as well as evidence of heterogeneity in association. More studies of FTO in multiple ethnic groups are needed. PMID:20299471

Variation in the fat mass and obesity-related (FTO) genotype is not associated with body fatness in infants, but possibly with their length.

PubMed

Henriksson, P; Löf, M; Söderkvist, P; Forsum, E

2014-10-01

Data relating variation at the fat mass and obesity-related (FTO) locus (rs9939609) to fat mass in infancy are inconclusive. To study relationships between FTO genotype and infant size (at 1 and 12 weeks and at 1 year of age) and body composition (at 1 and 12 weeks). Body composition was assessed using air displacement plethysmography in 207 infants. FTO was genotyped using the TaqMan assay. The number of risk alleles was related to length at 1 and 12 weeks (P = 0.007-0.033) but not to fat mass. The relationship to length was stronger in boys than in girls. Our results suggest that the FTO genotype is not related during infancy to fat mass but is related to length in boys but not in girls. © 2014 The Authors. Pediatric Obesity © 2014 World Obesity.

Associations of variants in FTO and near MC4R with obesity traits in South Asian Indians.

PubMed

Vasan, Senthil K; Fall, Tove; Neville, Matthew J; Antonisamy, Belavendra; Fall, Caroline H; Geethanjali, Finney S; Gu, Harvest F; Raghupathy, Palany; Samuel, Prasanna; Thomas, Nihal; Brismar, Kerstin; Ingelsson, Erik; Karpe, Fredrik

2012-11-01

Recent genome-wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity-related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity- and type 2 diabetes (T2DM)-related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity-related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist-hip ratio. Consistent associations were observed for adipose tissue-specific measurements such as skinfold thickness reinforcing the association with obesity-related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity-related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity-related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian "thin-fat" phenotype.

Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity.

PubMed

Pereira, Patrícia de Araújo; Alvim-Soares, António Marcos; Sandrim, Valéria Cristina; Lanna, Carla Márcia Moreira; Souza-Costa, Débora Cristine; Belo, Vanessa de Almeida; de Paula, Jonas Jardim; Tanus-Santos, José Eduardo; Romano-Silva, Marco Aurélio; Miranda, Débora Marques de

2016-01-01

Obesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. This was a case-control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. As expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA-IR index, total cholesterol, low-density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. The present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Physical activity attenuates the effect of the FTO genotype on obesity-related traits in European adults: Findings from the Food4Me study

USDA-ARS?s Scientific Manuscript database

Background. The FTO gene harbours the strongest known susceptibility locus for obesity. Studies of the interaction between genetic and environmental factors such as physical activity (PA) could contribute to the understanding of how lifestyle can modulate genetic susceptibility to obesity. In this s...

Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure.

PubMed

Speakman, John R; Rance, Kellie A; Johnstone, Alexandra M

2008-08-01

The FTO gene has significant polymorphic variation associated with obesity, but its function is unknown. We screened a population of 150 whites (103F/47M) resident in NE Scotland, United Kingdom, for variants of the FTO gene and linked these to phenotypic variation in their energy expenditure (basal metabolic rate (BMR) and maximal oxygen consumption VO(2)max) and energy intake. There was no significant association between the FTO genotype and BMR or VO(2)max. The FTO genotype was significantly associated (P = 0.024) with variation in energy intake, with average daily intake being 9.0 MJ for the wild-type TT genotype and 10.2 and 9.5 MJ for the "at risk" AT and AA genotypes, respectively. Adjusting intake for BMR did not remove the significance (P = 0.043). FTO genotype probably affects obesity via effects on food intake rather than energy expenditure.

Obesity-related genetic variants, human pigmentation, and risk of melanoma

PubMed Central

Li, Xin; Liang, Liming; Zhang, Mingfeng; Song, Fengju; Nan, Hongmei; Wang, Li-E; Wei, Qingyi; Lee, Jeffrey E.; Amos, Christopher I.; Qureshi, Abrar A.; Han, Jiali

2013-01-01

Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles=0.12, P-value=4 10−5). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R-square quality metric >0.8 using the 1000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity. PMID:23539184

Impact of obesity-related genes in Spanish population

PubMed Central

2013-01-01

Background The objective was to investigate the association between BMI and single nucleotide polymorphisms previously identified of obesity-related genes in two Spanish populations. Forty SNPs in 23 obesity-related genes were evaluated in a rural population characterized by a high prevalence of obesity (869 subjects, mean age 46 yr, 62% women, 36% obese) and in an urban population (1425 subjects, mean age 54 yr, 50% women, 19% obese). Genotyping was assessed by using SNPlex and PLINK for the association analysis. Results Polymorphisms of the FTO were significantly associated with BMI, in the rural population (beta 0.87, p-value <0.001). None of the other SNPs showed significant association after Bonferroni correction in the two populations or in the pooled analysis. A weighted genetic risk score (wGRS) was constructed using the risk alleles of the Tag-SNPs with a positive Beta parameter in both populations. From the first to the fifth quintile of the score, the BMI increased 0.45 kg/m2 in Hortega and 2.0 kg/m2 in Pizarra. Overall, the obesity predictive value was low (less than 1%). Conclusion The risk associated with polymorphisms is low and the overall effect on BMI or obesity prediction is minimal. A weighted genetic risk score based on genes mainly acting through central nervous system mechanisms was associated with BMI but it yields minimal clinical prediction for the obesity risk in the general population. PMID:24267414

Impact of obesity-related genes in Spanish population.

PubMed

Martínez-García, Fernando; Mansego, María L; Rojo-Martínez, Gemma; De Marco-Solar, Griselda; Morcillo, Sonsoles; Soriguer, Federico; Redón, Josep; Pineda Alonso, Monica; Martín-Escudero, Juan C; Cooper, Richard S; Chaves, Felipe J

2013-11-23

The objective was to investigate the association between BMI and single nucleotide polymorphisms previously identified of obesity-related genes in two Spanish populations. Forty SNPs in 23 obesity-related genes were evaluated in a rural population characterized by a high prevalence of obesity (869 subjects, mean age 46 yr, 62% women, 36% obese) and in an urban population (1425 subjects, mean age 54 yr, 50% women, 19% obese). Genotyping was assessed by using SNPlex and PLINK for the association analysis. Polymorphisms of the FTO were significantly associated with BMI, in the rural population (beta 0.87, p-value <0.001). None of the other SNPs showed significant association after Bonferroni correction in the two populations or in the pooled analysis. A weighted genetic risk score (wGRS) was constructed using the risk alleles of the Tag-SNPs with a positive Beta parameter in both populations. From the first to the fifth quintile of the score, the BMI increased 0.45 kg/m2 in Hortega and 2.0 kg/m2 in Pizarra. Overall, the obesity predictive value was low (less than 1%). The risk associated with polymorphisms is low and the overall effect on BMI or obesity prediction is minimal. A weighted genetic risk score based on genes mainly acting through central nervous system mechanisms was associated with BMI but it yields minimal clinical prediction for the obesity risk in the general population.

Association between FTO gene polymorphisms and type 2 diabetes mellitus, serum levels of apelin and androgen hormones among Iranian obese women.

PubMed

Ghafarian-Alipour, Farzaneh; Ziaee, Shayan; Ashoori, Mohamad Reza; Zakeri, Mir Saeid; Boroumand, Mohammad Ali; Aghamohammadzadeh, Naser; Abbasi-Majdi, Maryam; Shool, Fatemeh; Asbaghi, Navid Sarakhs; Mohammadi, Abolghasem; Zarghami, Nosratollah

2018-01-30

Recent studies show that FTO single nucleotide polymorphisms (SNPs) are associated with obesity and type 2 diabetes mellitus (T2DM). On the other hand, many animal models and clinical studies have demonstrated that apelin, an adipocytokine, is related to the obesity and T2DM. Additionally, obese women are at risk of Hyperandrogenemia. So, the aim of this study was to investigate the relationship between FTO variants (rs763967273, rs759031579, rs141115189, rs9926289, rs76804286 and rs9939609) with T2DM, serum apelin and androgenic hormones in Iranian obese women. 197 obese women (123 women with T2DM and 74 women as healthy control) were participated in this study. Anthropometrical and biochemical characteristics were measured. Serum apelin and androgen hormones levels were determined in 66 subjects consisting of 33 cases and 33 controls. PCR were carried out and subsequently, the PCR production was genotyped by Sanger sequencing assay. Our observations showed that all SNPs are related to T2DM. The rs9926289 FTO variant had a strong association with serum apelin and dehydroepiandrosterone-sulfate levels (P=0.04 and P=0.03, respectively) among SNPs. In addition, apelin and androgenic hormones were correlated with T2DM. Two polymorphisms including rs9939609 and rs9926289 had a strong Linkage disequilibrium (r 2 =1). FTO variants not only were associated with T2DM, but also some variants had a strong association with apelin and androgenic hormones profile. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of the Obesity Genes FTO and MC4R for Contribution to the Risk of Large Artery Atherosclerotic Stroke in a Chinese Population

PubMed Central

Song, Zhi; Qiu, Lingling; Hu, Zhongyang; Liu, Jia; Liu, Ding; Hou, Deren

2016-01-01

Background Obesity is a well-established risk factor for large artery atherosclerotic (LAA) stroke. The aim of the study was to explore whether obesity genes, such as MC4R and FTO, contribute to LAA stroke risk in the Chinese Han population. Methods 322 LAA stroke patients and 473 controls were recruited. Gene polymorphism of MC4R (rs17782313) and FTO (rs8050136 and rs9939609) were genotyped. Results No differences were observed in genotype frequencies of variants of FTO (rs8050136 and rs9939609) or MC4R (rs17782313) between LAA stroke patients and control subjects. However, rs17782313 of the MC4R gene was associated with LAA stroke susceptibility in smokers (rs17782313: p = 0.020, OR (95s% CI) = 1.55 (1.07–2.23)) in the stratified analysis. Furthermore, multifactor dimensionality reduction analysis revealed that the combination of MC4R variant (rs17782313), hypertension and smoking habit was significantly associated with increased risk of LAA stroke (p < 0.0001, OR (95s% CI) = 6.57 (4.79–9.01)). Conclusion Our study indicated that the synergistic effects of MC4R variants, hypertension, and smoking habit contribute significantly to the risk of LAA stroke in the Chinese Han population. The finding revealed that obesity gene MC4R contribute to the risk of LAA stroke via a synergistic mechanism, which will provide new insight into the genetic architecture of LAA stroke. PMID:27701175

Evaluation of the Obesity Genes FTO and MC4R for Contribution to the Risk of Large Artery Atherosclerotic Stroke in a Chinese Population.

PubMed

Song, Zhi; Qiu, Lingling; Hu, Zhongyang; Liu, Jia; Liu, Ding; Hou, Deren

2016-01-01

Obesity is a well-established risk factor for large artery atherosclerotic (LAA) stroke. The aim of the study was to explore whether obesity genes, such as MC4R and FTO, contribute to LAA stroke risk in the Chinese Han population. 322 LAA stroke patients and 473 controls were recruited. Gene polymorphism of MC4R (rs17782313) and FTO (rs8050136 and rs9939609) were genotyped. No differences were observed in genotype frequencies of variants of FTO (rs8050136 and rs9939609) or MC4R (rs17782313) between LAA stroke patients and control subjects. However, rs17782313 of the MC4R gene was associated with LAA stroke susceptibility in smokers (rs17782313: p = 0.020, OR (95% CI) = 1.55 (1.07-2.23)) in the stratified analysis. Furthermore, multifactor dimensionality reduction analysis revealed that the combination of MC4R variant (rs17782313), hypertension and smoking habit was significantly associated with increased risk of LAA stroke (p < 0.0001, OR (95% CI) = 6.57 (4.79-9.01)). Our study indicated that the synergistic effects of MC4R variants, hypertension, and smoking habit contribute significantly to the risk of LAA stroke in the Chinese Han population. The finding revealed that obesity gene MC4R contribute to the risk of LAA stroke via a synergistic mechanism, which will provide new insight into the genetic architecture of LAA stroke. © 2016 The Author(s) Published by S. Karger GmbH, Freiburg.

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.

PubMed

Claussnitzer, Melina; Dankel, Simon N; Kim, Kyoung-Han; Quon, Gerald; Meuleman, Wouter; Haugen, Christine; Glunk, Viktoria; Sousa, Isabel S; Beaudry, Jacqueline L; Puviindran, Vijitha; Abdennur, Nezar A; Liu, Jannel; Svensson, Per-Arne; Hsu, Yi-Hsiang; Drucker, Daniel J; Mellgren, Gunnar; Hui, Chi-Chung; Hauner, Hans; Kellis, Manolis

2015-09-03

Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7

Genetic variation in the fat mass and obesity-associated gene (FTO) in association with food preferences in healthy adults

PubMed Central

Brunkwall, Louise; Ericson, Ulrika; Hellstrand, Sophie; Gullberg, Bo; Orho-Melander, Marju; Sonestedt, Emily

2013-01-01

Background Earlier studies have indicated that the fat mass and obesity-associated gene (FTO) is not only associated with BMI and weight but also with appetite and dietary intake. Objectives We investigated if the FTO rs9939609 associates with food preferences in healthy adults with no cancer, cardiovascular disease, or diabetes. Additionally, we challenged the question if the associations are modified by obesity status (BMI ≤25 or >25 kg/m2). Design The analyses are made with 22,799 individuals from the Swedish population-based Malmö Diet and Cancer Cohort Study, who were born between 1923 and 1945. To investigate food preference, 27 food groups conducted from a modified diet history method including a 7-day registration of cooked meals and cold beverages were used in the analyses. Bonferroni correction was used to correct for multiple testing, resulting in a cut-off value for significance level of p<0.002. Results We observed that the obesity susceptible A-allele carriers reported a higher consumption of biscuits and pastry but lower consumption of soft drinks (P for trend <0.0001 for both) as compared to TT genotype carriers. In contrast to our hypothesis, the results did not significantly differ depending on obesity status except for consumption of juice, where only the overweight individuals with A-allele had a higher consumption as compared to TT carriers (P for interaction=0.04). Conclusion Our results indicate that the FTO A-allele may associate with certain food preference and in particular with certain energy-dense foods. PMID:23589710

Expression studies of six human obesity-related genes in seven tissues from divergent pig breeds.

PubMed

Cirera, S; Jensen, M S; Elbrønd, V S; Moesgaard, S G; Christoffersen, B Ø; Kadarmideen, H N; Skovgaard, K; Bruun, C V; Karlskov-Mortensen, P; Jørgensen, C B; Fredholm, M

2014-02-01

Obesity has reached epidemic proportions globally and has become the cause of several major health risks worldwide. Presently, more than 100 loci have been related to obesity and metabolic traits in humans by genome-wide association studies. The complex genetic architecture behind obesity has triggered a need for the development of better animal models than rodents. The pig has emerged as a very promising biomedical model to study human obesity traits. In this study, we have characterized the expression patterns of six obesity-related genes, leptin (LEP), leptin receptor (LEPR), melanocortin 4 receptor (MC4R), fat mass and obesity associated (FTO), neuronal growth regulator 1 (NEGR)1 and adiponectin (ADIPOQ), in seven obesity-relevant tissues (liver; muscle; pancreas; hypothalamus; and retroperitoneal, subcutaneous and mesenteric adipose tissues) in two pig breeds (production pigs and Göttingen minipigs) that deviate phenotypically and genetically from each other with respect to obesity traits. We observe significant differential expression for LEP, LEPR and ADIPOQ in muscle and in all three adipose tissues. Interestingly, in pancreas, LEP expression is only detected in the fat minipigs. FTO shows significant differential expression in all tissues analyzed, and NEGR1 shows significant differential expression in muscle, pancreas, hypothalamus and subcutaneous adipose tissue. The MC4R transcript can be detected only in hypothalamus. In general, the expression profiles of the investigated genes are in accordance with those observed in human studies. Our study shows that both the differences between the investigated breeds and the phenotypic state with respect to obesity/leanness play a large role for differential expression of the obesity-related genes. © 2013 The Authors, Animal Genetics © 2013 Stichting International Foundation for Animal Genetics.

Association of obesity susceptibility gene variants with metabolic syndrome and related traits in 1,443 Czech adolescents.

PubMed

Dušátková, L; Zamrazilová, H; Sedláčková, B; Včelák, J; Hlavatý, P; Aldhoon Hainerová, I; Korenková, V; Bradnová, O; Bendlová, B; Kunešová, M; Hainer, V

2013-01-01

Genome-wide association studies have revealed several gene variants associated with obesity; however, only a few studies have further investigated their association with metabolic syndrome. We performed a study of eleven variants in/near genes TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, and FTO in Czech adolescents and analysed their association with obesity, metabolic syndrome and related traits. Genotyping was performed in 1,443 adolescents aged 13.0-17.9 years. Anthropometric parameters, biochemical parameters and blood pressure were assessed. Metabolic syndrome was defined according to the International Diabetes Federation. The FTO rs9939609 variant was associated with overweight/obesity (OR 1.40, 95% CI 1.21-1.63, P < 0.001). The minor allele of TMEM18 rs7561317 was related to underweight (OR 1.78, 95% CI 1.14-2.79, P = 0.015). BDNF rs925946 and MC4R rs17782313 were associated with metabolic syndrome (OR 1.53, 95% CI 1.14-2.04, P = 0.005; 1.51, 95% CI 1.12-2.04, P = 0.009). The PCSK1 rs6235 variant was negatively related to increased blood glucose (OR 0.69, 95% CI 0.49-0.97, P = 0.040). In conclusion, the FTO variant was associated with overweight/obesity in Czech adolescents. Moreover, MC4R and BDNF variants increased the risk of metabolic syndrome, probably through their effect on abdominal obesity. The PCSK1 variant may have a protective role in the development of type 2 diabetes.

The role of early life growth development, the FTO gene and exclusive breastfeeding on child BMI trajectories.

PubMed

Wu, Yan Yan; Lye, Stephen; Briollais, Laurent

2017-10-01

Recent studies have implicated the FTO gene in child and adult obesity. A longer duration of exclusive breastfeeding (EXBF) has been shown to reduce body mass index (BMI) and the risk of being overweight in the general population and among FTO gene carriers. However, it remains unclear whether the preventive effect of EXBF could be explained by its impact on early life growth development, e.g. ages at adiposity peak (AP) and adiposity rebound (AR) and BMI velocities in the first years of life, which are major determinants of overweight and obesity later in life. We studied 5590 children from the British Avon Longitudinal Study of Parents and Children (ALSPAC) cohort and modelled their longitudinal BMI profiles with mixed effects models from birth to 16 years of age, as well as their ages at AP, AR and BMI velocities in relation to the FTO gene variant and EXBF. A longer duration of EXBF (i.e. at least 5 months) has substantial impact on BMI growth trajectories among children carrying the FTO adverse variant by modulating the age at AP, age at AR and BMI velocities. EXBF acts antagonistically to the FTO rs9939609 risk allele and by the age of 15, the predicted reduction in BMI after 5 months of EXBF is 0.56 kg/m2 [95% confidence interval (CI) 0.11-1.01; P = 0.003] and 1.14 kg/m2 (95% CI 0.67-1.62; P < 0.0001) in boys and girls, respectively. EXBF influences early life growth development and thus plays a critical role in preventing the risks of overweight and obesity even when those are exacerbated by genetic factors. © The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

Gene polymorphisms and increased DNA damage in morbidly obese women.

PubMed

Luperini, B C O; Almeida, D C; Porto, M P; Marcondes, J P C; Prado, R P; Rasera, I; Oliveira, M R M; Salvadori, D M F

2015-06-01

Obesity is characterized by increased adipose tissue mass resulting from a chronic imbalance between energy intake and expenditure. Furthermore, there is a clearly defined relationship among fat mass expansion, chronic low-grade systemic inflammation and reactive oxygen species (ROS) generation; leading to ROS-related pathological events. In the past years, genome-wide association studies have generated convincing evidence associating genetic variation at multiple regions of the genome with traits that reflect obesity. Therefore, the present study aimed to evaluate the relationships among the gene polymorphisms ghrelin (GHRL-rs26802), ghrelin receptor (GHSR-rs572169), leptin (LEP-rs7799039), leptin receptor (LEPR-rs1137101) and fat mass and obesity-associated (FTO-rs9939609) and obesity. The relationships among these gene variants and the amount of DNA damage were also investigated. Three hundred Caucasian morbidly obese and 300 eutrophic (controls) women were recruited. In summary, the results demonstrated that the frequencies of the GHRL, GHSR, LEP and LEPR polymorphisms were not different between Brazilian white morbidly obese and eutrophic women. Exceptions were the AA-FTO genotype and allele A, which were significantly more frequent in obese women than in the controls (0.23% vs. 0.10%; 0.46 vs. 0.36, respectively), and the TT-FTO genotype and the T allele, which were less frequent in morbidly obese women (p<0.01). Furthermore, significant differences in the amount of genetic lesions associated with FTO variants were observed only in obese women. In conclusion, this study demonstrated that the analyzed SNPs were not closely associated with morbid obesity, suggesting they are not the major contributors to obesity. Therefore, our data indicated that these gene variants are not good biomarkers for predicting risk susceptibility for obesity, whereas ROS generated by the inflammatory status might be one of the causes of DNA damage in obese women, favoring

Fat mass and obesity-associated (FTO) protein interacts with CaMKII and modulates the activity of CREB signaling pathway.

PubMed

Lin, Li; Hales, Chadwick M; Garber, Kathryn; Jin, Peng

2014-06-15

Polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. FTO is a nuclear protein and its physiological function remains largely unknown, but alterations in its expression in mice influence energy expenditure, food intake and, ultimately, body weight. To understand the molecular functions of FTO, we performed a yeast two-hybrid screen to identify the protein(s) that could directly interact with human FTO protein. Using multiple assays, we demonstrate that FTO interacts with three isoforms of calcium/calmodulin-dependent protein kinase II: α, β and γ, which are protein kinases that phosphorylate a broad range of substrates. This interaction is functional; overexpression of FTO delays the dephosphorylation of cAMP response element-binding protein (CREB) in human neuroblastoma (SK-N-SH) cells, which in turn leads to a dramatic increase in the expression of the CREB targets neuropeptide receptor 1 (NPY1R) and brain-derived neurotrophic factor (BDNF), which already are known to regulate food intake and energy homeostasis. Thus, our results suggest that FTO could modulate obesity by regulating the activity of the CREB signaling pathway. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Are obesity risk genes associated with binge eating in adolescence?

PubMed Central

Micali, Nadia; Field, Alison E; Treasure, Janet L; Evans, David M

2015-01-01

Objective Cognitions and behaviors characteristic of binge eating are associated with a polymorphism in the FTO gene, robustly related to body mass index (BMI) and obesity risk. We investigated the association between binge eating and the individual and combined effect of 32 SNPs robustly associated with BMI in a population-based sample. We hypothesized that higher BMI and binge eating might share a common genetic etiology. Methods Binge eating was assessed in adolescents from the Avon Longitudinal Study of Parents and Children at age 14 (n = 5,958) and 16 years (n = 4,948). We tested associations between 32 BMI-related SNPs and binge eating in crude and BMI-, age-, and gender-adjusted regression models. Results Crude analyses showed an association between binge eating and rs1558902 (FTO) that persisted after adjustment for BMI (OR = 1.20, P = 8 × 10−3). A weighted allelic score consisting of all 32 BMI-related SNPs was associated with binge eating (P = 8 × 10−4); this association attenuated (P = 0.08) when rs1558902 was removed from the weighted allelic score. Conclusions BMI-related genes are associated with adolescent binge eating, in particular an FTO polymorphism. Although replication is needed, our findings have biological plausibility and are consistent with a postulated effect of FTO on appetite and food intake. Future studies should aim to understand the mechanisms underlying the relationship between FTO, binge eating, and obesity. PMID:26193063

Replication of 6 obesity genes in a meta-analysis of genome-wide association studies from diverse ancestries.

PubMed

Tan, Li-Jun; Zhu, Hu; He, Hao; Wu, Ke-Hao; Li, Jian; Chen, Xiang-Ding; Zhang, Ji-Gang; Shen, Hui; Tian, Qing; Krousel-Wood, Marie; Papasian, Christopher J; Bouchard, Claude; Pérusse, Louis; Deng, Hong-Wen

2014-01-01

Obesity is a major public health problem with a significant genetic component. Multiple DNA polymorphisms/genes have been shown to be strongly associated with obesity, typically in populations of European descent. The aim of this study was to verify the extent to which 6 confirmed obesity genes (FTO, CTNNBL1, ADRB2, LEPR, PPARG and UCP2 genes) could be replicated in 8 different samples (n = 11,161) and to explore whether the same genes contribute to obesity-susceptibility in populations of different ancestries (five Caucasian, one Chinese, one African-American and one Hispanic population). GWAS-based data sets with 1000 G imputed variants were tested for association with obesity phenotypes individually in each population, and subsequently combined in a meta-analysis. Multiple variants at the FTO locus showed significant associations with BMI, fat mass (FM) and percentage of body fat (PBF) in meta-analysis. The strongest association was detected at rs7185735 (P-value = 1.01×10(-7) for BMI, 1.80×10(-6) for FM, and 5.29×10(-4) for PBF). Variants at the CTNNBL1, LEPR and PPARG loci demonstrated nominal association with obesity phenotypes (meta-analysis P-values ranging from 1.15×10(-3) to 4.94×10(-2)). There was no evidence of association with variants at ADRB2 and UCP2 genes. When stratified by sex and ethnicity, FTO variants showed sex-specific and ethnic-specific effects on obesity traits. Thus, it is likely that FTO has an important role in the sex- and ethnic-specific risk of obesity. Our data confirmed the role of FTO, CTNNBL1, LEPR and PPARG in obesity predisposition. These findings enhanced our knowledge of genetic associations between these genes and obesity-related phenotypes, and provided further justification for pursuing functional studies of these genes in the pathophysiology of obesity. Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized

Polymorphisms FTO rs9939609, PPARG rs1801282 and ADIPOQ rs4632532 and rs182052 but not lifestyle are associated with obesity related-traits in Mexican children.

PubMed

Muñoz-Yáñez, C; Pérez-Morales, R; Moreno-Macías, H; Calleros-Rincón, E; Ballesteros, G; González, R A; Espinosa, J

2016-01-01

Concerning the genetic factors of obesity, no consistent association between populations has been reported, which may be due to the frequency of polymorphisms, the lifestyle of studied populations and its interaction with other factors. We studied a possible association of polymorphisms FTO rs9939609, PPARG rs1801282, and ADIPOQ rs4632532 and rs182052 with obesity phenotypes in 215 Mexican children. Glucose, triglycerides, cholesterol, HDL and LDL were measured. In addition, weight, height, waist circumference and triceps skin thickness were recorded. High-energy diets and sedentary behavior were evaluated with a validated questionnaire. In contrast with other reports, only FTO rs9939609 was associated with obesity related-traits, including BMI (p = 0.03), waist circumference (p = 0.02), triceps skinfold (p = 0.03) and waist/height ratio (p = 0.01), and also with cholesterol levels (p = 0.02) and LDL (p = 0.009). Lower levels of triglycerides (p=0.04) were related with presence of PPARG rs1801282, while ADIPOQ rs4632532 showed an effect on HDL (p = 0.03) levels. On the other hand, diet, physical activity and screen time were not related with obesity. In summary, only FTO rs9939609 was associated with obesity related-traits, while PPARG2 rs1801282 and ADIPOQ rs4632532 were involved in lipid metabolism.

Polymorphisms FTO rs9939609, PPARG rs1801282 and ADIPOQ rs4632532 and rs182052 but not lifestyle are associated with obesity related-traits in Mexican children

PubMed Central

Muñoz-Yáñez, C; Pérez-Morales, R; Moreno-Macías, H; Calleros-Rincón, E; Ballesteros, G; González, R. A; Espinosa, J

2016-01-01

Abstract Concerning the genetic factors of obesity, no consistent association between populations has been reported, which may be due to the frequency of polymorphisms, the lifestyle of studied populations and its interaction with other factors. We studied a possible association of polymorphisms FTO rs9939609, PPARG rs1801282, and ADIPOQ rs4632532 and rs182052 with obesity phenotypes in 215 Mexican children. Glucose, triglycerides, cholesterol, HDL and LDL were measured. In addition, weight, height, waist circumference and triceps skin thickness were recorded. High-energy diets and sedentary behavior were evaluated with a validated questionnaire. In contrast with other reports, only FTO rs9939609 was associated with obesity related-traits, including BMI (p = 0.03), waist circumference (p = 0.02), triceps skinfold (p = 0.03) and waist/height ratio (p = 0.01), and also with cholesterol levels (p = 0.02) and LDL (p = 0.009). Lower levels of triglycerides (p=0.04) were related with presence of PPARG rs1801282, while ADIPOQ rs4632532 showed an effect on HDL (p = 0.03) levels. On the other hand, diet, physical activity and screen time were not related with obesity. In summary, only FTO rs9939609 was associated with obesity related-traits, while PPARG2 rs1801282 and ADIPOQ rs4632532 were involved in lipid metabolism. PMID:27560839

Nutritional state affects the expression of the obesity-associated genes Etv5, Faim2, Fto, and Negr1.

PubMed

Boender, Arjen J; van Rozen, Andrea J; Adan, Roger A H

2012-12-01

Obesity is a risk factor for type II diabetes, atherosclerosis, and some forms of cancer. Variation in common measures of obesity (e.g., BMI, waist/hip ratio) is largely explained by heritability. The advent of genome-wide association studies (GWAS) has made it possible to identify several genetic variants that associate with measures of obesity, but how exactly these genetic variants contribute to overweight has remained largely unresolved. One first hint is given by the fact that many of the associated variants reside in or near genes that act in the central nervous system, which implicates neuronal signaling in the etiology of obesity. Although the brain controls both energy intake and expenditure, it has more capacity to regulate energy intake rather than energy expenditure. In environments where food is abundant, this renders the body prone to weight increases. To gain more insight into the neurobiological mechanisms involved, we set out to investigate the effect of dietary exposure on the expression levels of obesity-associated genes in the ventro-medial hypothalamus (VMH)/arcuate nucleus (ARC) and the substantia nigra (SN)/ventral tegmental area (VTA), two brain regions that are implicated in feeding behavior. We show that the expression of Etv5, Faim2, Fto, Negr1 but not Sh2b1 is affected by nutritional state in these two areas, thereby providing insight into the relationship between nutritional state and expression levels of obesity-associated genes in two brain areas relevant to feeding.

A link between FTO, ghrelin, and impaired brain food-cue responsivity

PubMed Central

Karra, Efthimia; O’Daly, Owen G.; Choudhury, Agharul I.; Yousseif, Ahmed; Millership, Steven; Neary, Marianne T.; Scott, William R.; Chandarana, Keval; Manning, Sean; Hess, Martin E.; Iwakura, Hiroshi; Akamizu, Takashi; Millet, Queensta; Gelegen, Cigdem; Drew, Megan E.; Rahman, Sofia; Emmanuel, Julian J.; Williams, Steven C.R.; Rüther, Ulrich U.; Brüning, Jens C.; Withers, Dominic J.; Zelaya, Fernando O.; Batterham, Rachel L.

2013-01-01

Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N6-methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO “obesity-risk” rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N6-methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N6-methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans. PMID:23867619

A link between FTO, ghrelin, and impaired brain food-cue responsivity.

PubMed

Karra, Efthimia; O'Daly, Owen G; Choudhury, Agharul I; Yousseif, Ahmed; Millership, Steven; Neary, Marianne T; Scott, William R; Chandarana, Keval; Manning, Sean; Hess, Martin E; Iwakura, Hiroshi; Akamizu, Takashi; Millet, Queensta; Gelegen, Cigdem; Drew, Megan E; Rahman, Sofia; Emmanuel, Julian J; Williams, Steven C R; Rüther, Ulrich U; Brüning, Jens C; Withers, Dominic J; Zelaya, Fernando O; Batterham, Rachel L

2013-08-01

Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N6-methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO "obesity-risk" rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N6-methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N6-methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans.

Effect of FTO rs9939609 variant on insulin resistance in obese female adolescents.

PubMed

Iskandar, Kristy; Patria, Suryono Yudha; Huriyati, Emy; Luglio, Harry Freitag; Julia, Madarina; Susilowati, Rina

2018-05-15

FTO rs9939609 variant has been shown to be associated with insulin resistance in Caucasian children. However, studies in Asia show inconsistent findings. We investigated the association between FTO rs9939609 polymorphisms and insulin resistance in obese female adolescents in Indonesia, a genetically distinct group within Asia. A total of 78 obese female adolescents participated in this study. The risk allele (A) frequency of FTO rs9939609 variant in Indonesian obese female adolescence was 44.2%. The frequency of insulin resistance was higher in the subjects with AA (54.6%) or AT (59.6%) than the subject with TT genotype (50%), but did not statistically different (p = 0.81 and p = 0.47, respectively). The insulin resistance rate was also higher in the risk allele (A) than the non-risk allele (T) subjects (0.58 vs. 0.55), but did not statistically different (p = 0.75). There was no association between FTO rs9939609 variant and body mass index, fasting glucose level, fasting insulin level, homeostatic model assessment of insulin resistance, and waist circumference (p > 0.05). In conclusion, FTO rs9939609 variant may not be associated with insulin resistance in Indonesian obese female adolescents. A multicenter study with a larger sample size is needed to clarify these findings.

Two candidate genes (FTO and INSIG2) for fat accumulation in four canids: chromosome mapping, gene polymorphisms and association studies of body and skin weight of red foxes.

PubMed

Grzes, M; Szczerbal, I; Fijak-Nowak, H; Szydlowski, M; Switonski, M

2011-01-01

Fat accumulation is a polygenic trait which has a significant impact on human health and animal production. Obesity is also an increasingly serious problem in dog breeding. The FTO and INSIG2 are considered as candidate genes associated with predisposition for human obesity. In this report we present a comparative genomic analysis of these 2 genes in 4 species belonging to the family Canidae - the dog and 3 species which are kept in captivity for fur production, i.e. red fox, arctic fox and Chinese raccoon dog. We cytogenetically mapped these 2 loci by FISH and compared the entire coding sequence of INSIG2 and a fragment of the coding sequence of FTO. The FTO gene was assigned to the following chromosomes: CFA2q25 (dog), VVU2q21 (red fox), ALA8q25 (arctic fox) and NPP10q24-25 (Chinese raccoon dog), while the INSIG2 was mapped to CFA19q17, VVU5p14, ALA24q15 and NPP9q22, respectively. Altogether, 29 SNPs were identified (16 in INSIG2 and 13 in FTO) and among them 2 were missense substitutions in the dog (23C/T, Thr>Met in the FTO gene and 40C/A, Arg>Ser in INSIG2). The distribution of these 2 SNPs was studied in 14 dog breeds. Two synonymous SNPs, one in the FTO gene (-28T>C in the 5'-flanking region) and one in the INSIG2 (10175C>T in intron 2), were used for the association studies in red foxes (n = 390) and suggestive evidence was observed for their association with body weight (FTO, p < 0.08) and weight of raw skin (INSIG2, p < 0.05). These associations indicate that both genes are potential candidates for growth or adipose tissue accumulation in canids. We also suggest that the 2 missense substitutions found in dogs should be studied in terms of genetic predisposition to obesity. Copyright © 2011 S. Karger AG, Basel.

FTO genotype is associated with exercise training-induced changes in body composition

PubMed Central

Rankinen, Tuomo; Rice, Treva; Teran-Garcia, Margarita; Rao, D.C.; Bouchard, Claude

2010-01-01

The fat mass and obesity associated (FTO) gene is the first obesity-susceptibility gene identified by genome-wide association scans and confirmed in several follow-up studies. Homozygotes for the risk allele (A/A) have 1.67 times greater risk of obesity than those who do not have the allele. However, it is not known if regular exercise-induced changes in body composition are influenced by the FTO genotype. The purpose of our study was to test if the FTO genotype is associated with exercise-induced changes in adiposity. Body composition was derived from underwater weighing before and after a 20-week endurance training program in 481 previously sedentary white subjects of the HERITAGE Family Study. FTO SNP rs8050136 was genotyped using Illumina GoldenGate assay. In the sedentary state, the A/A homozygotes were significantly heavier and fatter than the heterozygotes and the C/C homozygotes in men (p=0.004) but not in women (p=0.331; gene-by-sex interaction p=0.0053). The FTO genotype was associated with body fat responses to regular exercise (p<0.005; adjusted for age, sex, and baseline value of response trait): carriers of the C-allele showed three times greater fat mass and %body fat losses than the A/A homozygotes. The FTO genotype explained 2% of the variance in adiposity changes. Our data suggest that the FTO obesity-susceptibility genotype influences the body fat responses to regular exercise. Resistance to exercise-induced reduction in total adiposity may represent one mechanism by which the FTO A allele promotes overweight and obesity. PMID:19543202

FTO Polymorphisms Moderate the Association of Food Reinforcement with Energy Intake

PubMed Central

Scheid, Jennifer L.; Carr, Katelyn A.; Lin, Henry; Fletcher, Kelly D.; Sucheston, Lara; Singh, Prashant K.; Salis, Robbert; Erbe, Richard; Faith, Myles S.; Allison, David B.; Epstein, Leonard H.

2015-01-01

Food reinforcement (RRVfood) is related to increased energy intake, cross-sectionally related to obesity, and prospectively related to weight gain. The fat mass and obesity-associated (FTO) gene is related to elevated body mass index and increased energy intake. The primary purpose of the current study was to determine whether any of 68 FTO single nucleotide polymorphisms (SNPs) or a FTO risk score moderate the association between food reinforcement and energy or macronutrient intake. Energy and macronutrient intake was measured using a laboratory ad libitum snack food consumption task in 237 adults of varying BMI. Controlling for BMI, the relative reinforcing value of reading (RRVreading) and proportion of African ancestry, RRVfood predicted 14.2% of the variance in energy intake, as well as predicted carbohydrate, fat, protein and sugar intake. In individual analyses, six FTO SNPs (rs12921970, rs9936768, rs12446047, rs7199716, rs8049933 and rs11076022, spanning approximately 251K bp) moderated the relationship between RRVfood and energy intake to predict an additional 4.9 - 7.4% of variance in energy intake. We created an FTO risk score based on 5 FTO SNPs (rs9939609, rs8050136, rs3751812, rs1421085, and rs1121980) that are related to BMI in multiple studies. The FTO risk score did not increase variance accounted for beyond individual FTO SNPs. Rs12921970 and rs12446047 served as moderators of the relationship between RRVfood and carbohydrate, fat, protein, and sugar intake. This study shows for the first time that the relationship between RRVfood and energy intake is moderated by FTO SNPs. Research is needed to understand how these processes interact to predict energy and macronutrient intake. PMID:24768648

Contribution of Common Genetic Variants to Obesity and Obesity-Related Traits in Mexican Children and Adults

PubMed Central

Villalobos-Comparán, Marisela; Villarreal-Molina, Teresa; Romero-Hidalgo, Sandra; López-Contreras, Blanca; Gutiérrez-Vidal, Roxana; Vega-Badillo, Joel; Jacobo-Albavera, Leonor; Posadas-Romeros, Carlos; Canizalez-Román, Adrián; Río-Navarro, Blanca Del; Campos-Pérez, Francisco; Acuña-Alonzo, Victor; Aguilar-Salinas, Carlos; Canizales-Quinteros, Samuel

2013-01-01

Background Several studies have identified multiple obesity-associated loci mainly in European populations. However, their contribution to obesity in other ethnicities such as Mexicans is largely unknown. The aim of this study was to examine 26 obesity-associated single-nucleotide polymorphisms (SNP) in a sample of Mexican mestizos. Methods 9 SNPs in biological candidate genes showing replications (PPARG, ADRB3, ADRB2, LEPR, GNB3, UCP3, ADIPOQ, UCP2, and NR3C1), and 17 SNPs in or near genes associated with obesity in first, second and third wave GWAS (INSIG2, FTO, MC4R, TMEM18, FAIM2/BCDIN3, BDNF, SH2B1, GNPDA2, NEGR1, KCTD15, SEC16B/RASAL2, NPC1, SFRF10/ETV5, MAF, PRL, MTCH2, and PTER) were genotyped in 1,156 unrelated Mexican-Mestizos including 683 cases (441 obese class I/II and 242 obese class III) and 473 normal-weight controls. In a second stage we selected 12 of the SNPs showing nominal associations with obesity, to seek associations with quantitative obesity-related traits in 3 cohorts including 1,218 Mexican Mestizo children, 945 Mexican Mestizo adults, and 543 Indigenous Mexican adults. Results After adjusting for age, sex and admixture, significant associations with obesity were found for 6 genes in the case-control study (ADIPOQ, FTO, TMEM18, INSIG2, FAIM2/BCDIN3 and BDNF). In addition, SH2B1 was associated only with class I/II obesity and MC4R only with class III obesity. SNPs located at or near FAIM2/BCDIN3, TMEM18, INSIG2, GNPDA2 and SEC16B/RASAL2 were significantly associated with BMI and/or WC in the combined analysis of Mexican-mestizo children and adults, and FTO locus was significantly associated with increased BMI in Indigenous Mexican populations. Conclusions Our findings replicate the association of 8 obesity-related SNPs with obesity risk in Mexican adults, and confirm the role of some of these SNPs in BMI in Mexican adults and children. PMID:23950976

The obesity-risk variant of FTO is inversely related with the So-Eum constitutional type: genome-wide association and replication analyses.

PubMed

Cha, Seongwon; Yu, Hyunjoo; Park, Ah Yeon; Oh, Soo A; Kim, Jong Yeol

2015-04-15

Body constitutional types described in the traditional Korean medicine system, Sasang constitutional medicine, are heritable, as has been revealed by twin and family studies. Thus, individuals with the same constitution type usually have similar pathophysiological and psychological traits. In several recent genome-wide association (GWA) analyses performed to identify constitution-associated variants, the association signals were not replicated due to small sample size and dissimilar, non-objective methods for classification of the constitutional types. We conducted GWA analysis and followed replication analysis in two large populations (5,490 subjects: 3,810 subjects at discovery stage and 1,680 subjects at replication stage) to identify the replicable constitution-associated variants, wherein subjects with the highest tertile of constitution probability values versus the reference with the lowest tertile of the values obtained from a recently developed constitution analysis tool were compared. We found that the obesity-risk variant in intron 1 of the fat mass and obesity-associated (FTO) gene was replicably inversely associated with the So-Eum (SE) type, characterized by reduced appetite, slim body, and cautious personality (rs7193144 in combined samples: odds ratio = 0.729, p = 1.47 × 10(-7)), and substantial association signal remained after controlling for body mass index (BMI). In contrast, the association of the variant with the Tae-Eum type, characterized by high body mass, disappeared after controlling BMI. In summary, the obesity-risk variant in FTO intron 1 was inversely associated with the SE type, independent of BMI, which corresponded well with the characteristics of the SE type, such as the lowest body mass and lowest susceptibility to metabolic disorders among the constitutional types. Therefore, the obesity-risk variant of FTO associated with body mass increase might be involved in the determination of body constitution type.

FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians.

PubMed

Yajnik, C S; Janipalli, C S; Bhaskar, S; Kulkarni, S R; Freathy, R M; Prakash, S; Mani, K R; Weedon, M N; Kale, S D; Deshpande, J; Krishnaveni, G V; Veena, S R; Fall, C H D; McCarthy, M I; Frayling, T M; Hattersley, A T; Chandak, G R

2009-02-01

Variants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not seem to be mediated through BMI. We studied the association of FTO variants with type 2 diabetes and measures of obesity in South Asian Indians in Pune. We genotyped, by sequencing, two single nucleotide polymorphisms, rs9939609 and rs7191344, in the FTO gene in 1,453 type 2 diabetes patients and 1,361 controls from Pune, Western India and a further 961 population-based individuals from Mysore, South India. We observed a strong association of the minor allele A at rs9939609 with type 2 diabetes (OR per allele 1.26; 95% CI 1.13-1.40; p = 3 x 10(-5)). The variant was also associated with BMI but this association appeared to be weaker (0.06 SDs; 95% CI 0.01-0.10) than the previously reported effect in Europeans (0.10 SDs; 95% CI 0.09-0.12; heterogeneity p = 0.06). Unlike in the Europeans, the association with type 2 diabetes remained significant after adjusting for BMI (OR per allele for type 2 diabetes 1.21; 95% CI 1.06-1.37; p = 4.0 x 10(-3)), and also for waist circumference and other anthropometric variables. Our study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely mediated through BMI. This could imply underlying differences between Indians and Europeans in the mechanisms linking body size with type 2 diabetes.

The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry.

PubMed

Deliard, Sandra; Panossian, Saarene; Mentch, Frank D; Kim, Cecilia E; Hou, Cuiping; Frackelton, Edward C; Bradfield, Jonathan P; Glessner, Joseph T; Zhang, Haitao; Wang, Kai; Sleiman, Patrick M A; Chiavacci, Rosetta M; Berkowitz, Robert I; Hakonarson, Hakon; Zhao, Jianhua; Grant, Struan F A

2013-01-01

Common variation at the loci harboring fat mass and obesity (FTO), melanocortin receptor 4 (MC4R), and transmembrane protein 18 (TMEM18) is consistently reported as being statistically most strongly associated with obesity. Investigations if these loci also harbor rarer missense variants that confer substantially higher risk of common childhood obesity in African American (AA) children were conducted. The exons of FTO, MC4R, and TMEM18 in an initial subset of our cohort were sequenced, that is, 200 obese (BMI ≥ 95 th percentile) and 200 lean AA children (BMI ≤ 5 th percentile). Any missense exonic variants that were uncovered went on to be further genotyped in a further 768 obese and 768 lean (BMI≤50th percentile) children of the same ethnicity. A number of exonic variants were observed from our sequencing effort: seven in FTO, of which four were non-synonymous (A163T, G182A, M400V, and A405V), thirteen in MC4R, of which six were non-synonymous (V103I, N123S, S136A, F202L, N240S, and I251L), and four in TMEM18, of which two were non-synonymous (P2S and V113L). Follow-up genotyping of these missense variants revealed only one significant difference in allele frequency between cases and controls, namely with N240S in MC4R (Fisher's exact P = 0.0001). In summary, moderately rare missense variants within the FTO, MC4R, and TMEM18 genes observed in our study did not confer risk of common childhood obesity in African Americans except for a degree of evidence for one known loss-of-function variant in MC4R. Copyright © 2012 The Obesity Society.

Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals†

PubMed Central

Rivera, Margarita; Locke, Adam E.; Corre, Tanguy; Czamara, Darina; Wolf, Christiane; Ching-Lopez, Ana; Milaneschi, Yuri; Kloiber, Stefan; Cohen-Woods, Sara; Rucker, James; Aitchison, Katherine J.; Bergmann, Sven; Boomsma, Dorret I.; Craddock, Nick; Gill, Michael; Holsboer, Florian; Hottenga, Jouke-Jan; Korszun, Ania; Kutalik, Zoltan; Lucae, Susanne; Maier, Wolfgang; Mors, Ole; Müller-Myhsok, Bertram; Owen, Michael J.; Penninx, Brenda W. J. H.; Preisig, Martin; Rice, John; Rietschel, Marcella; Tozzi, Federica; Uher, Rudolf; Vollenweider, Peter; Waeber, Gerard; Willemsen, Gonneke; Craig, Ian W.; Farmer, Anne E.; Lewis, Cathryn M.; Breen, Gerome; McGuffin, Peter

2017-01-01

Background Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity. Aims To confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis. Method The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT. Results In the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β = 0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO. Conclusions This meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression. PMID:28642257

FTO polymorphisms moderate the association of food reinforcement with energy intake.

PubMed

Scheid, Jennifer L; Carr, Katelyn A; Lin, Henry; Fletcher, Kelly D; Sucheston, Lara; Singh, Prashant K; Salis, Robbert; Erbe, Richard W; Faith, Myles S; Allison, David B; Epstein, Leonard H

2014-06-10

Food reinforcement (RRVfood) is related to increased energy intake, cross-sectionally related to obesity, and prospectively related to weight gain. The fat mass and obesity-associated (FTO) gene is related to elevated body mass index and increased energy intake. The primary purpose of the current study was to determine whether any of 68 FTO single nucleotide polymorphisms (SNPs) or a FTO risk score moderate the association between food reinforcement and energy or macronutrient intake. Energy and macronutrient intake was measured using a laboratory ad libitum snack food consumption task in 237 adults of varying BMI. Controlling for BMI, the relative reinforcing value of reading (RRVreading) and proportion of African ancestry, RRVfood predicted 14.2% of the variance in energy intake, as well as predicted carbohydrate, fat, protein and sugar intake. In individual analyses, six FTO SNPs (rs12921970, rs9936768, rs12446047, rs7199716, rs8049933 and rs11076022, spanning approximately 251kbp) moderated the relationship between RRVfood and energy intake to predict an additional 4.9-7.4% of variance in energy intake. We created an FTO risk score based on 5 FTO SNPs (rs9939609, rs8050136, rs3751812, rs1421085, and rs1121980) that are related to BMI in multiple studies. The FTO risk score did not increase variance accounted for beyond individual FTO SNPs. rs12921970 and rs12446047 served as moderators of the relationship between RRVfood and carbohydrate, fat, protein, and sugar intake. This study shows for the first time that the relationship between RRVfood and energy intake is moderated by FTO SNPs. Research is needed to understand how these processes interact to predict energy and macronutrient intake. Copyright © 2014 Elsevier Inc. All rights reserved.

Macronutrients and the FTO gene expression in hypothalamus; a systematic review of experimental studies.

PubMed

Doaei, Saeid; Kalantari, Naser; Mohammadi, Nastaran Keshavarz; Tabesh, Ghasem Azizi; Gholamalizadeh, Maryam

The various studies have examined the relationship between FTO gene expression and macronutrients levels. In order to obtain better viewpoint from this interactions, all of existing studies were reviewed systematically. All published papers have been obtained and reviewed using standard and sensitive keywords from databases such as CINAHL, Embase, PubMed, PsycInfo, and the Cochrane, from 1990 to 2016. The results indicated that all of 6 studies that met the inclusion criteria (from a total of 428 published article) found FTO gene expression changes at short-term follow-ups. Four of six studies found an increased FTO gene expression after calorie restriction, while two of them indicated decreased FTO gene expression. The effect of protein, carbohydrate and fat were separately assessed and suggested by all of six studies. In Conclusion, The level of FTO gene expression in hypothalamus is related to macronutrients levels. Future research should evaluate the long-term impact of dietary interventions. Copyright © 2017. Published by Elsevier B.V.

Dietary fatty acid distribution modifies obesity risk linked to the rs9939609 polymorphism of the fat mass and obesity-associated gene in a Spanish case-control study of children.

PubMed

Moleres, Adriana; Ochoa, M Carmen; Rendo-Urteaga, Tara; Martínez-González, M Angel; Azcona San Julián, M Cristina; Martínez, J Alfredo; Marti, Amelia

2012-02-01

The rs9939609 polymorphism of the fat mass and obesity-associated (FTO) gene has been widely associated with childhood obesity in several European cohorts. This association appears to be dependent on dietary macronutrients. Therefore, the aim of the present study was to evaluate whether dietary fatty acid intake distribution could interact with this FTO genetic variation and obesity in a Spanish case-control study of children and adolescents. A total of 354 Spanish children and adolescents aged 6-18 years (49 % males) were genotyped for the rs9939609 variant of the FTO gene. Anthropometric parameters were taken and energy intake was measured. We observed an interaction between the consumption of SFA (percentage of total energy) and PUFA:SFA ratio and obesity risk linked to the rs9939609 SNP of the FTO gene. In the study population of the present study, the risk allele carriers consuming more than 12·6 % SFA (of total energy) had an increased obesity risk compared with TT carriers. In a similar way, A allele carriers with an intake ratio lower than 0·43 PUFA:SFA presented a higher obesity risk than TT subjects. In summary, the present study reports for the first time the influence of dietary fatty acid distribution on the effect of the rs9939609 polymorphism of the FTO gene on children and adolescents' obesity risk.

Physical activity attenuates the effect of the FTO genotype on obesity traits in European adults: The Food4Me study.

PubMed

Celis-Morales, Carlos; Marsaux, Cyril F M; Livingstone, Katherine M; Navas-Carretero, Santiago; San-Cristobal, Rodrigo; O'donovan, Clare B; Forster, Hannah; Woolhead, Clara; Fallaize, Rosalind; Macready, Anna L; Kolossa, Silvia; Hallmann, Jacqueline; Tsirigoti, Lydia; Lambrinou, Christina P; Moschonis, George; Godlewska, Magdalena; Surwiłło, Agnieszka; Grimaldi, Keith; Bouwman, Jildau; Manios, Yannis; Traczyk, Iwona; Drevon, Christian A; Parnell, Laurence D; Daniel, Hannelore; Gibney, Eileen R; Brennan, Lorraine; Walsh, Marianne C; Gibney, Mike; Lovegrove, Julie A; Martinez, J Alfredo; Saris, Wim H M; Mathers, John C

2016-04-01

To examine whether the effect of FTO loci on obesity-related traits could be modified by physical activity (PA) levels in European adults. Of 1,607 Food4Me participants randomized, 1,280 were genotyped for FTO (rs9939609) and had available PA data. PA was measured objectively using accelerometers (TracmorD, Philips), whereas anthropometric measures [BMI and waist circumference (WC)] were self-reported via the Internet. FTO genotype was associated with a higher body weight [β: 1.09 kg per risk allele, (95% CI: 0.14-2.04), P = 0.024], BMI [β: 0.54 kg m(-2) , (0.23-0.83), P < 0.0001], and WC [β: 1.07 cm, (0.24-1.90), P = 0.011]. Moderate-equivalent PA attenuated the effect of FTO on BMI (P[interaction]  = 0.020). Among inactive individuals, FTO increased BMI by 1.06 kg m(-2) per allele (P = 0.024), whereas the increase in BMI was substantially attenuated among active individuals (0.16 kg m(-2) , P = 0.388). We observed similar effects for WC (P[interaction]  = 0.005): the FTO risk allele increased WC by 2.72 cm per allele among inactive individuals but by only 0.49 cm in active individuals. PA attenuates the effect of FTO genotype on BMI and WC. This may have important public health implications because genetic susceptibility to obesity in the presence of FTO variants may be reduced by adopting a physically active lifestyle. © 2016 The Obesity Society.

Impact of variation at the FTO locus on milk fat yield in Holstein dairy cattle.

PubMed

Zielke, Lea G; Bortfeldt, Ralf H; Reissmann, Monika; Tetens, Jens; Thaller, Georg; Brockmann, Gudrun A

2013-01-01

This study explores the biological role of the Fat Mass and Obesity associated (FTO) gene locus on milk composition in German Holstein cattle. Since FTO controls energy homeostasis and expenditure and the FTO locus has repeatedly shown association with obesity in human studies, we tested FTO as a candidate gene in particular for milk fat yield, which represents a high amount of energy secreted during lactation. The study was performed on 2,402 bulls and 860 cows where dense milk composition data were available. Genetic information was taken from a 2 Mb region around FTO. Five SNPs and two haplotype blocks in a 725 kb region covering FTO and the neighboring genes RPGRIP1L, U6ATAC, and 5 S rRNA were associated with milk fat yield and also affected protein yield in the same direction. Interestingly, higher frequency SNP alleles and haplotypes within the FTO gene increased milk fat and protein yields by up to 2.8 and 2.2 kg per lactation, respectively, while the most frequent haplotype in the upstream block covering exon 1 of FTO to exon 15 of RPGRIP1L had opposite effects with lower fat and milk yield. Both haplotype blocks were also significant in cows. The loci accounted for about 1% of the corresponding trait variance in the population. The association signals not only provided evidence for at least two causative mutations in the FTO locus with a functional effect on milk but also milk protein yield. The pleiotropic effects suggest a biological function on the usage of energy resources and the control of energy balance rather than directly affecting fat and protein synthesis. The identified effect of the obesity gene locus on milk energy content suggests an impact on infant nutrition by breast feeding in humans.

Impact of Variation at the FTO Locus on Milk Fat Yield in Holstein Dairy Cattle

PubMed Central

Zielke, Lea G.; Bortfeldt, Ralf H.; Reissmann, Monika; Tetens, Jens; Thaller, Georg; Brockmann, Gudrun A.

2013-01-01

This study explores the biological role of the Fat Mass and Obesity associated (FTO) gene locus on milk composition in German Holstein cattle. Since FTO controls energy homeostasis and expenditure and the FTO locus has repeatedly shown association with obesity in human studies, we tested FTO as a candidate gene in particular for milk fat yield, which represents a high amount of energy secreted during lactation. The study was performed on 2,402 bulls and 860 cows where dense milk composition data were available. Genetic information was taken from a 2 Mb region around FTO. Five SNPs and two haplotype blocks in a 725 kb region covering FTO and the neighboring genes RPGRIP1L, U6ATAC, and 5 S rRNA were associated with milk fat yield and also affected protein yield in the same direction. Interestingly, higher frequency SNP alleles and haplotypes within the FTO gene increased milk fat and protein yields by up to 2.8 and 2.2 kg per lactation, respectively, while the most frequent haplotype in the upstream block covering exon 1 of FTO to exon 15 of RPGRIP1L had opposite effects with lower fat and milk yield. Both haplotype blocks were also significant in cows. The loci accounted for about 1% of the corresponding trait variance in the population. The association signals not only provided evidence for at least two causative mutations in the FTO locus with a functional effect on milk but also milk protein yield. The pleiotropic effects suggest a biological function on the usage of energy resources and the control of energy balance rather than directly affecting fat and protein synthesis. The identified effect of the obesity gene locus on milk energy content suggests an impact on infant nutrition by breast feeding in humans. PMID:23691044

Lifestyle Interaction With Fat Mass and Obesity-Associated (FTO) Genotype and Risk of Obesity in Apparently Healthy U.S. Women

PubMed Central

Ahmad, Tariq; Lee, I-Min; Paré, Guillaume; Chasman, Daniel I.; Rose, Lynda; Ridker, Paul M.; Mora, Samia

2011-01-01

OBJECTIVE Variation in the fat mass and obesity-associated (FTO) gene is associated with obesity. The extent to which separate and combined effects of physical activity and caloric intake modify this association remains unclear. RESEARCH DESIGN AND METHODS FTO polymorphism rs8050136 was measured, and physical activity, caloric intake, and anthropometrics were self-reported in 21,675 apparently healthy Caucasian women. RESULTS The effect of the risk allele (A) on BMI was larger among inactive or higher intake women, with additive effects of inactivity and high intake on the associated genetic risk. Specifically, each A allele was associated with mean BMI difference of +0.73 (SE 0.08) kg/m2 among inactive women (≤median, 8.8 MET-hours/week), compared with +0.31 (0.06) kg/m2, P < 0.0001, among active women (>8.8 MET-hours/week). Similarly, each A allele was associated with mean BMI difference of +0.65 (0.07) among high intake women (>median, 1,679 kcals/day), compared with +0.38 (0.07) kg/m2, P = 0.005, among low intake women (≤1,679 kcals/day). Among inactive/high intake women, each A allele was associated with mean BMI difference of +0.97 (0.11) kg/m2 vs. +0.22 (0.08) kg/m2 among inactive/low intake women, P < 0.0001. Among inactive/high intake women, each A allele carried increased risk of obesity (odds ratio 1.39, 95% CI 1.27–1.52) and diabetes (odds ratio 1.36, 95% CI 1.07–1.73). CONCLUSIONS In this study, lifestyle factors modified the genetic risk of FTO on obesity phenotypes, particularly among women who were both inactive and had high intake. Healthier lifestyle patterns blunted but did not completely eliminate the associated genetic risk. PMID:21266646

Influence of FTO rs9939609 polymorphism on appetite, ghrelin, leptin, IL6, TNFα levels, and food intake of women with morbid obesity.

PubMed

Magno, Fernanda Cristina Carvalho Mattos; Guaraná, Helena Chrispim; Fonseca, Ana Carolina Proença; Cabello, Giselda Maria Kalil; Carneiro, João Régis Ivar; Pedrosa, Aline Pereira; Ximenes, Ana Carolina; Rosado, Eliane Lopes

2018-01-01

The fat mass and obesity-related ( FTO ) gene has a strong relationship with obesity, extreme obesity and inflammatory state, and may also be associated with food intake regulation. The aim of the present study was to evaluate the influence of the rs9939609 single-nucleotide polymorphism of the FTO gene on appetite, ghrelin, leptin, interleukin 6 (IL6), tumor necrosis factor α (TNFα) levels and food intake of morbidly obese women. The study comprised 70 women, aged between 20 and 48 years, from Rio de Janeiro, Brazil. The participants were selected according to the body mass index between 40 and 60 kg/m 2 . Anthropometric and biochemical data were measured during fasting. Hormones and inflammatory data were measured before and after the participants ate an isocaloric meal. Dietary records were calculated and analyzed using a nutritional assessment program. Visual analog scales were used for behaviors of the sensations of appetite and food preferences. The FTO rs9939609 variant was genotyped using real-time polymerase chain reaction. Participants with the AA genotype had lower values of ghrelin and IL6 and higher values of leptin than those with TT and TA in the postprandial period. Comparing the plasma concentrations of ghrelin, insulin, IL6 and TNFα intragenotypes, it was observed that those with TT had decreased leptin and increased IL6 at the postprandial period. Subjects with TA showed increased postprandial IL6, and those with AA had decreased postprandial ghrelin. There was no difference in TNFα intra- and intergenotypes. The postprandial sensations of hunger were lower in AA than those with TT. There were differences between genotypes regarding ingested grams of protein by weight, cholesterol, B3, B5, B6 and B12 vitamins, and selenium potassium and sodium minerals. These findings suggest that genetics may exert an influence on physiologic factors and might alter eating behavior.

Differences in body mass index according to fat mass- and obesity-associated (FTO) genotype in Mexican patients with bipolar disorder.

PubMed

Díaz-Anzaldúa, Adriana; Ocampo-Mendoza, Yolanda; Hernández-Lagunas, José Octavio; Díaz-Madrid, Federico Alejandro; Romo-Nava, Francisco; Juárez-García, Francisco; Ortega-Ortiz, Hiram; Díaz-Anzaldúa, Alejandro; Gutiérrez-Mora, Doris; Becerra-Palars, Claudia; Berlanga-Cisneros, Carlos

2015-09-01

The prevalence of obesity has dramatically increased in many countries and it is particularly high in patients with bipolar disorder (BD). A region in the first intron of the fat mass- and obesity-associated (FTO) gene, encompassing markers rs9939973, rs8050136, and rs9939609, has been consistently associated with obesity and body mass index (BMI) in different populations. We sought to determine whether FTO is associated with BMI and/or obesity in patients with BD. The sample included 129 Mexican Mestizo patients with bipolar I or bipolar II disorder. After obtaining informed consent, participants were evaluated with the Structured Clinical Interview for DSM-IV Axis I Disorders and weight, height, and body measurements were recorded. DNA was extracted from a 5-mL blood sample and real-time polymerase chain reaction was performed. The results were analyzed with Haploview v4.2 and SPSS v21. Differences in mean BMI were explained by rs8050136 and rs9939609 genotypes, especially by comparing non-carriers and carriers of two copies of the risk allele (Tukey's p ≤ 0.019), with a mean difference in BMI as high as 7.81 kg/m(2) . Differences in BMI were also explained by the interaction of the genotype (rs8050136 and/or rs9939609), the use of second-generation antipsychotics, and the use of mood stabilizers (p ≤ 0.41). Obesity was also associated with these two markers when patients with and without obesity were compared. In patients with BD, differences in BMI may be affected by the presence of FTO risk alleles, especially in homozygous individuals for these variants. Besides evaluating the possible metabolic effects of certain antipsychotics or mood stabilizers, it is important to evaluate the role of other factors such as FTO risk alleles. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Impact of obesity-related gene polymorphism on risk of obesity and metabolic disorder in childhood].

PubMed

Zhang, Meixian; Zhao, Xiaoyuan; Xi, Bo; Shen, Yue; Wu, Lijun; Cheng, Hong; Hou, Dongqing; Mi, Jie

2014-09-01

To examine the impact of single nucleotide polymorphisms in obesity-related genes on risk of obesity and metabolic disorder in childhood. A total of 3 503 Chinese children aged 6 to 18 years participated in the study, including 1 229 obese, 655 overweight and 1 619 normal weight children (diagnosed by the Chinese age- and sex- specific BMI cutoffs). Body size parameters were assessed and venipuncture blood samples were collected after a 12-hour overnight fast. Plasma glucose, insulin and serum lipid profiles were measured.Genomic DNA was isolated from peripheral blood white cells using the salt fractionation method. A total of 11 single nucleotide polymorphisms were genotyped by TaqMan allelic discrimination assays with the GeneAmp 7900 sequence detection system (Applied Biosystems, Foster City, CA, USA) (FTO rs9939609, MC4R rs17782313, GNPDA2 rs10938397, FAIM2 rs7138803, BDNF rs6265, NPC1 rs1805081, PCSK1 rs6235, KCTD15 rs29941, BAT2 rs2844479, SEC16B rs10913469 and SH2B1 rs4788102). Multiple factor analysis was performed to estimate the association between the variant and obesity-related traits. The false discovery rate (FDR) approach was used to correct for multiple comparisons. After sex, age and pubertal stage adjustment and correction for multiple testing, the rs9939609-A, rs17782313-C, rs10938397-G, and rs7138803-A alleles were associated with higher BMI (β = 0.352-0.747), fat mass percentage(β = 0.568-1.113), waist circumference (β = 0.885-1.649) and waist-to-height ratio(β = 0.005-0.010) (all P values < 0.01) in Chinese children. The rs6265-G allele increased BMI(β = 0.251, P = 0.020). The rs9939609-A, rs17782313-C, and rs10938397-G and rs6265-G alleles were also associated with risk of obesity (OR = 1.386, 95%CI:1.171-1.642; OR = 1.367, 95%CI:1.196-1.563; OR = 1.242, 95%CI:1.102-1.400; OR = 1.156, 95%CI:1.031-1.296).Rs7138803 was associated with risk of obesity only in boys (OR = 1.234, 95%CI:1.043-1.460). GNPDA2 rs10938397-G allele was associated

Fat mass and obesity associated (FTO) gene influences skeletal muscle phenotypes in non-resistance trained males and elite rugby playing position.

PubMed

Heffernan, S M; Stebbings, G K; Kilduff, L P; Erskine, R M; Day, S H; Morse, C I; McPhee, J S; Cook, C J; Vance, B; Ribbans, W J; Raleigh, S M; Roberts, C; Bennett, M A; Wang, G; Collins, M; Pitsiladis, Y P; Williams, A G

2017-01-19

FTO gene variants have been associated with obesity phenotypes in sedentary and obese populations, but rarely with skeletal muscle and elite athlete phenotypes. In 1089 participants, comprising 530 elite rugby athletes and 559 non-athletes, DNA was collected and genotyped for the FTO rs9939609 variant using real-time PCR. In a subgroup of non-resistance trained individuals (NT; n = 120), we also assessed structural and functional skeletal muscle phenotypes using dual energy x-ray absorptiometry, ultrasound and isokinetic dynamometry. In a subgroup of rugby athletes (n = 77), we assessed muscle power during a countermovement jump. In NT, TT genotype and T allele carriers had greater total body (4.8% and 4.1%) and total appendicular lean mass (LM; 3.0% and 2.1%) compared to AA genotype, with greater arm LM (0.8%) in T allele carriers and leg LM (2.1%) for TT, compared to AA genotype. Furthermore, the T allele was more common (94%) in selected elite rugby union athletes (back three and centre players) who are most reliant on LM rather than total body mass for success, compared to other rugby athletes (82%; P = 0.01, OR = 3.34) and controls (84%; P = 0.03, OR = 2.88). Accordingly, these athletes had greater peak power relative to body mass than other rugby athletes (14%; P = 2 x 10 -6 ). Collectively, these results suggest that the T allele is associated with increased LM and elite athletic success. This has implications for athletic populations, as well as conditions characterised by low LM such as sarcopenia and cachexia.

Expression of fourteen novel obesity-related genes in Zucker diabetic fatty rats.

PubMed

Schmid, Peter M; Heid, Iris; Buechler, Christa; Steege, Andreas; Resch, Markus; Birner, Christoph; Endemann, Dierk H; Riegger, Guenter A; Luchner, Andreas

2012-07-13

Genome-wide association studies (GWAS) are useful to reveal an association between single nucleotide polymorphisms and different measures of obesity. A multitude of new loci has recently been reported, but the exact function of most of the according genes is not known. The aim of our study was to start elucidating the function of some of these genes. We performed an expression analysis of fourteen genes, namely BDNF, ETV5, FAIM2, FTO, GNPDA2, KCTD15, LYPLAL1, MCR4, MTCH2, NEGR1, NRXN3, TMEM18, SEC16B and TFAP2B, via real-time RT-PCR in adipose tissue of the kidney capsule, the mesenterium and subcutaneum as well as the hypothalamus of obese Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats at an age of 22 weeks. All of our target genes except for SEC16B showed the highest expression in the hypothalamus. This suggests a critical role of these obesity-related genes in the central regulation of energy balance. Interestingly, the expression pattern in the hypothalamus showed no differences between obese ZDF and lean ZL rats. However, LYPLAL1, TFAP2B, SEC16B and FAIM2 were significantly lower expressed in the kidney fat of ZDF than ZL rats. NEGR1 was even lower expressed in subcutaneous and mesenterial fat, while MTCH2 was higher expressed in the subcutaneous and mesenterial fat of ZDF rats. The expression pattern of the investigated obesity genes implies for most of them a role in the central regulation of energy balance, but for some also a role in the adipose tissue itself. For the development of the ZDF phenotype peripheral rather than central mechanisms of the investigated genes seem to be relevant.

Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children

PubMed Central

Kilpeläinen, Tuomas O.; Qi, Lu; Brage, Soren; Sharp, Stephen J.; Sonestedt, Emily; Demerath, Ellen; Ahmad, Tariq; Mora, Samia; Kaakinen, Marika; Sandholt, Camilla Helene; Holzapfel, Christina; Autenrieth, Christine S.; Hyppönen, Elina; Cauchi, Stéphane; He, Meian; Kutalik, Zoltan; Kumari, Meena; Stančáková, Alena; Meidtner, Karina; Balkau, Beverley; Tan, Jonathan T.; Mangino, Massimo; Timpson, Nicholas J.; Song, Yiqing; Zillikens, M. Carola; Jablonski, Kathleen A.; Garcia, Melissa E.; Johansson, Stefan; Bragg-Gresham, Jennifer L.; Wu, Ying; van Vliet-Ostaptchouk, Jana V.; Onland-Moret, N. Charlotte; Zimmermann, Esther; Rivera, Natalia V.; Tanaka, Toshiko; Stringham, Heather M.; Silbernagel, Günther; Kanoni, Stavroula; Feitosa, Mary F.; Snitker, Soren; Ruiz, Jonatan R.; Metter, Jeffery; Larrad, Maria Teresa Martinez; Atalay, Mustafa; Hakanen, Maarit; Amin, Najaf; Cavalcanti-Proença, Christine; Grøntved, Anders; Hallmans, Göran; Jansson, John-Olov; Kuusisto, Johanna; Kähönen, Mika; Lutsey, Pamela L.; Nolan, John J.; Palla, Luigi; Pedersen, Oluf; Pérusse, Louis; Renström, Frida; Scott, Robert A.; Shungin, Dmitry; Sovio, Ulla; Tammelin, Tuija H.; Rönnemaa, Tapani; Lakka, Timo A.; Uusitupa, Matti; Rios, Manuel Serrano; Ferrucci, Luigi; Bouchard, Claude; Meirhaeghe, Aline; Fu, Mao; Walker, Mark; Borecki, Ingrid B.; Dedoussis, George V.; Fritsche, Andreas; Ohlsson, Claes; Boehnke, Michael; Bandinelli, Stefania; van Duijn, Cornelia M.; Ebrahim, Shah; Lawlor, Debbie A.; Gudnason, Vilmundur; Harris, Tamara B.; Sørensen, Thorkild I. A.; Mohlke, Karen L.; Hofman, Albert; Uitterlinden, André G.; Tuomilehto, Jaakko; Lehtimäki, Terho; Raitakari, Olli; Isomaa, Bo; Njølstad, Pål R.; Florez, Jose C.; Liu, Simin; Ness, Andy; Spector, Timothy D.; Tai, E. Shyong; Froguel, Philippe; Boeing, Heiner; Laakso, Markku; Marmot, Michael; Bergmann, Sven; Power, Chris; Khaw, Kay-Tee; Chasman, Daniel; Ridker, Paul; Hansen, Torben; Monda, Keri L.; Illig, Thomas; Järvelin, Marjo-Riitta; Wareham, Nicholas J.; Hu, Frank B.; Groop, Leif C.; Orho-Melander, Marju; Ekelund, Ulf; Franks, Paul W.; Loos, Ruth J. F.

2011-01-01

Background The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings All studies identified to have data on the FTO rs9939609 variant (or any proxy [r 2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (p interaction  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents. Conclusions The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors' Summary PMID:22069379

Association of adenovirus 36 infection with obesity-related gene variants in adolescents.

PubMed

Dušátková, L; Zamrazilová, H; Aldhoon Hainerová, I; Atkinson, R L; Sedláčková, B; Lee, Z P; Včelák, J; Bendlová, B; Kunešová, M; Hainer, V

2015-01-01

Both, common gene variants and human adenovirus 36 (Adv36) are involved in the pathogenesis of obesity. The potential relationship between these two pathogenic factors has not yet been investigated. The aim of our study was to examine the association of obesity susceptibility loci with Adv36 status. Genotyping of ten gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, FTO) and analysis of Adv36 antibodies was performed in 1,027 Czech adolescents aged 13.0-17.9 years. Variants of two genes (PCSK1 and BDNF) were associated with Adv36 seropositivity. A higher prevalence of Adv36 antibody positivity was observed in obesity risk allele carriers of PCSK1 rs6232, rs6235 and BDNF rs4923461 vs. non-carriers (chi(2)=6.59, p=0.010; chi(2)=7.56, p=0.023 and chi(2)=6.84, p=0.033, respectively). The increased risk of Adv36 positivity was also found in PCSK1 variants: rs6232 (OR=1.67, 95 % CI 1.11-2.49, p=0.016) and rs6235 (OR=1.34, 95 % CI 1.08-1.67, p=0.010). PCSK1 rs6232 and BDNF rs925946 variants were closely associated with Adv36 status in boys and girls, respectively (chi(2)=5.09, p=0.024; chi(2)=7.29, p=0.026). Furthermore, PCSK1 rs6235 risk allele was related to Adv36 seropositivity (chi(2)=6.85, p=0.033) in overweight/obese subgroup. In conclusion, our results suggest that obesity risk variants of PCSK1 and BDNF genes may be related to Adv36 infection.

[Gene-gene interaction on central obesity in school-aged children in China].

PubMed

Fu, L W; Zhang, M X; Wu, L J; Gao, L W; Mi, J

2017-07-10

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

Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.

PubMed

Osborn, Daniel P S; Roccasecca, Rosa Maria; McMurray, Fiona; Hernandez-Hernandez, Victor; Mukherjee, Sriparna; Barroso, Inês; Stemple, Derek; Cox, Roger; Beales, Philip L; Christou-Savina, Sonia

2014-01-01

Common intronic variants in the Human fat mass and obesity-associated gene (FTO) are found to be associated with an increased risk of obesity. Overexpression of FTO correlates with increased food intake and obesity, whilst loss-of-function results in lethality and severe developmental defects. Despite intense scientific discussions around the role of FTO in energy metabolism, the function of FTO during development remains undefined. Here, we show that loss of Fto leads to developmental defects such as growth retardation, craniofacial dysmorphism and aberrant neural crest cells migration in Zebrafish. We find that the important developmental pathway, Wnt, is compromised in the absence of FTO, both in vivo (zebrafish) and in vitro (Fto(-/-) MEFs and HEK293T). Canonical Wnt signalling is down regulated by abrogated β-Catenin translocation to the nucleus whilst non-canonical Wnt/Ca(2+) pathway is activated via its key signal mediators CaMKII and PKCδ. Moreover, we demonstrate that loss of Fto results in short, absent or disorganised cilia leading to situs inversus, renal cystogenesis, neural crest cell defects and microcephaly in Zebrafish. Congruently, Fto knockout mice display aberrant tissue specific cilia. These data identify FTO as a protein-regulator of the balanced activation between canonical and non-canonical branches of the Wnt pathway. Furthermore, we present the first evidence that FTO plays a role in development and cilia formation/function.

Macronutrient-specific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans.

PubMed

Grau, K; Hansen, T; Holst, C; Astrup, A; Saris, W H M; Arner, P; Rössner, S; Macdonald, I; Polak, J; Oppert, J-M; Langin, D; Martinez, J A; Pedersen, O; Sørensen, T I A

2009-11-01

The A risk allele of rs9939609 of the fat mass- and obesity-associated gene (FTO) increases body fat mass. To examine whether FTO rs9939609 affects obese individuals' response to a high-fat, low-carbohydrate (CHO) (HF) or low-fat, high-CHO (LF), hypo-energetic diet and whether the effect of the FTO variant depends on dietary fat and CHO content. In a 10-week, European, multi-centre dietary intervention study 771 obese women and men were randomized to either LF (20-25% of energy (%E) from fat, 60-65%E from CHO) or HF (40-45%E from fat, 40-45%E from CHO), hypo-energetic diet (measured resting metabolic rate multiplied by 1.3-600 kcal day(-1)). Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation as % of REE (FatOx), insulin release (HOMA-beta) and a surrogate measure of insulin resistance (HOMA-IR) were measured at baseline and after the intervention. In all, 764 individuals were genotyped for FTO rs9939609. For A-allele carriers the drop-out rate was higher on HF than LF diet (in AT, P=0.002; in AT/AA combined, P=0.003). Among those individuals completing the intervention, we found no effect of FTO rs9939609 genotype on Deltaweight, DeltaFM, DeltaFFM, DeltaWC or DeltaFatOx. However, participants with TT had a smaller reduction in REE on LF than on HF diet (75 kcal/24 h; interaction: P=0.0055). These individuals also showed the greatest reduction in HOMA-beta and HOMA-IR (interaction: P=0.0083 and P=0.047). The FTO rs9939609 may interact with the macronutrient composition in weight loss diets in various ways; carriers of the A allele on LF diet appear to have a lower risk for drop out, and TT individuals have a smaller decrease in REE and greater decrease in HOMA-beta and HOMA-IR on LF than on HF diet.

No association between FTO or HHEX andendometrial cancer risk

PubMed Central

Gaudet, Mia M.; Yang, Hannah P.; Bosquet, Jesus Gonzalez; Healey, Catherine S.; Ahmed, Shahana; Dunning, Alison M.; Easton, Doug F.; Spurdle, Amanda B.; Ferguson, Kaltin; O’Mara, Tracy; Group, ANECS; Lambrechts, Diether; Despierre, Evelyn; Vergote, Ignace; Amant, Frederic; Lacey, James V.; Lissowska, Jola; Peplonska, Beata; Brinton, Louise A.; Chanock, Stephen; Garcia-Closas, Montserrat

2010-01-01

Introduction Obesity and diabetes are known risk factors for endometrial cancer; thus genetic risk factors of these phenotypes may also be associated with endometrial cancer risk. To evaluate this hypothesis, we genotyped tagSNPs and candidate SNPs in FTO and HHEX in a primary set of 417 endometrial cancer cases and 406 population-based controls, and validated significant findings in a replication set of approximately 2,347 cases and 3,140 controls from three additional studies. Methods We genotyped 189 tagSNPs in FTO (including rs8050136) and five tagSNPs in HHEX (including rs1111875) in the primary set and one SNP in each of FTO (rs12927155) and HHEX (rs1111875) in the validation set. Per allele odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the association between the genotypes of each SNPs(as an ordinal variable)and endometrial cancer risk using unconditional logistic regression models, controlling for age and site. Results In the primary study, the most significant findings in FTO was rs12927155 (OR=1.56, 95% CI 1.21–2.01, p=5.8×10−4) and HHEX was rs1111875 (OR=0.80, 95% CI 0.66–0.97; p=0.026). In the validation studies, the pooled per allele ORs, adjusted for age and study, were for FTO rs12927155: OR=0.94, 95% CI 0.83–1.06, p=0.29 and for HHEX rs1111875: OR=1.00, 95%CI 0.92–1.10, p=0.96. Conclusion Our data indicate that common genetic variants in two genes previously related to obesity (FTO) and diabetes (HHEX) by genome-wide association scans are not associatedwith endometrial cancer risk. Impact Polymorphisms in FTO and HHEX are unlikely to have large effects on endometrial cancer risk but may have weaker effects. PMID:20647405

Gene-Diet Interactions in Childhood Obesity

PubMed Central

Garver, William S

2011-01-01

Childhood overweight and obesity have reached epidemic proportions worldwide, and the increase in weight-associated co-morbidities including premature type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease will soon become major healthcare and economic problems. A number of studies now indicate that the childhood obesity epidemic which has emerged during the past 30 years is a complex multi-factorial disease resulting from interaction of susceptibility genes with an obesogenic environment. This review will focus on gene-diet interactions suspected of having a prominent role in promoting childhood obesity. In particular, the specific genes that will be presented (FTO, MC4R, and NPC1) have recently been associated with childhood obesity through a genome-wide association study (GWAS) and were shown to interact with nutritional components to increase weight gain. Although a fourth gene (APOA2) has not yet been associated with childhood obesity, this review will also present information on what now represents the best characterized gene-diet interaction in promoting weight gain. PMID:22043166

Interaction between FTO rs9939609 and the Native American-origin ABCA1 rs9282541 affects BMI in the admixed Mexican population.

PubMed

Villalobos-Comparán, Marisela; Antuna-Puente, Bárbara; Villarreal-Molina, María Teresa; Canizales-Quinteros, Samuel; Velázquez-Cruz, Rafael; León-Mimila, Paola; Villamil-Ramírez, Hugo; González-Barrios, Juan Antonio; Merino-García, José Luis; Thompson-Bonilla, María Rocío; Jarquin, Diego; Sánchez-Hernández, Osvaldo Erik; Rodríguez-Arellano, Martha Eunice; Posadas-Romero, Carlos; Vargas-Alarcón, Gilberto; Campos-Pérez, Francisco; Quiterio, Manuel; Salmerón-Castro, Jorge; Carnevale, Alessandra; Romero-Hidalgo, Sandra

2017-05-02

The aim of this study was to explore whether interactions between FTO rs9939609 and ABCA1 rs9282541 affect BMI and waist circumference (WC), and could explain previously reported population differences in FTO-obesity and FTO-BMI associations in the Mexican and European populations. A total of 3938 adults and 636 school-aged children from Central Mexico were genotyped for both polymorphisms. Subcutaneous and visceral adipose tissue biopsies from 22 class III obesity patients were analyzed for FTO and ABCA1 mRNA expression. Generalized linear models were used to test for associations and gene-gene interactions affecting BMI, WC and FTO expression. FTO and ABCA1 risk alleles were not individually associated with higher BMI or WC. However, in the absence of the ABCA1 risk allele, the FTO risk variant was significantly associated with higher BMI (P = 0.043) and marginally associated with higher WC (P = 0.067), as reported in Europeans. The gene-gene interaction affecting BMI and WC was statistically significant only in adults. FTO mRNA expression in subcutaneous abdominal adipose tissue according to ABCA1 genotype was consistent with these findings. This is the first report showing evidence of FTO and ABCA1 gene variant interactions affecting BMI, which may explain previously reported population differences. Further studies are needed to confirm this interaction.

Association of the FTO fat mass and obesity-associated gene rs9939609 polymorphism with rewarding value of food and eating behavior in Chilean children.

PubMed

Obregón Rivas, Ana Maria; Santos, Jose L; Valladares, Macarena A; Cameron, Jameson; Goldfield, Gary

2018-03-27

The aim of this study was to assess the association between the single-nucleotide polymorphism rs9939609 in the FTO gene and homeostatic/non-homeostatic eating behavior patterns in Chilean children. A cross-sectional study was conducted in 258 children (44% female; 8-14 y of age). Anthropometric measurements (weight, height, Z-score of height, body mass index, and waist circumference) were performed. Eating behavior was assessed using the Eating in Absence of Hunger Questionnaire; the Child Eating Behavior Questionnaire; the Three Factor Eating Questionnaire, and the Food Reinforcement Value Questionnaire. Genotype of rs9939609 was determined by a Taqman assay. Association of rs9939609 with eating behavior was assessed using non-parametric tests. Allelic frequencies of rs9939609 were estimated as 77% for the A allele and 23% for the T allele. We found that normal-weight girl A carriers had higher scores of Satiety Responsiveness and Slowness on the Eating subscale. Normal-weight boy A carriers showed significantly higher scores on the Negative Affect and lower scores of the Desire to Drink subscale. In overweight children, A carriers showed higher scores on the Food Responsiveness, Emotional Overeating, Enjoyment of Food, and Food Choice subscales and lower scores on the Satiety- Responsiveness and Slowness in Eating subscales. In obese children, we found higher scores on the Cognitive Restrained subscale and lower Food Choice. The rs9939609 A allele of the FTO gene is associated with eating behavior traits and may predispose to obesity. Copyright © 2018 Elsevier Inc. All rights reserved.

FTO genotype, physical activity, and coronary heart disease risk in Swedish men and women.

PubMed

Gustavsson, Jaana; Mehlig, Kirsten; Leander, Karin; Lissner, Lauren; Björck, Lena; Rosengren, Annika; Nyberg, Fredrik

2014-04-01

Variants in the fat mass- and obesity-associated gene (FTO) predisposing to obesity and diabetes mellitus have also been associated with cardiovascular disease. Physical activity has been suggested to attenuate the FTO effect on obesity, but it is unknown whether this is also true for cardiovascular disease. Therefore, we explored whether physical activity modifies the FTO association with coronary heart disease (CHD). FTO rs9939609 (T>A) polymorphism was genotyped in 2 Swedish population-based case-control studies with 1743 CHD cases and 4402 population controls (25-74 years of age; 41% women). Leisure time physical activity was assessed by questionnaires, and 3 levels were defined: low, medium, and high. Overall, carriers of the FTO A allele had an increased risk of CHD (odds ratio, 1.20; 95% confidence interval, 1.06-1.37) adjusted for age, sex, study, and body mass index. Although A-allele carriers with low physical activity had the highest CHD risk (odds ratio, 3.30; 95% confidence interval, 2.44-4.46) compared with those with TT genotype and high activity, the effects of FTO genotype and physical activity on CHD risk were approximately additive, indicating the absence of additive interaction. The stratum-specific relative risks of CHD from the A allele in subjects with low, medium, and high physical activity were odds ratio 1.11 (95% confidence interval, 0.77-1.60), 1.22 (1.04-1.44), and 1.38 (1.06-1.80), respectively, but the suggested multiplicative interaction was not significant. FTO rs9939609 A-allele carriers have an increased CHD risk, and the association is not counteracted by increased physical activity.

Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases.

PubMed

Melnik, Bodo C

2015-12-21

Single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity-associated) gene are associated with enhanced FTO expression, increased body weight, obesity and type 2 diabetes mellitus (T2DM). The N (6) -methyladenosine (m(6)A) demethylase FTO plays a pivotal regulatory role for postnatal growth and energy expenditure. The purpose of this review is to provide translational evidence that links milk signaling with FTO-activated transcription of the milk recipient. FTO-dependent demethylation of m(6)A regulates mRNA splicing required for adipogenesis, increases the stability of mRNAs, and affects microRNA (miRNA) expression and miRNA biosynthesis. FTO senses branched-chain amino acids (BCAAs) and activates the nutrient sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), which plays a key role in translation. Milk provides abundant BCAAs and glutamine, critical components increasing FTO expression. CpG hypomethylation in the first intron of FTO has recently been associated with T2DM. CpG methylation is generally associated with gene silencing. In contrast, CpG demethylation generally increases transcription. DNA de novo methylation of CpG sites is facilitated by DNA methyltransferases (DNMT) 3A and 3B, whereas DNA maintenance methylation is controlled by DNMT1. MiRNA-29s target all DNMTs and thus reduce DNA CpG methylation. Cow´s milk provides substantial amounts of exosomal miRNA-29s that reach the systemic circulation and target mRNAs of the milk recipient. Via DNMT suppression, milk exosomal miRNA-29s may reduce the magnitude of FTO methylation, thereby epigenetically increasing FTO expression in the milk consumer. High lactation performance with increased milk yield has recently been associated with excessive miRNA-29 expression of dairy cow mammary epithelial cells (DCMECs). Notably, the galactopoietic hormone prolactin upregulates the transcription factor STAT3, which induces miRNA-29 expression. In a retrovirus-like manner

The (FTO) gene polymorphism is associated with metabolic syndrome risk in Egyptian females: a case- control study.

PubMed

Khella, Mina S; Hamdy, Nadia M; Amin, Ashraf I; El-Mesallamy, Hala O

2017-09-16

Variations within fat mass and obesity associated (FTO) gene had crosstalk with obesity risk in European and some Asian populations. This study was designed to investigate FTO rs9939609 association with metabolic syndrome (MetS) as well as biochemical parameters as plasma glucose, serum triacylglycerol (TAG), total cholesterol (TC) and transaminases enzymes in Arab female population from Egypt. In order to achieve that, FTO gene rs9939609 (A < T) was genotyped using TaqMan SNP Genotyping Assay in a total of 197 females which were enrolled in this study. Fasting levels of serum insulin, lipid profile and plasma glucose, in addition to liver transaminases were measured. The association between the genotype distribution and MetS risk was evaluated using Chi-square and logistic regression tests in a case-control design under different genetic models. The association of genotype distribution with MetS was significant (χ2 = 8.6/P = 0.014) with an increased odds ratio under dominant model (OR = 1.97, P = 0.029 and 95%C.I = 1.07-3.6) and recessive model (OR = 2.95, P = 0.017 and 95%C.I = 1.22-7.22). Moreover, (AA) subjects showed significant lower HDL-C levels (P = 0.009) when compared to (TT) ones. In addition, interestingly subjects with (AA) genotype have significantly higher ALT levels (P = 0.02) that remained significant after correction of major confounders as body mass index and serum triacylglycerols but not after conservative Bonferroni adjustment. The present study shows for first time that FTO gene rs9939609 is genetic risk factor for metabolic syndrome in Egyptian population which may help in understanding the biology of this complex syndrome and highlighted that this association may be through HDL-C component. The association of this genetic polymorphism with ALT levels needs to be studied in other populations with larger sample size.

The rs9939609 gene variant in FTO modified the metabolic response of weight loss after a 3-month intervention with a hypocaloric diet.

PubMed

de Luis, Daniel Antonio; Aller, Rocío; Conde, Rosa; Izaola, Olatz; Gonzalez Sagrado, Manuel; Castrodeza Sanz, Javier

2013-01-01

Common polymorphisms in the fat mass and obesity associated gene (FTO) have been linked to obesity in some populations. Nevertheless, the role of FTO variants on body weight response after dietary intervention remains equivocal. We decided to analyze the effects of the rs9939609 FTO gene polymorphism on body weight changes and metabolic parameters after 3 months of a hypocaloric diet. Before and after 3 months on a low-fat hypocaloric diet, a white population of 106 subjects with obesity was analyzed. Of the study subjects, 35 (33%) had the genotype TT and 71 (67%) had the next genotypes; TA (46 study subjects, 43.4%) or AA (25 study subjects, 23.6%). After dietary treatment and in TT group, weight, waist circumference, total cholesterol, LDL-cholesterol, insulin, and homeostasis model assessment decreases were less than subjects carrying the A allele [-3.1 (3.6) vs -2.4 (4.1) kg: P < 0.05], waist circumference [-5.4 (6.4) vs -2.6 (4.8) cm; P < 0.05], total cholesterol [-12.3 (35.3) vs -6.4 (4.7) mg/dL; P < 0.05], LDL-cholesterol [-22.3 (30.5) vs -10.7 (30.5) mg/dL; P < 0.05], insulin [-1.89 (5.5) vs +0.94 (8.2) mUI/L; P < 0.05], and homeostasis model assessment [-0.46 (1.11) vs -0.01 (2.4); P < 0.05]. Our study confirmed a higher weight loss in A carriers of FTO rs9939609 polymorphism than in TT genotype study subjects.

Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes to obesity in Mexican children.

PubMed

Mejía-Benítez, Aurora; Klünder-Klünder, Miguel; Yengo, Loic; Meyre, David; Aradillas, Celia; Cruz, Esperanza; Pérez-Luque, Elva; Malacara, Juan Manuel; Garay, Maria Eugenia; Peralta-Romero, Jesús; Flores-Huerta, Samuel; García-Mena, Jaime; Froguel, Philippe; Cruz, Miguel; Bonnefond, Amélie

2013-02-01

Recent genome wide association studies (GWAS) and previous positional linkage studies have identified more than 50 single nucleotide polymorphisms (SNPs) associated with obesity, mostly in Europeans. We aimed to assess the contribution of some of these SNPs to obesity risk and to the variation of related metabolic traits, in Mexican children. The association of six European obesity-related SNPs in or near FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes with risk of obesity was tested in 1,463 school-aged Mexican children (N(cases) = 514; N(controls) = 949). We also assessed effects of these SNPs on the variation of body mass index (BMI), fasting serum insulin levels, fasting plasma glucose levels, total cholesterol and triglyceride levels, in a subset of 1,171 nonobese Mexican children. We found a significant effect of GNPDA2 rs10938397 on risk of obesity (odds ratio [OR] = 1.30; P = 1.34 × 10-3). Furthermore, we found nominal associations between obesity risk or BMI variation and the following SNPs: ENPP1 rs7754561, MC4R rs17782313 and NEGR1 rs2815752. Importantly, the at-risk alleles of both MC4R rs17782313 and NPC1 rs1805081 showed significant effect on increased fasting glucose levels (β = 0.36 mmol/L; P = 1.47 × 10(-3)) and decreased fasting serum insulin levels (β = -0.10 μU/mL; P = 1.21 × 10(-3)), respectively. Our present results suggest that some obesity-associated SNPs previously reported in Europeans also associate with risk of obesity, or metabolic quantitative traits, in Mexican children. Importantly, we found new associations between MC4R and fasting glucose levels, and between NPC1 and fasting insulin levels.

FTO genotype, dietary protein, and change in appetite: the Preventing Overweight Using Novel Dietary Strategies trial.

PubMed

Huang, Tao; Qi, Qibin; Li, Yanping; Hu, Frank B; Bray, George A; Sacks, Frank M; Williamson, Donald A; Qi, Lu

2014-05-01

A common obesity-risk variant rs9939609 in the fat mass- and obesity-associated (FTO) gene was recently shown to affect appetite, and the gene is sensitive to the regulation of amino acids. We examined the interaction between FTO genotype and protein intake on the long-term changes in appetite in a randomized controlled trial. We genotyped FTO rs9939609 in 737 overweight adults in the 2-y Preventing Overweight Using Novel Dietary Strategies trial and assessed 4 appetite-related traits including cravings, fullness, hunger, and prospective consumption. We showed that dietary protein significantly modified genetic effects on changes in food cravings and appetite scores at 6 mo after adjustment for age, sex, ethnicity, baseline body mass index, weight change, and baseline value for respective outcomes (P-interaction = 0.027 and 0.048, respectively). The A allele was associated with a greater decrease in food cravings and appetite scores in participants with high-protein-diet intake (P = 0.027 and 0.047, respectively) but not in subjects in the low-protein-diet group (P = 0.384 and 0.078, respectively). The weight regain from 6 to 24 mo attenuated gene-protein interactions. Protein intakes did not modify FTO genotype effects on other appetite measures. Our data suggest that individuals with the FTO rs9939609 A allele might obtain more benefits in a reduction of food cravings and appetite by choosing a hypocaloric and higher-protein weight-loss diet. This trial was registered at clinicaltrials.gov as NCT00072995.

FTO rs9939609 Does Not Interact with Physical Exercise but Influences Basal Insulin Metabolism in Brazilian Overweight and Obese Adolescents

PubMed Central

Leite, Neiva; Furtado-Alle, Lupe; Teixeira, Mayza Dalcin; de Souza, Ricardo Lehtonen Rodrigues; da Silva, Larissa Rosa; Pizzi, Juliana; Lopes, Maria de Fátima Aguiar; Titski, Ana Cláudia Kapp

2018-01-01

Purpose The rs9939609 SNP (T > A) in FTO gene is associated with obesity and type 2 diabetes. The present study aimed at verifying whether this SNP influenced biochemical outcomes of children and adolescents who are overweight/obese submitted to a program of physical exercise and also if there was influence on basal levels of these biochemical variables. Methods The sample was composed by 432 children and adolescents grouped in three ways (obese, overweight, and normal weight); of these, 135 children and adoloescents who are obese and overweight were submitted to a physical exercise program for 12 weeks. All were genotyped by TaqMan SNP genotyping assay. Results The children and adolescents who are overweight/obese and carriers of AA genotype had higher levels of insulin (p=0.03) and HOMA (p=0.007) and lower levels of glucose (p=0.003), but the SNP did not modulate the response to physical exercise. Conclusions In our study, the rs9939609 AA genotype was associated with parameters related to insulin metabolism but did not interact with physical exercise. PMID:29854435

FTO genotype, dietary protein, and change in appetite: the Preventing Overweight Using Novel Dietary Strategies trial123

PubMed Central

Huang, Tao; Li, Yanping; Hu, Frank B; Bray, George A; Sacks, Frank M; Williamson, Donald A; Qi, Lu

2014-01-01

Background: A common obesity-risk variant rs9939609 in the fat mass– and obesity-associated (FTO) gene was recently shown to affect appetite, and the gene is sensitive to the regulation of amino acids. Objective: We examined the interaction between FTO genotype and protein intake on the long-term changes in appetite in a randomized controlled trial. Design: We genotyped FTO rs9939609 in 737 overweight adults in the 2-y Preventing Overweight Using Novel Dietary Strategies trial and assessed 4 appetite-related traits including cravings, fullness, hunger, and prospective consumption. Results: We showed that dietary protein significantly modified genetic effects on changes in food cravings and appetite scores at 6 mo after adjustment for age, sex, ethnicity, baseline body mass index, weight change, and baseline value for respective outcomes (P-interaction = 0.027 and 0.048, respectively). The A allele was associated with a greater decrease in food cravings and appetite scores in participants with high-protein–diet intake (P = 0.027 and 0.047, respectively) but not in subjects in the low-protein–diet group (P = 0.384 and 0.078, respectively). The weight regain from 6 to 24 mo attenuated gene-protein interactions. Protein intakes did not modify FTO genotype effects on other appetite measures. Conclusion: Our data suggest that individuals with the FTO rs9939609 A allele might obtain more benefits in a reduction of food cravings and appetite by choosing a hypocaloric and higher-protein weight-loss diet. This trial was registered at clinicaltrials.gov as NCT00072995. PMID:24622803

A multianalytical approach to evaluate the association of 55 SNPs in 28 genes with obesity risk in North Indian adults.

PubMed

Srivastava, Apurva; Mittal, Balraj; Prakash, Jai; Srivastava, Pranjal; Srivastava, Nimisha; Srivastava, Neena

2017-03-01

The aim of the study was to investigate the association of 55 SNPs in 28 genes with obesity risk in a North Indian population using a multianalytical approach. Overall, 480 subjects from the North Indian population were studied using strict inclusion/exclusion criteria. SNP Genotyping was carried out by Sequenom Mass ARRAY platform (Sequenom, San Diego, CA) and validated Taqman ® allelic discrimination (Applied Biosystems ® ). Statistical analyses were performed using SPSS software version 19.0, SNPStats, GMDR software (version 6) and GENEMANIA. Logistic regression analysis of 55 SNPs revealed significant associations (P < .05) of 49 SNPs with BMI linked obesity risk whereas the remaining 6 SNPs revealed no association (P > .05). The pathway-wise G-score revealed the significant role (P = .0001) of food intake-energy expenditure pathway genes. In CART analysis, the combined genotypes of FTO rs9939609 and TCF7L2 rs7903146 revealed the highest risk for BMI linked obesity. The analysis of the FTO-IRX3 locus revealed high LD and high order gene-gene interactions for BMI linked obesity. The interaction network of all of the associated genes in the present study generated by GENEMANIA revealed direct and indirect connections. In addition, the analysis with centralized obesity revealed that none of the SNPs except for FTO rs17818902 were significantly associated (P < .05). In this multi-analytical approach, FTO rs9939609 and IRX3 rs3751723, along with TCF7L2 rs7903146 and TMEM18 rs6548238, emerged as the major SNPs contributing to BMI linked obesity risk in the North Indian population. © 2016 Wiley Periodicals, Inc.

Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study.

PubMed

Do, Ron; Bailey, Swneke D; Desbiens, Katia; Belisle, Alexandre; Montpetit, Alexandre; Bouchard, Claude; Pérusse, Louis; Vohl, Marie-Claude; Engert, James C

2008-04-01

A genome-wide association study conducted by the Wellcome Trust Case Control Consortium recently associated single nucleotide polymorphisms (SNPs) in the FTO (fatso/fat mass and obesity associated) gene with type 2 diabetes. These associations were shown to be mediated by obesity. Other research groups found similar results in Europeans and Hispanics but not African Americans. The mechanism by which FTO influences obesity and type 2 diabetes is currently unknown. The present study investigated the role of two FTO SNPs (rs17817449 and rs1421085) in adiposity, insulin sensitivity, and body weight regulation, including energy intake and expenditure. We genotyped 908 individuals from the Quebec City metropolitan area that participated in the Quebec Family Study, a long-term study of extensively phenotyped individuals designed to investigate factors involved in adiposity. We found significant associations for both SNPs with several obesity-related phenotypes. In particular, rs17817449 was associated with BMI (P = 0.0014), weight (P = 0.0059), and waist circumference (P = 0.0021) under an additive model. In addition, this FTO SNP influenced fasting insulin (P = 0.011), homeostasis model assessment of insulin resistance (P = 0.038), and an insulin sensitivity index derived from an oral glucose tolerance test (P = 0.0091). Associations were also found with resting metabolic rate (RMR) (P = 0.042) and plasma leptin levels (P = 0.036). Adjustment for BMI abolished the associations with insulin sensitivity, RMR, and plasma leptin levels. These results confirm that genetic variation at the FTO locus contributes to the etiology of obesity, insulin resistance, and increased plasma leptin levels.

Structure-based design and evaluation of novel N-phenyl-1H-indol-2-amine derivatives for fat mass and obesity-associated (FTO) protein inhibition.

PubMed

Padariya, Monikaben; Kalathiya, Umesh

2016-10-01

Fat mass and obesity-associated (FTO) protein contributes to non-syndromic human obesity which refers to excessive fat accumulation in human body and results in health risk. FTO protein has become a promising target for anti-obesity medicines as there is an immense need for the rational design of potent inhibitors to treat obesity. In our study, a new scaffold N-phenyl-1H-indol-2-amine was selected as a base for FTO protein inhibitors by applying scaffold hopping approach. Using this novel scaffold, different derivatives were designed by extending scaffold structure with potential functional groups. Molecular docking simulations were carried out by using two different docking algorithm implemented in CDOCKER (flexible docking) and AutoDock programs (rigid docking). Analyzing results of rigid and flexible docking, compound MU06 was selected based on different properties and predicted binding affinities for further analysis. Molecular dynamics simulation of FTO/MU06 complex was performed to characterize structure rationale and binding stability. Certainly, Arg96 and His231 residue of FTO protein showed stable interaction with inhibitor MU06 throughout the production dynamics phase. Three residues of FTO protein (Arg96, Asp233, and His231) were found common in making H-bond interactions with MU06 during molecular dynamics simulation and CDOCKER docking. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identification of Fat Mass and Obesity Associated (FTO) Protein Expression in Cardiomyocytes: Regulation by Leptin and Its Contribution to Leptin-Induced Hypertrophy

PubMed Central

Gan, Xiaohong Tracey; Zhao, Ganjian; Huang, Cathy X.; Rowe, Adrianna C.; Purdham, Daniel M.; Karmazyn, Morris

2013-01-01

The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation. Ubiquitously expressed, FTO was identified in heart homogenates although its function is unknown. We studied whether FTO is specifically expressed within the cardiac myocyte and its potential role pertaining to the hypertrophic effect of the adipokine leptin. Most experiments were performed using cultured neonatal rat cardiomyocytes which showed nuclei-specific FTO expression. Leptin significantly increased FTO expression which was associated with myocyte hypertrophy although both events were abrogated by FTO knockdown with siRNA. Administration of a leptin receptor antibody to either normal or obese rats significant reduced myocardial FTO protein expression. Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects. Expression of the cut-like homeobox 1(CUX1) transcriptional factor was significantly increased by leptin although this was restricted to the cathepsin L-dependent, proteolytically-derived shorter p110CUX1 isoform whereas the longer p200CUX1 protein was not significantly affected. Cathepsin L expression and activity were both significantly increased by leptin whereas a cathepsin L peptide inhibitor or siRNA specific for CUX1 completely prevented the leptin-induced increase in FTO expression. The cathepsin L peptide inhibitor or siRNA-induced knockdown of either CUX1 or FTO abrogated the hypertrophic response to leptin. Two other pro-hypertrophic factors, endothelin-1 or angiotensin II had no effect on FTO expression and FTO knockdown did not alter the hypertrophic response to either agent. This study demonstrates leptin-induced FTO upregulation in cardiomyocytes via JAK2/STAT3- dependent CUX1 upregulation and suggests an FTO regulatory function of leptin. It also demonstrates for the first time a functional role of FTO in the

Identification of fat mass and obesity associated (FTO) protein expression in cardiomyocytes: regulation by leptin and its contribution to leptin-induced hypertrophy.

PubMed

Gan, Xiaohong Tracey; Zhao, Ganjian; Huang, Cathy X; Rowe, Adrianna C; Purdham, Daniel M; Karmazyn, Morris

2013-01-01

The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation. Ubiquitously expressed, FTO was identified in heart homogenates although its function is unknown. We studied whether FTO is specifically expressed within the cardiac myocyte and its potential role pertaining to the hypertrophic effect of the adipokine leptin. Most experiments were performed using cultured neonatal rat cardiomyocytes which showed nuclei-specific FTO expression. Leptin significantly increased FTO expression which was associated with myocyte hypertrophy although both events were abrogated by FTO knockdown with siRNA. Administration of a leptin receptor antibody to either normal or obese rats significant reduced myocardial FTO protein expression. Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects. Expression of the cut-like homeobox 1(CUX1) transcriptional factor was significantly increased by leptin although this was restricted to the cathepsin L-dependent, proteolytically-derived shorter p110CUX1 isoform whereas the longer p200CUX1 protein was not significantly affected. Cathepsin L expression and activity were both significantly increased by leptin whereas a cathepsin L peptide inhibitor or siRNA specific for CUX1 completely prevented the leptin-induced increase in FTO expression. The cathepsin L peptide inhibitor or siRNA-induced knockdown of either CUX1 or FTO abrogated the hypertrophic response to leptin. Two other pro-hypertrophic factors, endothelin-1 or angiotensin II had no effect on FTO expression and FTO knockdown did not alter the hypertrophic response to either agent. This study demonstrates leptin-induced FTO upregulation in cardiomyocytes via JAK2/STAT3- dependent CUX1 upregulation and suggests an FTO regulatory function of leptin. It also demonstrates for the first time a functional role of FTO in the

Resting-State Brain and the FTO Obesity Risk Allele: Default Mode, Sensorimotor, and Salience Network Connectivity Underlying Different Somatosensory Integration and Reward Processing between Genotypes.

PubMed

Olivo, Gaia; Wiemerslage, Lyle; Nilsson, Emil K; Solstrand Dahlberg, Linda; Larsen, Anna L; Olaya Búcaro, Marcela; Gustafsson, Veronica P; Titova, Olga E; Bandstein, Marcus; Larsson, Elna-Marie; Benedict, Christian; Brooks, Samantha J; Schiöth, Helgi B

2016-01-01

Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene are linked to obesity, but how these SNPs influence resting-state neural activation is unknown. Few brain-imaging studies have investigated the influence of obesity-related SNPs on neural activity, and no study has investigated resting-state connectivity patterns. We tested connectivity within three, main resting-state networks: default mode (DMN), sensorimotor (SMN), and salience network (SN) in 30 male participants, grouped based on genotype for the rs9939609 FTO SNP, as well as punishment and reward sensitivity measured by the Behavioral Inhibition (BIS) and Behavioral Activation System (BAS) questionnaires. Because obesity is associated with anomalies in both systems, we calculated a BIS/BAS ratio (BBr) accounting for features of both scores. A prominence of BIS over BAS (higher BBr) resulted in increased connectivity in frontal and paralimbic regions. These alterations were more evident in the obesity-associated AA genotype, where a high BBr was also associated with increased SN connectivity in dopaminergic circuitries, and in a subnetwork involved in somatosensory integration regarding food. Participants with AA genotype and high BBr, compared to corresponding participants in the TT genotype, also showed greater DMN connectivity in regions involved in the processing of food cues, and in the SMN for regions involved in visceral perception and reward-based learning. These findings suggest that neural connectivity patterns influence the sensitivity toward punishment and reward more closely in the AA carriers, predisposing them to developing obesity. Our work explains a complex interaction between genetics, neural patterns, and behavioral measures in determining the risk for obesity and may help develop individually-tailored strategies for obesity prevention.

Resting-State Brain and the FTO Obesity Risk Allele: Default Mode, Sensorimotor, and Salience Network Connectivity Underlying Different Somatosensory Integration and Reward Processing between Genotypes

PubMed Central

Olivo, Gaia; Wiemerslage, Lyle; Nilsson, Emil K.; Solstrand Dahlberg, Linda; Larsen, Anna L.; Olaya Búcaro, Marcela; Gustafsson, Veronica P.; Titova, Olga E.; Bandstein, Marcus; Larsson, Elna-Marie; Benedict, Christian; Brooks, Samantha J.; Schiöth, Helgi B.

2016-01-01

Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene are linked to obesity, but how these SNPs influence resting-state neural activation is unknown. Few brain-imaging studies have investigated the influence of obesity-related SNPs on neural activity, and no study has investigated resting-state connectivity patterns. We tested connectivity within three, main resting-state networks: default mode (DMN), sensorimotor (SMN), and salience network (SN) in 30 male participants, grouped based on genotype for the rs9939609 FTO SNP, as well as punishment and reward sensitivity measured by the Behavioral Inhibition (BIS) and Behavioral Activation System (BAS) questionnaires. Because obesity is associated with anomalies in both systems, we calculated a BIS/BAS ratio (BBr) accounting for features of both scores. A prominence of BIS over BAS (higher BBr) resulted in increased connectivity in frontal and paralimbic regions. These alterations were more evident in the obesity-associated AA genotype, where a high BBr was also associated with increased SN connectivity in dopaminergic circuitries, and in a subnetwork involved in somatosensory integration regarding food. Participants with AA genotype and high BBr, compared to corresponding participants in the TT genotype, also showed greater DMN connectivity in regions involved in the processing of food cues, and in the SMN for regions involved in visceral perception and reward-based learning. These findings suggest that neural connectivity patterns influence the sensitivity toward punishment and reward more closely in the AA carriers, predisposing them to developing obesity. Our work explains a complex interaction between genetics, neural patterns, and behavioral measures in determining the risk for obesity and may help develop individually-tailored strategies for obesity prevention. PMID:26924971

Effect of dietary consumption as a modifier on the association between FTO gene variants and excess body weight in children from an admixed population in Brazil: the Social Changes, Asthma and Allergy in Latin America (SCAALA) cohort study.

PubMed

Vilella, Marília; Nunes de Oliveira Costa, Gustavo; Lima Barreto, Maurício; Alexandrina Figueredo, Camila; Maria Alcantara-Neves, Neuza; Cunha Rodrigues, Laura; Maria Alvim de Matos, Sheila; Leovigildo Fiaccone, Rosemeire; Oliveira, Pablo; Rocha, Aline; de Cássia Ribeiro-Silva, Rita

2017-06-01

Previous studies have shown associations of variants of the FTO gene with body weight, but none of these have involved Latin American populations with a high level of miscegenation, as is seen in the north-eastern Brazilian population. This study evaluated the association between SNP in the FTO gene and excess weight in Salvador, Bahia, Brazil. In addition, the effect of diet as a modifier on this association was also investigated. This cross-sectional study included 1191 participants aged 4-11 years, who were genotyped for 400 variants of the FTO gene. Direct anthropometric measures were made and dietary data were obtained by 24-h food recall. Multivariate logistic regression analyses were used to assess the associations of interest. Overall, 11·2 % of the individuals included in the study were overweight/obese. Interactions were identified between the percentage energy intake from proteins and obesity risk linked to the rs62048379 SNP (P interaction=0·01) and also between fat intake (PUFA:SFA ratio) and obesity risk linked to the rs62048379 SNP (P interaction=0·01). The T allele for the variant rs62048379 was positively associated with overweight/obesity in individuals whose percentage energy intake from protein was above the median (OR 2·00; 95 % CI 1·05, 3·82). The rs62048379 SNP was also associated with overweight/obesity in individuals whose PUFA:SFA ratio was below the median (OR 1·63; 95 % CI 1·05, 2·55). The association between FTO gene variants and excess body weight can be modulated by dietary characteristics, particularly by fatty acid distribution and dietary protein intake in children.

Correlation between polymorphism of FTO gene and type 2 diabetes mellitus in Uygur people from northwest China.

PubMed

Xiao, Shan; Zeng, Xiaoyun; Quan, Li; Zhu, Jun

2015-01-01

To explore the correlation between FTO (fat mass and obesity associated) gene, which is associated with 3 single nucleotide polymorphisms (SNP) of fat mass and obesity, type 2 diabetes and body mass index (BMI) in the Uygur population in northwest China. A total of 849 Uygur patients with type 2 diabetes mellitus were selected from the hospitalized patients in the First Affiliated Hospital of Xinjiang Medical University, the First People's Hospital of Kashi and the hospitals in the Turpan areas. At the same time, 873 cases of healthy persons who conducted a medical checkup in the physical examination centre of the above hospitals were enrolled as controls. The present investigation used the case-control research method, and physical examination and biochemical index determination were carried out. The Sequenom MassARRAY technology was employed in the detection of 3 SNP loci of the FTO gene. The representative population of each SNP in the control group was analyzed by Hardy-Weinberg law. The differences of each clinical parameter in the two groups were analyzed by t-test analysis. The differences of genotype and allele of each SNP in the two groups were analyzed by χ(2) test. BMI, waistline (WL), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), total cholesterol (TC), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the type 2 diabetes group were higher than those in the control group, while the high density lipoprotein (HDL) and low density lipoprotein (LDL) were lower than those of the control group; 2. The allele frequency of A of rs8050136 and rs9939609 in the type 2 diabetes mellitus group was higher than that of the control group. The BMI of the whole population and type 2 diabetes group with genotype C/A+A/A of rs8050136 was higher than that in C/C group, and the BMI with genotype T/A+A/A of rs9939609 was higher than that in group T/T. Stratification was conducted on BMI according to the

Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly

PubMed Central

Jacobsson, Josefin A.; Almén, Markus Sällman; Benedict, Christian; Hedberg, Lilia A.; Michaëlsson, Karl; Brooks, Samantha; Kullberg, Joel; Axelsson, Tomas; Johansson, Lars; Ahlström, Håkan; Fredriksson, Robert; Lind, Lars; Schiöth, Helgi B.

2011-01-01

Background The rs9939609 single-nucleotide polymorphism (SNP) in the fat mass and obesity (FTO) gene has previously been associated with higher BMI levels in children and young adults. In contrast, this association was not found in elderly men. BMI is a measure of overweight in relation to the individuals' height, but offers no insight into the regional body fat composition or distribution. Objective To examine whether the FTO gene is associated with overweight and body composition-related phenotypes rather than BMI, we measured waist circumference, total fat mass, trunk fat mass, leg fat mass, visceral and subcutaneous adipose tissue, and daily energy intake in 985 humans (493 women) at the age of 70 years. In total, 733 SNPs located in the FTO gene were genotyped in order to examine whether rs9939609 alone or the other SNPs, or their combinations, are linked to obesity-related measures in elderly humans. Design Cross-sectional analysis of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Results Neither a single SNP, such as rs9939609, nor a SNP combination was significantly linked to overweight, body composition-related measures, or daily energy intake in elderly humans. Of note, these observations hold both among men and women. Conclusions Due to the diversity of measurements included in the study, our findings strengthen the view that the effect of FTO on body composition appears to be less profound in later life compared to younger ages and that this is seemingly independent of gender. PMID:21637715

Exenatide ameliorates hepatic steatosis and attenuates fat mass and FTO gene expression through PI3K signaling pathway in nonalcoholic fatty liver disease.

PubMed

Li, Shan; Wang, Xiaoman; Zhang, Jielei; Li, Jingyi; Liu, Xiaogang; Ma, Yuanyuan; Han, Chao; Zhang, Lixia; Zheng, Lili

2018-01-01

Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.

Fat mass and obesity-associated gene rs11642015 polymorphism is significantly associated with prediabetes and type 2 diabetes subsequent to adjustment for body mass index.

PubMed

Han, Liyuan; Tang, Linlin; Wang, Changyi; Chen, Zhongwei; Zhang, Tao; Chen, Sihan; Liu, Shengyuan; Peng, Xiaolin; Mai, Yifeng; Duan, Shiwei

2014-09-01

The association of the fat mass and obesity-associated gene ( FTO ) rs11642015 polymorphism with prediabetes, type 2 diabetes and obesity in certain populations has not been previously reported. A population-based study was conducted that included 490 type 2 diabetic, 471 prediabetic and 575 normal subjects. The main outcomes of the study were prediabetes, type 2 diabetes and obesity. Binary logistic regression was performed to estimate the association of FTO rs11642015 with the risk of prediabetes, type 2 diabetes and obesity following adjustment for the corresponding confounders. A meta-analysis was also conducted to evaluate the association between FTO rs11642015 and obesity. FTO rs11642015 was significantly associated with prediabetes in the whole sample under the additive model [odds ratio (OR), 1.50; 95% confidence interval (CI), 1.17-1.93; P=0.002], particularly in females. The polymorphism remained consistently significant following adjustment for age and body mass index (BMI), showing an increased prediabetes risk with an additive effect (OR, 1.55; 95% CI, 1.19-2.01; P=0.001). In addition, a significant association was found for rs11642015 with prediabetes and type 2 diabetes under the dominant model. However, under the stringent Bonferroni's correction there was no evidence of positive associations for FTO rs11642015 with obesity in the whole sample, females or males. Findings of the meta-analysis showed that FTO rs11642015 was not predisposed to obesity. In conclusion, the T allele of FTO rs11642015 is positively associated with an increased risk of prediabetes, even after adjustment for age and BMI, particularly in females. Subjects carrying the CT + TT genotype are predisposed to prediabetes and type 2 diabetes. Therefore, results of the population-based study and follow-up meta-analysis suggested that FTO rs11642015 is not significantly associated with susceptibility to obesity.

Association between LEPR, FTO, MC4R, and PPARG-2 polymorphisms with obesity traits and metabolic phenotypes in school-aged children.

PubMed

Almeida, Sílvia M; Furtado, José M; Mascarenhas, Paulo; Ferraz, Maria E; Ferreira, José C; Monteiro, Mariana P; Vilanova, Manuel; Ferraz, Fernando P

2018-06-01

Evaluate the relationship of leptin receptor (LEPR) rs1137101, fat mass obesity-associated (FTO) receptors 9939609, melanocortin-4 receptors (MC4R) rs2229616 and rs17782313, and proliferator-activated receptor-gamma (PPARG) rs1801282 with clinical and metabolic phenotypes in prepubertal children. What is the effect of polymorphisms on clinical and metabolic phenotypes in prepubertal children? A cross-sectional descriptive study was performed to evaluate anthropometric features, percentage body fat (%BF), biochemical parameters, and genotype in 773 prepubertal children. FTO rs9939609 was associated with an increase in body mass index (BMI) and BMI z-score (zBMI). MC4R rs17782313 was associated with a decrease in BMI and +0.06 units in zBMI. LEPR, and PPARG-2 polymorphisms were associated with decreases in BMI and an increase and decrease units in zBMI, respectively. The homozygous SNPs demonstrated increases (FTO rs993609 and MC4R rs17782313) and decreases (LEPR rs1137101, PPARG rs1801282) in zBMI than the homozygous form of the major allele. In the overweight/obese group, the MC4R rs17782313 CC genotype showed higher average weight, zBMI, waist circumference, waist-circumference-to-height ratio, and waist-hip ratio, and lower BMI, mid-upper arm circumference, calf circumference, and %BF (P< 0.05). FTO rs9939609 AT and AA genotypes were associated with lower triglycerides (P < 0.05). We showed that MC4R rs17782313 and FTO rs9939609 were positively associated with zBMI, with weak and very weak effects, respectively, suggesting a very scarce contribution to childhood obesity. LEPR rs1137101 and PPARG-2 rs1801282 had weak and medium negative effects on zBMI, respectively, and may slightly protect against childhood obesity.

Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects

PubMed Central

Shabana; Ullah Shahid, Saleem; Wah Li, Ka; Acharya, Jayshree; Cooper, Jackie A; Hasnain, Shahida; Humphries, Stephen E

2016-01-01

The aim of the current study was to analyze the effect of six type II diabetes GWAS loci rs3923113 (GRB14), rs16861329 (ST6GAL1), rs1802295 (VPS26A), rs7178572 (HMG20A), rs2028299 (AP3S2) and rs4812829 (HNF4A), and an FTO polymorphism (rs9939609) on obesity. The probable mechanism of action of these SNPs was analyzed by studying their association with various biochemical and anthropometric parameters. A total of 475 subjects (obese=250, controls=225) were genotyped by TaqMan assay and their lipid profile was determined. Allele/genotype frequencies and an unweighted/weighted gene score were calculated. The effect of the gene score on anthropometric and biochemical parameters was analyzed. The minor allele frequencies of all variants were comparable to that reported in the original studies and were associated with obesity in these Pakistani subjects. Subjects with 9 risk alleles differ from those with <3 and overall there is no significant effect (P-value for trend 0.26). None of the SNPs were associated with any of the serum lipid traits. We are the first to report the association of these T2D SNPs with obesity. In the Pakistani population the reported effect of six SNPs for obesity is similar to that reported for T2D and having a combination of risk alleles on obesity can be considerable. The mechanism of this effect is unclear, but appears not to be mediated by changing serum lipid chemistry. PMID:26395551

Analysis of association of gene variants with obesity traits in New Zealand European children at 6 years of age.

PubMed

Krishnan, Mohanraj; Thompson, John M D; Mitchell, Edwin A; Murphy, Rinki; McCowan, Lesley M E; Shelling, Andrew N; On Behalf Of The Children Of Scope Study Group, G

2017-07-25

Childhood obesity is a public health problem, which is associated with a long-term increased risk of cardiovascular disease and premature mortality. Several gene variants have previously been identified that have provided novel insights into biological factors that contribute to the development of obesity. As obesity tracks through childhood into adulthood, identification of the genetic factors for obesity in early life is important. The objective of this study was to identify putative associations between genetic variants and obesity traits in children at 6 years of age. We recruited 1208 children of mothers from the New Zealand centre of the international Screening for Pregnancy Endpoints (SCOPE) study. Eighty common genetic variants associated with obesity traits were evaluated by the Sequenom assay. Body mass index standardised scores (BMI z-scores) and percentage body fat (PBF; measured by bio-impedance assay (BIA)) were used as anthropometric measures of obesity. A positive correlation was found between BMI z-scores and PBF (p < 0.001, r = 0.756). Two subsets of gene variants were associated with BMI z-scores (HOXB5-rs9299, SH2B1-rs7498665, NPC1-rs1805081 and MSRA-rs545854) and PBF (TMEM18-rs6548238, NPY-rs17149106, ETV-rs7647305, NPY-rs16139, TIMELESS-rs4630333, FTO-rs9939609, UCP2-rs659366, MAP2K5-rs2241423 and FAIM2-rs7138803) in the genotype models. However, there was an absence of overlapping association between any of the gene variants with BMI z-scores and PBF. A further five variants were associated with BMI z-scores (TMEM18-rs6548238, FTO-rs9939609 and MC4R-rs17782313) and PBF (SH2B1-rs7498665 and FTO-rs1421085) once separated by genetic models (additive, recessive and dominant) of inheritance. This study has identified significant associations between numerous gene variants selected on the basis of prior association with obesity and obesity traits in New Zealand European children.

FTO promotes SREBP1c maturation and enhances CIDEC transcription during lipid accumulation in HepG2 cells.

PubMed

Chen, Ao; Chen, Xiaodong; Cheng, Shiqiang; Shu, Le; Yan, Meiping; Yao, Lun; Wang, Binyu; Huang, Shuguang; Zhou, Lei; Yang, Zaiqing; Liu, Guoquan

2018-05-01

The fat mass and obesity-associated (FTO) gene is tightly related to body weight and fat mass, and plays a pivotal role in regulating lipid accumulation in hepatocytes. However, the mechanisms underlying its function are poorly understood. Sterol regulatory element binding protein-1c (SREBP1c) is a transcription factor that regulates lipogenesis. Cell death-inducing DFFA (DNA fragmentation factor-α)-like effector c (CIDEC) plays a crucial role in lipid droplets (LDs) size controlling and lipid accumulation. In this report, we first observed that FTO overexpression in HepG2 cells resulted in an increase of lipogenesis and up-regulation of SREBP1c and CIDEC, two key regulatory factors in lipogenesis. In contrast, FTO knockdown in HepG2 cells resulted in a decrease of lipogenesis and down-regulation of SREBP1c and CIDEC expression. Moreover, SREBP1c knockdown resulted in a decrease of lipogenesis in HepG2 cells with FTO overexpression. In addition, FTO demethylation defect mutant presented less transcription of the key genes, and less nuclear translocation and maturation of SREBP1c. Further investigation demonstrated that overexpression of SREBP1c in HepG2 cells also promoted high CIDEC expression. Luciferase reporter assays showed that SREBP1c significantly stimulated CIDEC gene promoter activity. Finally, CIDEC knockdown reduced SREBP1c-induced lipogenesis. In conclusion, our studies suggest that FTO increased the lipid accumulation in hepatocytes by increasing nuclear translocation of SREBP1c and SREBP1c maturation, thus improving the transcriptional activity of LD-associated protein CIDEC. Our studies may provide new mechanistic insight into nonalcoholic fatty liver disease (NAFLD) mediated by FTO. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Excessive fuel availability amplifies the FTO-mediated obesity risk: results from the TUEF and Whitehall II studies.

PubMed

Wagner, Róbert; Tabák, Ádám G; Fehlert, Ellen; Fritsche, Louise; Jaghutriz, Benjamin A; Bánhegyi, Róbert J; Schmid, Sebastian M; Staiger, Harald; Machicao, Fausto; Peter, Andreas; Häring, Hans-Ulrich; Fritsche, Andreas; Heni, Martin

2017-11-14

Variation in FTO is the most important common genetic determinant of body weight. Altered energy metabolism could underlie this association. We hypothesized that higher circulating glucose or triglycerides can amplify the FTO impact on BMI. In 2671 subjects of the TUEF study, we investigated the interaction effect of fasting glucose and triglyceride levels with rs9939609 in FTO on BMI. We analysed the same interaction effect by longitudinally utilizing mixed effect models in the prospective Whitehall II study. In TUEF, we detected an interaction effect between fasting glucose and fasting triglycerides with rs9939609 on BMI (p = 0.0005 and p = 5 × 10 -7 , respectively). The effect size of one risk allele was 1.4 ± 0.3 vs. 2.2 ± 0.44 kg/m² in persons with fasting glucose levels below and above the median, respectively. Fasting triglycerides above the median increased the per-allele effect from 1.4 ± 0.3 to 1.7 ± 0.4 kg/m 2 . In the Whitehall II study, body weight increased by 2.96 ± 6.5 kg during a follow-up of 13.5 ± 4.6 yrs. Baseline fasting glucose and rs9939609 interacted on weight change (p = 0.009). Higher fasting glucose levels may amplify obesity-risk in FTO carriers and lead to an exaggerated weight gain over time. Since weight gain perpetuates metabolic alterations, this interplay may trigger a vicious circle that leads to obesity and diabetes.

Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients.

PubMed

Mitropoulos, Konstantinos; Merkouri Papadima, Eleni; Xiromerisiou, Georgia; Balasopoulou, Angeliki; Charalampidou, Kyriaki; Galani, Vasiliki; Zafeiri, Krystallia-Vassiliki; Dardiotis, Efthymios; Ralli, Styliani; Deretzi, Georgia; John, Anne; Kydonopoulou, Kyriaki; Papadopoulou, Elpida; di Pardo, Alba; Akcimen, Fulya; Loizedda, Annalisa; Dobričić, Valerija; Novaković, Ivana; Kostić, Vladimir S; Mizzi, Clint; Peters, Brock A; Basak, Nazli; Orrù, Sandro; Kiskinis, Evangelos; Cooper, David N; Gerou, Spyridon; Drmanac, Radoje; Bartsakoulia, Marina; Tsermpini, Evangelia-Eirini; Hadjigeorgiou, Georgios M; Ali, Bassam R; Katsila, Theodora; Patrinos, George P

2017-12-08

Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance.

A haplotype of three SNPs in FTO had a strong association with body composition and BMI in Iranian male adolescents.

PubMed

Kalantari, Naser; Keshavarz Mohammadi, Nastaran; Izadi, Pantea; Doaei, Saeid; Gholamalizadeh, Maryam; Eini-Zinab, Hassan; Salonurmi, Tuire; Rafieifar, Shahram; Janipoor, Reza; Azizi Tabesh, Ghasem

2018-01-01

Single-nucleotide polymorphisms (SNPs), which are located in the first intron of the FTO gene, are reported to be associated with body weight and the body mass index (BMI). However, their effects on anthropometric measurements in adolescents are poorly understood. This study aimed to investigate the association of three adjacent polymorphisms (rs9930506, rs9930501, & rs9932754) in the FTO gene with anthropometric indices in Iranian adolescent males. The participants comprised a total of 237 adolescent males who were recruited randomly from two high schools in Tehran, Iran. The DNA samples were genotyped for the FTO gene polymorphisms by DNA sequencing. BMI, body fat percentage (BF%), and body muscle percentage (BM%) were determined using a validated bioelectrical impedance analysis scale. The association of the FTO polymorphisms with weight, height, BMI, BF%, and BM% was investigated. A haplotype of rs9930506, rs9930501, and rs9932754 (GGT) in the first intron of the FTO with complete linkage disequilibrium (LD) was found to be significantly associated with higher weight (OR = 1.32), BMI (OR = 5.36) and BF% (OR = 1.46), and lower BM% (OR = 3.59) (all P<0.001). None of the students with GGC genotypes were underweight, while all of the students with AAT genotypes had high muscle mass. A haplotype in the first intron of the FTO gene had a strong association with obesity indices in Iranian adolescent males. The FTO gene polymorphisms might have greater effects on anthropometric indices than what was previously imagined. Moreover, we suggested that the FTO gene exerted their effects on anthropometric measurements through haplotypes (and not single SNPs).

The association of variants in the FTO gene with longitudinal body mass index profiles in non-Hispanic white children and adolescents.

PubMed

Hallman, D M; Friedel, V C; Eissa, M A H; Boerwinkle, E; Huber, J C; Harrist, R B; Srinivasan, S R; Chen, W; Dai, S; Labarthe, D R; Berenson, G S

2012-01-01

To investigate possible age-related changes in associations between polymorphisms in the fat mass and obesity-associated (FTO) gene and higher body mass index (BMI). Multilevel mixed regression models were used to examine associations between four FTO variants and longitudinal BMI profiles in non-Hispanic white and African American children and adolescents 8-17 years of age from two different longitudinal cohort studies, the Bogalusa Heart Study (BHS) and Project HeartBeat! (PHB). In the BHS, there were 1551 examinations of 478 African Americans and 3210 examinations of 1081 non-Hispanic whites; in PHB, there were 971 examinations of 131 African Americans and 4458 examinations of 505 non-Hispanic whites. In African Americans, no significant FTO associations with BMI were found. In non-Hispanic whites, linkage disequilibrium among all four variants made haplotype analysis superfluous, so we focused on the single-nucleotide polymorphism, rs9939609. In longitudinal multilevel models, the A/A genotype of rs9939609 was associated with higher BMI in non-Hispanic whites in both cohorts at all ages. A significant age-by-genotype interaction found only in the BHS cohort predicted that in those with the A/A genotype, BMI would be ∼0.7 kg m(-2) higher at age 8 and ∼1.6 kg m(-2) higher at age 17 than in those with A/T or T/T genotypes. The design of PHB limited follow-up of any single individual to 4 years, and may have reduced the ability to detect any age-by-genotype interaction in this cohort. The A/A genotype of rs9939609 in the FTO gene is associated with higher longitudinal BMI profiles in non-Hispanic whites from two different cohorts. The association may change with age, with the A/A genotype being associated with a larger BMI difference in late adolescence than in childhood, though this was observed only in the BHS cohort and requires verification.

Association between overweight and obesity in schoolchildren with rs9939609 polymorphism (FTO) and family history for obesity.

PubMed

Reuter, Cézane Priscila; Burgos, Miria Suzana; Bernhard, Joana Carolina; Tornquist, Debora; Klinger, Elisa Inês; Borges, Tássia Silvana; Renner, Jane Dagmar Pollo; de Moura Valim, Andréia Rosane; de Mello, Elza Daniel

2016-01-01

To determine the association between overweight/obesity in schoolchildren with FTO rs9939609 polymorphism (fatmass and obesity associated) and family history of obesity. Cross-sectional study comprising a sample of 406 children aged 7-17 years in a city in southern Brazil. Overweight/obesity in schoolchildren was assessed by body mass index (BMI), and family history of obesity was self-reported by parents. Polymorphism genotyping was performed by real time PCR (polymerase chain reaction). The association between the nutritional status of schoolchildren with the presence of family obesity, stratified by polymorphism genotypes (AA [at-risk for obesity], AT, and TT), was assessed by prevalence ratio values (PR) through Poisson regression. Among schoolchildren with the AA genotype, 57.4% had overweight/obesity; the percentage was lower for the AT and TT genotypes (33.1% and 28.9%, respectively). Overweight/obesity in schoolchildren was associated with a family history of obesity, especially among children with the AA genotype. The prevalence was higher among those with an obese mother (PR: 1.28; p<0.001), obese maternal or paternal grandmother (PR: 1.22; p=0.047), and obese paternal grandfather (PR: 1.32; p<0.001). There is an association between the AA genotype of rs9939609 polymorphism and BMI among schoolchildren. The association between overweight/obesity in schoolchildren with a family history of obesity was found mainly among students with the AA genotype. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier

PubMed Central

Taylor, A. E.; Sandeep, M. N.; Janipalli, C. S.; Giambartolomei, C.; Evans, D. M.; Kranthi Kumar, M. V.; Vinay, D. G.; Smitha, P.; Gupta, V.; Aruna, M.; Kinra, S.; Sullivan, R. M.; Bowen, L.; Timpson, N. J.; Davey Smith, G.; Dudbridge, F.; Prabhakaran, D.; Ben-Shlomo, Y.; Reddy, K. S.; Ebrahim, S.; Chandak, G. R.

2011-01-01

Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity. PMID:21785715

Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier.

PubMed

Taylor, A E; Sandeep, M N; Janipalli, C S; Giambartolomei, C; Evans, D M; Kranthi Kumar, M V; Vinay, D G; Smitha, P; Gupta, V; Aruna, M; Kinra, S; Sullivan, R M; Bowen, L; Timpson, N J; Davey Smith, G; Dudbridge, F; Prabhakaran, D; Ben-Shlomo, Y; Reddy, K S; Ebrahim, S; Chandak, G R

2011-01-01

Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.

Mapping and annotating obesity-related genes in pig and human genomes.

PubMed

Martelli, Pier Luigi; Fontanesi, Luca; Piovesan, Damiano; Fariselli, Piero; Casadio, Rita

2014-01-01

Background. Obesity is a major health problem in both developed and emerging countries. Obesity is a complex disease whose etiology involves genetic factors in strong interplay with environmental determinants and lifestyle. The discovery of genetic factors and biological pathways underlying human obesity is hampered by the difficulty in controlling the genetic background of human cohorts. Animal models are then necessary to further dissect the genetics of obesity. Pig has emerged as one of the most attractive models, because of the similarity with humans in the mechanisms regulating the fat deposition. Results. We collected the genes related to obesity in humans and to fat deposition traits in pig. We localized them on both human and pig genomes, building a map useful to interpret comparative studies on obesity. We characterized the collected genes structurally and functionally with BAR+ and mapped them on KEGG pathways and on STRING protein interaction network. Conclusions. The collected set consists of 361 obesity related genes in human and pig genomes. All genes were mapped on the human genome, and 54 could not be localized on the pig genome (release 2012). Only for 3 human genes there is no counterpart in pig, confirming that this animal is a good model for human obesity studies. Obesity related genes are mostly involved in regulation and signaling processes/pathways and relevant connection emerges between obesity-related genes and diseases such as cancer and infectious diseases.

Aerobic fitness does not modify the effect of FTO variation on body composition traits.

PubMed

Huuskonen, Antti; Lappalainen, Jani; Oksala, Niku; Santtila, Matti; Häkkinen, Keijo; Kyröläinen, Heikki; Atalay, Mustafa

2012-01-01

Poor physical fitness and obesity are risk factors for all cause morbidity and mortality. We aimed to clarify whether common genetic variants of key energy intake determinants in leptin (LEP), leptin receptor (LEPR), and fat mass and obesity-associated (FTO) are associated with aerobic and neuromuscular performance, and whether aerobic fitness can alter the effect of these genotypes on body composition. 846 healthy Finnish males of Caucasian origin were genotyped for FTO (rs8050136), LEP (rs7799039) and LEPR (rs8179183 and rs1137101) single nucleotide polymorphisms (SNPs), and studied for associations with maximal oxygen consumption, body fat percent, serum leptin levels, waist circumference and maximal force of leg extensor muscles. Genotype AA of the FTO SNP rs8050136 associated with higher BMI and greater waist circumference compared to the genotype CC. In general linear model, no significant interaction for FTO genotype-relative VO(2)max (mL·kg(-1)·min(-1)) or FTO genotype-absolute VO(2)max (L·min(-1)) on BMI or waist circumference was found. Main effects of aerobic performance on body composition traits were significant (p<0.001). Logistic regression modelling found no significant interaction between aerobic fitness and FTO genotype. LEP SNP rs7799039, LEPR SNPs rs8179183 and rs1137101 did not associate with any of the measured variables, and no significant interactions of LEP or LEPR genotype with aerobic fitness were observed. In addition, none of the studied SNPs associated with aerobic or neuromuscular performance. Aerobic fitness may not modify the effect of FTO variation on body composition traits. However, relative aerobic capacity associates with lower BMI and waist circumference regardless of the FTO genotype. FTO, LEP and LEPR genotypes unlikely associate with physical performance.

Polymorphisms in FTO and TCF7L2 genes of Euro-Brazilian women with gestational diabetes.

PubMed

de Melo, Sandra Fabrico; Frigeri, Henrique Ravanhol; dos Santos-Weiss, Izabella Castilhos Ribeiro; Réa, Rosângela Roginski; de Souza, Emanuel Maltempi; Alberton, Dayane; Gomes de Moraes Rego, Fabiane; Picheth, Geraldo

2015-11-01

To investigate the association between fat mass and obesity-associated (FTO) gene polymorphisms rs8050136C>A and rs9939609T>A, and transcription factor 7-like 2 (TCF7L2) gene polymorphisms rs12255372G>T and rs7903146C>T, in a sample group of pregnant Euro-Brazilian women with or without gestational diabetes mellitus (GDM). Subjects were classified as either healthy pregnant control (n=200) or GDM (n=200) according to the 2010 criteria of the American Diabetes Association. The polymorphisms were genotyped using fluorescent probes (TaqMan®). All groups were in the Hardy-Weinberg equilibrium. The genotype and allele frequencies of the examined polymorphisms did not exhibit significant difference (P>0.05) between the groups. In the healthy and GDM pregnant women groups, the A-allele frequencies (95% CI) of FTO polymorphisms rs8050136 and rs9939609 were 39% (34-44%); 38% (33-43%) and 40% (35-45%); 41% (36-46%), respectively; and the T-allele frequencies of TCF7L2 polymorphisms rs12255372 and rs7903146 were 30% (26-35%), 32% (27-37%) and 29% (25-34%), 36% (31-41%), respectively. The examined polymorphisms were not associated with GDM in the Euro-Brazilian population studied. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Physical activity modifies the FTO effect on BMI change in Japanese adolescents.

PubMed

Shinozaki, Keiko; Okuda, Masayuki; Okayama, Naoko; Kunitsugu, Ichiro

2018-04-14

Evidence of the effects of fat mass and obesity-associated (FTO) gene variation and long-term effects of physical activity (PA) on adiposity in adolescents is largely scarce. This study aimed to investigate whether physical activity modulates the effects of the FTO gene on body mass index (BMI) changes in Japanese adolescents between the ages of 13 and 18 years. Data of 343 subjects (156 boys; 187 girls) who were enrolled in 2006 and 2007 from schools on Shunan City, Japan, were collected. Genotyping (rs1558902) was conducted, and anthropometric measurements and blood test results were recorded for subjects in the eighth grade. A second survey involving self-reporting of anthropometric measurements was conducted when the subjects were in the twelfth grade. PA was estimated using the International Physical Activity Questionnaire in this survey. BMI and the standard deviation score for BMI (BMI-SDS) were calculated. BMI changes and BMI-SDS changes were compared among FTO genotypes using a multivariate model. The effect of the interaction between PA and the FTO genotype on BMI changes was significant among boys but not girls. Among boys, PA had a significant negative influence on BMI-SDS changes in those with the AA genotype and a significant positive influence on BMI and BMI-SDS changes in those with the TT genotype. These data suggest that the influence of PA on BMI changes and BMI-SDS changes varied on the basis of genotype. PA modified the effect of the FTO gene on BMI changes in Japanese boys. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Long-term effects of Garcinia cambogia/Glucomannan on weight loss in people with obesity, PLIN4, FTO and Trp64Arg polymorphisms.

PubMed

Maia-Landim, Andrea; Ramírez, Juan M; Lancho, Carolina; Poblador, María S; Lancho, José L

2018-01-24

Overweight and obesity are considered major health problems that contribute to increase mortality and quality of life. Both conditions have a high prevalence across the world reaching epidemic numbers. Our aim was to evaluate the effects of the administration of Garcinia cambogia (GC) and Glucomannan (GNN) on long-term weight loss in people with overweight or obesity. Prospective, not-randomized controlled intervention trial was conducted. We treated 214 subjects with overweight or obesity with GC and GNN (500 mg twice a day, each) for 6 months evaluating weight, fat mass, visceral fat, basal metabolic rate, and lipid and glucose blood profiles comparing them with basal values. Some patients were carriers of polymorphisms PLIN4 -11482G > A-, fat mass and obesity-associated (FTO) -rs9939609 A/T- and β-adrenergic receptor 3 (ADRB3) -Trp64Arg. Treatment produced weight loss, reducing fat mass, visceral fat, lipid and blood glucose profiles while increasing basal metabolic rate. Results were independent of sex, age or suffering from hypertension, diabetes mellitus type 2 or dyslipidemia and were attenuated in carriers of PLIN4, FTO, Trp64Arg polymorphisms. Administration of GC and GNN reduce weight and improve lipid and glucose blood profiles in people with overweight or obesity, although the presence of polymorphisms PLIN4, FTO and ADRB3 might hinder in some degree these effects. ISRCTN78807585, 19 September 2017, retrospective study.

Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

PubMed

Lim, Andrea; Zhou, Jin; Sinha, Rohit A; Singh, Brijesh K; Ghosh, Sujoy; Lim, Kiat-Hon; Chow, Pierce Kah-Hoe; Woon, Esther C Y; Yen, Paul M

2016-10-21

Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH. Copyright © 2016 Elsevier Inc. All rights reserved.

FTO genotype and 2-year change in body composition and fat distribution in response to weight-loss diets: the POUNDS LOST Trial.

PubMed

Zhang, Xiaomin; Qi, Qibin; Zhang, Cuilin; Smith, Steven R; Hu, Frank B; Sacks, Frank M; Bray, George A; Qi, Lu

2012-11-01

Recent evidence suggests that the fat mass and obesity-associated gene (FTO) genotype may interact with dietary intakes in relation to adiposity. We tested the effect of FTO variant on weight loss in response to 2-year diet interventions. FTO rs1558902 was genotyped in 742 obese adults who were randomly assigned to one of four diets differing in the proportions of fat, protein, and carbohydrate. Body composition and fat distribution were measured by dual-energy x-ray absorptiometry and computed tomography. We found significant modification effects for intervention varying in dietary protein on 2-year changes in fat-free mass, whole body total percentage of fat mass, total adipose tissue mass, visceral adipose tissue mass, and superficial adipose tissue mass (for all interactions, P < 0.05). Carriers of the risk allele had a greater reduction in weight, body composition, and fat distribution in response to a high-protein diet, whereas an opposite genetic effect was observed on changes in fat distribution in response to a low-protein diet. Likewise, significant interaction patterns also were observed at 6 months. Our data suggest that a high-protein diet may be beneficial for weight loss and improvement of body composition and fat distribution in individuals with the risk allele of the FTO variant rs1558902.

Association of gene polymorphism of the fat mass and obesity associated gene with metabolic syndrome: a retrospective cohort study in Japanese workers.

PubMed

Kawajiri, Tomoka; Osaki, Yoneatsu; Kishimoto, Takuji

2012-06-01

To investigate whether gene polymorphism of the fat mass and obesity associated gene (FTO) is associated with metabolic syndrome (MS), we used two MS criteria, the National Cholesterol Education Program-Adult Treatment panel III (NCEP-ATPIII) definition in 2003 and the Japanese definition in 2005. Subjects were respectively 859 and 865 Japanese workers at a company in Shimane Prefecture, Japan. They were non-MS individuals in 1998 and had regular health checkups between 1998 and 2006. The Cox proportional hazard regression was used to predict MS. Three SNPs in the FTO, rs9939609, rs1121980 and rs1558902, were genotyped by the TaqMan PCR assay and a retrospective study was performed. The three SNPs in the FTO were significantly associated with body mass index, and rs1121980 and rs1558902 were associated with fasting plasma glucose. MS defined by the NCEP-ATPIII definition was significantly associated with additive and dominant models of rs9939609 and rs1121980, and the dominant model of rs1558902, even after adjusting for confounding factors such as age, sex and lifestyle. MS defined by the Japanese definition was significantly associated with the additive model of rs1121980 and additive and dominant models of rs1558902 in multivariate analysis. These results suggested that FTO gene polymorphisms, rs9939609, rs1121980 and rs1558902, were associated with an increased risk of MS among Japanese workers.

Television food advertisement exposure and FTO rs9939609 genotype in relation to excess consumption in children.

PubMed

Gilbert-Diamond, D; Emond, J A; Lansigan, R K; Rapuano, K M; Kelley, W M; Heatherton, T F; Sargent, J D

2017-01-01

Exposure to food advertisements may cue overeating among children, especially among those genetically predisposed to respond to food cues. We aimed to assess how television food advertisements affect eating in the absence of hunger among children in a randomized trial. We hypothesized that the fat mass and obesity-associated gene (FTO) rs9939609 single-nucleotide polymorphism would modify the effect of food advertisements. In this randomized experiment, 200 children aged 9-10 years were served a standardized lunch and then shown a 34-min television show embedded with either food or toy advertisements. Children were provided with snack food to consume ad libitum while watching the show and we measured caloric intake. Children were genotyped for rs9939609 and analyses were conducted in the overall sample and stratified by genotype. A formal test for interaction of the food advertisement effect on consumption by rs9939609 was conducted. About 172 unrelated participants were included in this analysis. Children consumed on average 453 (s.d.=185) kcals during lunch and 482 (s.d.=274) kcals during the experimental exposure. Children who viewed food advertisements consumed an average of 48 kcals (95% confidence interval: 10, 85; P=0.01) more of a recently advertised food than those who viewed toy advertisements. There was a statistically significant interaction between genotype and food advertisement condition (P for interaction=0.02), where the difference in consumption of a recently advertised food related to food advertisement exposure increased linearly with each additional FTO risk allele, even after controlling for body mass index percentile. Food advertisement exposure was associated with greater caloric consumption of a recently advertised food, and this effect was modified by an FTO genotype. Future research is needed to understand the neurological mechanism underlying these associations.

Television food advertisement exposure and FTO rs9939609 genotype in relation to excess consumption in children

PubMed Central

Gilbert-Diamond, Diane; Emond, Jennifer A.; Lansigan, Reina K.; Rapuano, Kristina M.; Kelley, William M.; Heatherton, Todd F.; Sargent, James D.

2016-01-01

BACKGROUND/OBJECTIVE Exposure to food advertisements may cue overeating among children, especially among those genetically predisposed to respond to food cues. We aimed to assess how television food advertisements affect eating in the absence of hunger among children in a randomized trial. We hypothesized that the Fat Mass and Obesity Associated Gene (FTO) rs9939609 single nucleotide polymorphism would modify the effect of food advertisements. SUBJECTS/METHODS In this randomized experiment, 200 children aged 9–10 years old were served a standardized lunch and then shown a 34-minute television show embedded with either food or toy advertisements. Children were provided with snack food to consume ad libitum while watching the show and we measured caloric intake. Children were genotyped for rs9939609 and analyses were conducted in the overall sample and stratified by genotype. A formal test for interaction of the food ad effect on consumption by rs9939609 was conducted. RESULTS 172 unrelated participants were included in this analysis. Children consumed on average 453 (SD=185) kCals during lunch and 482 (SD=274) kCals during the experimental exposure. Children who viewed food advertisements consumed an average of 48 kCals (95% CI: 10, 85; P=0.01) more of a recently advertised food than those who viewed toy advertisements. There was a statistically significant interaction between genotype and food advertisement condition (P for interaction = 0.02), where the difference in consumption of a recently advertised food related to food advertisement exposure increased linearly with each additional FTO risk allele, even after controlling for BMI percentile. CONCLUSIONS Food advertisement exposure was associated with greater caloric consumption of a recently advertised food, and this effect was modified by an FTO genotype. Future research is needed to understand the neurological mechanism underlying these associations. PMID:27654143

Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibers and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609.

PubMed

Grunnet, Louise G; Brøns, Charlotte; Jacobsen, Stine; Nilsson, Emma; Astrup, Arne; Hansen, Torben; Pedersen, Oluf; Poulsen, Pernille; Quistorff, Bjørn; Vaag, Allan

2009-02-01

Recent studies identified the rs9939609 A-allele of the FTO (fat mass and obesity associated) gene as being associated with obesity and type 2 diabetes. We studied the role of the A-allele in the regulation of peripheral organ functions involved in the pathogenesis of obesity and type 2 diabetes. Forty-six young men underwent a hyperinsulinemic euglycemic clamp with excision of skeletal muscle biopsies, an iv glucose tolerance test, 31phosphorous magnetic resonance spectroscopy, and 24-h whole body metabolism was measured in a respiratory chamber. The FTO rs9939609 A-allele was associated with elevated fasting blood glucose and plasma insulin, hepatic insulin resistance, and shorter recovery half-times of phosphocreatine and inorganic phosphate after exercise in a primarily type I muscle. These relationships--except for fasting insulin--remained significant after correction for body fat percentage. The risk allele was not associated with fat distribution, peripheral insulin sensitivity, insulin secretion, 24-h energy expenditure, or glucose and fat oxidation. The FTO genotype did not influence the mRNA expression of FTO or a set of key nuclear or mitochondrially encoded genes in skeletal muscle during rest. Increased energy efficiency--and potentially increased mitochondrial coupling--as suggested by faster recovery rates of phosphocreatine and inorganic phosphate in oxidative muscle fibers may contribute to the increased risk of obesity and type 2 diabetes in homozygous carriers of the FTO A-risk allele. Hepatic insulin resistance may represent the key metabolic defect responsible for mild elevations of fasting blood glucose associated with the FTO phenotype.

Association of fatty acid-binding protein 2 and fat mass and obesity-associated gene polymorphism with primary open-angle glaucoma

PubMed Central

Abbas, Shania; Raza, Syed Tasleem; Chandra, Anu; Singh, Luxmi; Mahdi, Farzana

2017-01-01

PURPOSE: The present study was carried out to investigate the association of fatty acid-binding protein 2 (FABP2) and fat mass and obesity-associated (FTO) gene polymorphism with primary open-angle glaucoma (POAG) cases and controls. MATERIALS AND METHODS: This study includes 122 POAG cases and 112 controls. FABP2 and FTO gene polymorphisms in cases and controls were evaluated by polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The mean ages were 49.88 ± 12.34 and 53.74 ± 11.87 years in POAG cases and control groups, respectively. The FABP2 gene AA, AT, TT genotype frequencies were 12.90%, 62.40%, 24.80% in POAG cases and 20.60%, 64.70%, 14.70% in healthy controls, respectively. The frequencies of A and T allele in POAG cases were 44.06% and 55.94% as compared to 52.94% and 47.06% in the controls. The FTO gene AA, AT, TT genotype frequencies were 2.00%, 79.20%, 18.80% in cases and 0%, 75.50%, 24.50% in healthy controls, respectively. The frequencies of A and T allele in POAG cases were 41.58% and 58.42% as compared to 37.75% and 62.25% in the controls. No significant difference in the frequencies of FABP2 and FTO genotype was found between POAG cases and controls. CONCLUSION: We could not identify the possible association of FABP2 and FTO gene polymorphism with POAG; however, further studies with larger sample size in different population are require to clarify the role of FABP2 and FTO genes in susceptibility to POAG. PMID:29034152

Expression of candidate genes associated with obesity in peripheral white blood cells of Mexican children

PubMed Central

Ulloa-Martínez, Marcela; Burguete-García, Ana I.; Murugesan, Selvasankar; Hoyo-Vadillo, Carlos; Cruz-Lopez, Miguel

2016-01-01

Introduction Obesity is a chronic, complex, and multifactorial disease, characterized by excess body fat. Diverse studies of the human genome have led to the identification of susceptibility genes that contribute to obesity. However, relatively few studies have addressed specifically the association between the level of expression of these genes and obesity. Material and methods We studied 160 healthy and obese unrelated Mexican children aged 6 to 14 years. We measured the transcriptional expression of 20 genes associated with obesity, in addition to the biochemical parameters, in peripheral white blood cells. The detection of mRNA levels was performed using the OpenArray Real-Time PCR System (Applied Biosystems). Results Obese children exhibited higher values of fasting glucose (p = 0.034), fasting insulin (p = 0.004), low-density lipoprotein (p = 0.006), triglycerides (p < 0.001), systolic blood pressure and diastolic blood pressure (p < 0.001), and lower values of high-density lipoprotein (p < 0.001) compared to lean children. Analysis of transcriptional expression data showed a difference for ADRB1 (p = 0.0297), ADIPOR1 (p = 0.0317), GHRL (p = 0.0060) and FTO (p = 0.0348) genes. Conclusions Our results suggest that changes in the expression level of the studied genes are involved in biological processes implicated in the development of childhood obesity. Our study contributes new perspectives for a better understanding of biological processes involved in obesity. The protocol was approved by the National Committee and Ethical Committee Board from the Mexican Social Security Institute (IMSS) (IMSS FIS/IMSS/PRIO/10/011). PMID:27695486

Genetic and epigenetic associations to obesity-related appetite phenotypes among African-American children.

PubMed

Gardner, K R; Sapienza, C; Fisher, J O

2015-12-01

Genetic and epigenetic variations may be an important contributer to altered eating behaviors in childhood which may lead to weight gain and obesity later in life. This study aimed to evaluate epigenetic as well as genetic associations with appetite in young children. Participants were 32 non-obese and 32 obese African-American children aged 5-6 years. Saliva was collected from each child, and RNA and DNA were extracted for analysis. Individuals were genotyped for eating- and obesity-associated single nucleotide polymorphisms in seven candidate genes (FTO, MAOA, SH2B1, LEPR, DNMT3B, BDNF and CCKAR), and DNA methylation levels were measured in the upstream promoter region of each. Transcript levels of MAOA and FTO were also assessed. The Children's Eating Behavior Questionnaire (CEBQ) was used to assess the aspects of appetite. Child obesity was assessed using measured height and weight, and percent body fat was measured by dual-energy X-ray absorptiometry. Food responsiveness was higher and satiety responsiveness was lower among obese than non-obese female children (P = 0.001 and P = 0.031), but did not differ among male children. Epigenetic analysis of the BDNF promoter revealed associations with altered satiety responsiveness among female children (P < 0.01). The findings provide new evidence of epigenetic associations with altered appetite among young African-American girls. © 2015 World Obesity.

The FTO gene is associated with an atherogenic lipid profile and myocardial infarction in patients with type 2 diabetes: a Genetics of Diabetes Audit and Research Study in Tayside Scotland (Go-DARTS) study.

PubMed

Doney, Alex S F; Dannfald, Jennifer; Kimber, Charlotte H; Donnelly, Louise A; Pearson, Ewan; Morris, Andrew D; Palmer, Colin N A

2009-06-01

Common variation in the fat mass and obesity (FTO)-related gene is associated with increased body fat and susceptibility to type 2 diabetes. We hypothesized that this would also associate with metabolic phenotypes of insulin resistance and increased risk of cardiovascular morbidity and mortality. FTO rs9939609 genotype was determined in 4897 patients with type 2 diabetes in the prospective Genetics of Diabetes Audit and Research Study in Tayside Scotland study. The A allele was associated with lower plasma high-density lipoprotein cholesterol (mean difference, 0.03 mmol/L; P=0.008), higher triglycerides (0.1 mmol/L, P=0.007), higher atherogenic index of plasma (0.03, P=0.003), and, as expected, increased body mass index (0.77 kg/m(2), P=8.8 x 10(-6)). During a mean follow-up of 3.6 years, the A allele was also associated with increased risk (hazard ratio, 2.36; CI, 1.49 to 3.74; P=0.0002) of fatal and nonfatal myocardial infarction (total of 324 events) in a model, including baseline age, gender, prevalent myocardial infarction, smoking status, statin, and insulin use. This association diminished but remained significant when obesity-related traits, such as body mass index, glycohemoglobin, and lipid parameters, were also included (hazard ratio, 2.01; CI, 1.18 to 3.45, P=0.011). There was a strong interaction of FTO genotype and statin use and cardiovascular outcome (P=0.001), such that cardiovascular morbidity and mortality was completely abrogated in individuals who were prescribed statins. The increased fat mass in carriers of the A allele of rs9939609 of FTO is associated not only with increased risk of type 2 diabetes, but also with an increase in atherogenic lipid profile and myocardial infarction in these patients. This variant may, therefore, in the future contribute to more effective targeting of specific preventative therapy.

Effects of MC4R, FTO, and NMB gene variants to obesity, physical activity, and eating behavior phenotypes.

PubMed

Kirac, Deniz; Kasimay Cakir, Ozgur; Avcilar, Tuba; Deyneli, Oguzhan; Kurtel, Hizir; Yazici, Dilek; Kaspar, Elif Cigdem; Celik, Nurgul; Guney, Ahmet Ilter

2016-10-01

Obesity is a major contributory factor of morbidity and mortality. It has been suggested that biological systems may be involved in the tendency to be and to remain physically inactive also behaviors such as food and beverage preferences and nutrient intake may at least partially genetically determined. Consequently, besides environment, genetic factors may also contribute to the level of physical activity and eating behaviors thus effect obesity. Therefore the aim of this study is to investigate the effect of various gene mutations on obesity, physical activity levels and eating behavior phenotypes. One hundred patients and 100 controls were enrolled to the study. Physical activity levels were measured with an actical acceloremeter device. Eating behaviors were evaluated using Three-Factor Eating questionnaire (TFEQ). Associations between eating behavior scores and physical characteristics were also evaluated. The information about other obesity risk factors were also collected. Mutations were investigated with PCR, direct sequencing and Real-Time PCR. rs1051168, rs8050146 -2778C > T mutations were found statistically significant in patients, rs1121980 was found statistically significant in controls. 21 mutations were found in MC4R and near MC4R of which 18 of them are novel and 8 of them cause amino acid change. In addition, it was found that, some obesity related factors and questions of TFEQ are associated with various investigated gene mutations. Any relation between gene mutations and physical activity levels were not detected. It is thought that, due to the genotype data and eating behaviors, it may be possible to recommend patients for proper eating patterns to prevent obesity. © 2016 IUBMB Life, 68(10):806-816, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

An integrated approach of comparative genomics and heritability analysis of pig and human on obesity trait: evidence for candidate genes on human chromosome 2.

PubMed

Kim, Jaemin; Lee, Taeheon; Kim, Tae-Hun; Lee, Kyung-Tai; Kim, Heebal

2012-12-19

Traditional candidate gene approach has been widely used for the study of complex diseases including obesity. However, this approach is largely limited by its dependence on existing knowledge of presumed biology of the phenotype under investigation. Our combined strategy of comparative genomics and chromosomal heritability estimate analysis of obesity traits, subscapular skinfold thickness and back-fat thickness in Korean cohorts and pig (Sus scrofa), may overcome the limitations of candidate gene analysis and allow us to better understand genetic predisposition to human obesity. We found common genes including FTO, the fat mass and obesity associated gene, identified from significant SNPs by association studies of each trait. These common genes were related to blood pressure and arterial stiffness (P = 1.65E-05) and type 2 diabetes (P = 0.00578). Through the estimation of variance of genetic component (heritability) for each chromosome by SNPs, we observed a significant positive correlation (r = 0.479) between genetic contributions of human and pig to obesity traits. Furthermore, we noted that human chromosome 2 (syntenic to pig chromosomes 3 and 15) was most important in explaining the phenotypic variance for obesity. Obesity genetics still awaits further discovery. Navigating syntenic regions suggests obesity candidate genes on chromosome 2 that are previously known to be associated with obesity-related diseases: MRPL33, PARD3B, ERBB4, STK39, and ZNF385B.

A high intake of saturated fatty acids strengthens the association between the fat mass and obesity-associated gene and BMI

USDA-ARS?s Scientific Manuscript database

Evidence that physical activity (PA) modulates the association between the fat mass and obesity-associated gene (FTO) and BMI is emerging; however, information about dietary factors modulating this association is scarce. We investigated whether fat and carbohydrate intake modified the association of...

The Effects of Genetic Variation in FTO rs9939609 on Obesity and Dietary Preferences in Chinese Han Children and Adolescents

PubMed Central

Yang, Min; Xu, Yuyang; Liang, Li; Fu, Junfen; Xiong, Feng; Liu, Geli; Gong, Chunxiu; Luo, Feihong; Chen, Shaoke; Xu, Chunxiao; Zhang, Dandan; Li, Zhengli; Zhang, Shuai; Zhang, Yan; Wang, Hao; Zhu, Yimin

2014-01-01

The association of the rs9939609 single nucleotide polymorphism in FTO gene with obesity has been extensively investigated in studies of populations of European, African, and Asian ancestry. However, inconsistent results have been reported in Asian populations, and the relationship of FTO variation and dietary behaviors has only rarely been examined in Chinese children and adolescents. The aim of this study was to assess the association of rs9939609 with obesity and dietary preferences in childhood in a Chinese population. Epidemiological data including dietary preferences were collected in interviews using survey questionnaires, and rs9939609 genotype was determined by real-time PCR. The associations of rs9939609 genotypes with obesity and dietary preferences were analyzed by multivariate logistic regression using both additive and dominant models. The results showed that subjects with a TA or AA genotype had an increased risk of obesity compared with the TT participants; the odds ratios (ORs) were 1.47 (95% CI: 1.25–1.71, P = 1.73×10−6), and 3.32 (95% CI: 2.01–5.47, P = 2.68×10−6), respectively. After adjusting for age and gender, body mass index, waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol were higher, and high-density lipoprotein cholesterol was lower in TA and AA participants than in those with the TT genotype. After additionally controlling for body mass index, the association remained significant only for systolic blood pressure (P = 0.005). Compared with TT participants, those with the AA genotype were more likely to prefer a meat-based diet (OR = 2.81, 95% CI: 1.52–5.21). The combined OR for obesity in participants with TA/AA genotypes and preference for a meat-based diet was 4.04 (95% CI: 2.8–5.81) compared with the TT participants who preferred a plant-based diet. These findings indicate the genetic

Effects of energy expenditure gene polymorphisms on obesity-related traits in obese children.

PubMed

Csernus, Katalin; Pauler, Gábor; Erhardt, Éva; Lányi, Éva; Molnár, Dénes

2015-01-01

To assess the frequencies of common polymorphisms of genes associated with energy expenditure among Hungarian obese children and investigate their influences on obesity-related traits and metabolic complications of common childhood obesity. In a total of 528 obese children (age 13.2±2.6 years) an oral glucose tolerance test and determination of fasting serum lipid levels were carried out, blood pressure and resting energy expenditure were measured and the children were genotyped for the following gene polymorphisms: Trp64Arg of β3-adrenoreceptor (ADRB3), -3826 A/G of uncoupling protein (UCP)-1, exon 8 45 bp del/ins and -866 G/A of UCP-2, -55 C/T of UCP-3, and Pro12Ala of peroxisome-proliferator activated receptor gamma-2. Carriers of the ADRB3 Arg64 allele had a significantly higher relative body weight and relative body mass index compared with non-carriers. The UCP-2 exon 8 del/ins polymorphism was associated with higher degree of obesity, insulin resistance, dyslipideamia and lower adjusted metabolic rate. Children with UCP-3 -55 T/T genotype had a significantly lower adjusted metabolic rate than the C allele carriers. We found evidence for associations between common polymorphisms of the ADRB3, the UCP-2 and UCP-3 genes and basic metabolic rate as well as level and metabolic consequences of common obesity among Hungarian school-aged children. Copyright © 2014 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse

PubMed Central

Wells, Sara; Teboul, Lydia; Tung, Y. C. Loraine; Rimmington, Debra; Bosch, Fatima; Jimenez, Veronica; Yeo, Giles S. H.; O'Rahilly, Stephen; Ashcroft, Frances M.; Coll, Anthony P.; Cox, Roger D.

2013-01-01

The strongest BMI–associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake. PMID:23300482

Sexual dimorphism in obesity-related genes in the epicardial fat during aging.

PubMed

Kocher, Caitlin; Christiansen, Matthew; Martin, Sarah; Adams, Christopher; Wehner, Paulette; Gress, Todd; Santanam, Nalini

2017-05-01

Aging increases the risk of cardiovascular disease and metabolic syndrome. Alterations in epicardial fat play an important pathophysiological role in coronary artery disease and hypertension. We investigated the impact of normal aging on obesity-related genes in epicardial fat. Sex-specific changes in obesity-related genes with aging in epicardial fat (EF) were determined in young (6 months) and old (30/36 months) female and male, Fischer 344 × Brown Norway hybrid (FBN) rats, using a rat obesity RT 2 PCR Array. Circulating sex hormone levels, body and heart weights were determined. Statistical significance was determined using two-tailed Student's t test and Pearson's correlation. Our results revealed sex-specific differences in obesity-related genes with aging. Dramatic changes in the expression profile of obesity-related genes in EF with aging in female, but not in male, FBN rats were observed. The older (30 months) female rats had more significant variations in the abundance of obesity-related genes in the EF compared to that seen in younger female rats or both age groups in male rats. A correlation of changes in obesity-related genes in EF to heart weights was observed in female rats, but not in male rats with aging. No correlation was observed to circulating sex hormone levels. Our findings indicate a dysfunctional EF in female rats with aging compared to male rats. These findings, with further functional validation, might help explain the sex differences in cardiovascular risk and mortality associated with aging observed in humans.

Analysis of vascular endothelial dysfunction genes and related pathways in obesity through systematic bioinformatics.

PubMed

Zhang, Hui; Wang, Jing; Sun, Ling; Xu, Qiuqin; Hou, Miao; Ding, Yueyue; Huang, Jie; Chen, Ye; Cao, Lei; Zhang, Jianmin; Qian, Weiguo; Lv, Haitao

2015-01-01

Obesity has become an increasingly serious health problem and popular research topic. It is associated with many diseases, especially cardiovascular disease (CVD)-related endothelial dysfunction. This study analyzed genes related to endothelial dysfunction and obesity and then summarized their most significant signaling pathways. Genes related to vascular endothelial dysfunction and obesity were extracted from a PubMed database, and analyzed by STRING, DAVID, and Gene-Go Meta-Core software. 142 genes associated with obesity were found to play a role in endothelial dysfunction in PubMed. A significant pathway (Angiotensin system maturation in protein folding and maturation) associated with obesity and endothelial dysfunction was explored. The genes and the pathway explored may play an important role in obesity. Further studies about preventing vascular endothelial dysfunction obesity should be conducted through targeting these loci and pathways.

Disease associated clinical factors and FTO polymorphism: effect on body mass in children with type 1 diabetes mellitus.

PubMed

Łuczyński, Włodzimierz; Szypowska, Agnieszka; Głowińska-Olszewska, Barbara; Szadkowska, Agnieszka; Bossowski, Artur

2014-08-01

One of the consequences of excessive weight gain during insulin therapy in type 1 diabetes mellitus (T1DM) is an increased predisposition to cardiovascular diseases (CVD). Not only clinical but also genetic factors may play a role in the pathogenesis of this phenomenon. The aim of this study was to evaluate the prevalence of cardiovascular disease risk factors as well as the fat mass and obesity associated (FTO) gene rs9939609 variant in a large group of children with T1DM of the same ethnic-Polish origin. A total of 1237 children with T1DM and 1015 controls were recruited. The proportions of patients with obesity, hypertension, and abnormal LDL-cholesterol levels among children with T1DM were significantly higher than those in the non-diabetic. There was a higher rate of overweight, central obesity, and abnormal LDL-cholesterol levels among girls in comparison to that in boys in the group of children with diabetes. Children with inadequate metabolic control were characterized by the presence of more CVD risk factors. Similar differences were observed in children treated with the use of pens versus those using insulin pumps. The FTO gene single nucleotide polymorphism (SNP) correlated with body mass index (BMI) in both control and diabetic children, but the effect was lesser in diabetics. In a regression model the current BMI-SDS value in diabetics was significantly affected by the baseline BMI, disease duration, metabolic control, and subject's sex, but not the FTO genotype. Clinical rather than genetic factors have a greater impact on the development of overweight and obesity in insulin-treated children

Protein kinase Cβ activates fat mass and obesity-associated protein by influencing its ubiquitin/proteasome degradation.

PubMed

Tai, Haoran; Wang, Xiaobo; Zhou, Jiao; Han, Xiaojuan; Fang, Tingting; Gong, Hui; Huang, Ning; Chen, Honghan; Qin, Jianqiong; Yang, Ming; Wei, Xiawei; Yang, Li; Xiao, Hengyi

2017-10-01

Protein kinase Cβ (PKCβ) is a serine-threonine kinase associated with obesity and diabetic complications; its activation contributes to weight gain, and deletion of its gene results in resistance to genetic- and diet-induced obesity. Fat mass and obesity-associated (FTO) protein is a recently identified RNA demethylase, and its overexpression in mice leads to increased body weight as well as fat mass. Although sharing some features in anabolism regulation, PKCβ and FTO have not been investigated together; therefore, their relationship has not been established. We report that PKCβ positively regulates FTO on the posttranslation level, evidenced by the facts that PKCβ activation contributes to high-glucose-induced FTO up-regulation, and overexpression of PKCβ suppresses ubiquitin-proteasome degradation of FTO, whereas PKCβ inactivation acts in the opposite manner. It was also found that PKCβ can phosphorylate FTO on threonine, and this phosphorylation requires both catalytic and regulatory domains of PKCβ. Moreover, PKCβ inhibition can suppress 3T3-L1 cell differentiation in normal and FTO-overexpressing cells but not in FTO-silenced or -inhibited cells. We propose that PKCβ acts to suppress the degradation of FTO protein and reveals the associated role of PKCβ and FTO in adipogenesis, suggesting a new pathway that affects the development of obesity and metabolic diseases.-Tai, H., Wang, X., Zhou, J., Han, X., Fang, T., Gong, H., Huang, N., Chen, H., Qin, J., Yang, M., Wei, X., Yang, L., Xiao, H. Protein kinase Cβ activates fat mass and obesity-associated protein by influencing its ubiquitin/proteasome degradation. © FASEB.

An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference

PubMed Central

Rees, S. D.; Islam, M.; Hydrie, M. Z. I.; Chaudhary, B.; Bellary, S.; Hashmi, S.; O’Hare, J. P.; Kumar, S.; Sanghera, D. K.; Chaturvedi, N.; Barnett, A. H.; Shera, A. S.; Weedon, M. N.; Basit, A.; Frayling, T. M.; Kelly, M. A.; Jafar, T. H.

2011-01-01

Aims A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. Methods We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥ 40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case–control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. Results In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95% CI 0.24–0.67) kg/m2 per A-allele (P = 3.0× 10−5) and with waist circumference was 0.88 (95% CI 0.36–1.41) cm per A-allele (P = 0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95% CI) 1.18 (1.07–1.30); P = 0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95% CI 1.14–1.31); P = 1.07× 10−8] even after adjusting for BMI [1.18 (95% CI 1.10–1.27); P = 1.02× 10−5] or waist circumference [1.18 (95% CI 1.10–1.27); P = 3.97× 10−5]. Conclusions The

Polygenic obesity in humans.

PubMed

Hinney, Anke; Hebebrand, Johannes

2008-01-01

The molecular genetic analysis of obesity has led to the identification of a limited number of confirmed major genes. While such major genes have a clear influence on the development of the phenotype, the underlying mutations are however (extremely) infrequent and thus of minor clinical importance only. The genetic predisposition to obesity must thus be polygenic; a number of such variants should be found in most obese subjects; however, these variants predisposing to obesity are also found in normal weight and even lean individuals. Therefore, a polygene can only be identified and validated by statistical analyses: the appropriate gene variant (allele) occurs more frequently in obese than in non-obese subjects. Each single polygene makes only a small contribution to the development of obesity. The 103Ile allele of the Val103Ile single nucleotide polymorphism (SNP) of the melanocortin-4 receptor gene (MC4R) was the first confirmed polygenetic variant with an influence on the body mass index (BMI); the more common Val103 allele is more frequent in obese individuals. As determined in a recent, large-scaled meta-analysis the effect size of this allele on mean BMI was approximately -0.5 kg/m(2). The first genome-wide association study (GWA) for obesity, based on approximately 100,000 SNPs analyzed in families of the Framingham study, revealed that a SNP in the proximity of the insulin-induced gene 2 (INSIG2) was associated with obesity. The positive result was replicated in independent samples; however, some other study groups detected no association. Currently, a meta-analysis is ongoing; its result will contribute to the evaluation of the importance of the INSIG2 polymorphism in body weight regulation. SNP alleles in intron 1 of the fat mass and obesity associated gene (FTO) confer the most relevant polygenic effect on obesity. In the first GWA for extreme early onset obesity we substantiated that variation in FTO strongly contributes to early onset obesity

Common variants in FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 show evidence of association with adult obesity in the Greek population.

PubMed

Rouskas, Konstantinos; Kouvatsi, Anastasia; Paletas, Konstantinos; Papazoglou, Dimitrios; Tsapas, Apostolos; Lobbens, Stéphane; Vatin, Vincent; Durand, Emmanuelle; Labrune, Yann; Delplanque, Jérôme; Meyre, David; Froguel, Philippe

2012-02-01

Twenty-four single-nucleotide polymorphisms (SNPs) have been reproducibly associated with obesity. We performed a follow-up study for obesity in the Greek adult population. A total of 510 obese and 469 lean adults were genotyped for 24 SNPs. We tested the association with obesity status using logistic regression and we evaluated the combined genetic risk of 24 SNPs by calculating the area under the receiver-operating characteristic (ROC) curves. We nominally replicated the association with obesity (BMI ≥30 kg/m(2)) of six SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci (1.28 ≤ odds ratio (OR) ≤ 1.35; 0.004 ≤ P ≤ 0.043). The discrimination ability for obesity was slightly stronger (P = 9.59 × 10(-6)) when the genetic information of the 24 SNPs was added to nongenetic risk factors (area under the curve (AUC) = 0.722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population.

Obesity genes and risk of major depressive disorder in a multiethnic population: a cross-sectional study.

PubMed

Samaan, Zainab; Lee, Yvonne K; Gerstein, Hertzel C; Engert, James C; Bosch, Jackie; Mohan, Viswanathan; Diaz, Rafael; Yusuf, Salim; Anand, Sonia S; Meyre, David

2015-12-01

Observational studies have shown a positive association between obesity (body mass index [BMI] ≥ 30 kg/m2) and depression. Around 120 obesity-associated loci have been identified, but genetic variants associated with depression remain elusive. Recently, our team reported that the fat mass and obesity-associated (FTO) gene rs9939609 obesity-risk variant is paradoxically inversely associated with the risk of depression. This finding raises the question as to whether other obesity-associated genetic variants are also associated with depression. Twenty-one obesity gene variants other than FTO were selected from a custom ∼50,000 single-nucleotide polymorphisms (SNPs) genotyping array (ITMAT-Broad-CARe array). Associations of these 21 SNPs and an unweighted genotype score with BMI and major depressive disorder (determined using the DSM-IV diagnostic criteria) were tested in 3,209 cases and 14,195 noncases, using baseline data collected from July 2001 to August 2003 from the multiethnic EpiDREAM study. Body mass index was positively associated with depression status (odds ratio [OR] = 1.02; 95% CI, 1.02-1.03 per BMI unit; P = 2.9 × 10(-12), adjusted for age, sex, and ethnicity). Six of 21 genetic variants (rs1514176 [TNN13K], rs2206734 [CDKAL1], rs11671664 [GIPR], rs2984618 [TAL1], rs3824755 [NT5C2], and rs7903146 [TCF7L2]) and the genotype score were significantly associated with BMI (1.47 × 10(-14) ≤ P ≤ .04). Of the 21 SNPs, TAL1 rs2984618 obesity-risk allele was associated with a higher risk of major depressive disorder (P = 1.79 × 10(-4), adjusted for age, sex, BMI, and ethnicity), and BDNF rs1401635 demonstrated significant ethnic-dependent association with major depressive disorder (OR = 0.88; 95% CI, 0.80-0.97; P = .01 in non-Europeans and OR = 1.11; 95% CI, 1.02-1.20; P = .02 in Europeans; Pinteraction = 2.73 × 10(-4)). The genotype score, calculated with or without FTO rs9939609, and adjusted for the same covariates, was not associated with

Association between FTO polymorphism in exon 3 with carcass and meat quality traits in crossbred ducks.

PubMed

Gan, W; Song, Q; Zhang, N N; Xiong, X P; Wang, D M C; Li, L

2015-06-18

The fat mass and obesity-associated gene (FTO) is an excellent candidate gene that affects energy metabolism. Single nucleotide polymorphisms (SNPs) in FTO are associated with carcass and meat quality traits in pigs, cattle, and rabbits. The aim of this study was to investigate the association between novel SNPs in the FTO coding region and carcass and meat quality traits in 95 crossbred ducks, using DNA sequencing. We found two transitions G/A (SNP 387 and 473) within exon 3. SNP 387 was a synonymous mutation, whereas SNP 473 was a missense mutation. Association analysis suggested that SNP g.387G>A was significantly associated with all of the carcass traits measured, the intramuscular fat content (IMF), cooking yield (CY), pH values 45 min after slaughter (pH45m), drip losses from the breast muscle, and the leg muscle (P < 0.05). For SNP g.473G>A, the genotype AA exhibited greater leg muscle weight than the genotypes GG or AG (P < 0.05). The D value suggested that the two SNPs exhibited strong linkage disequilibrium. Three haplotypes (G1G2, G1A2, and A1A2) were significantly associated with IMF, CY, the a* value, and all of the carcass traits measured (P < 0.05). The results suggest that FTO is a candidate locus that affects carcass and meat quality traits in ducks.

Important Role of FTO in the Survival of Rare Panresistant Triple-Negative Inflammatory Breast Cancer Cells Facing a Severe Metabolic Challenge

PubMed Central

Singh, Balraj; Kinne, Hannah E.; Milligan, Ryan D.; Washburn, Laura J.; Olsen, Mark; Lucci, Anthony

2016-01-01

We have previously shown that only 0.01% cells survive a metabolic challenge involving lack of glutamine in culture medium of SUM149 triple-negative Inflammatory Breast Cancer cell line. These cells, designated as SUM149-MA for metabolic adaptability, are resistant to chemotherapeutic drugs, and they efficiently metastasize to multiple organs in nude mice. We hypothesized that obesity-related molecular networks, which normally help in cellular and organismal survival under metabolic challenges, may help in the survival of MA cells. The fat mass and obesity-associated protein FTO is overexpressed in MA cells. Obesity-associated cis-acting elements in non-coding region of FTO regulate the expression of IRX3 gene, thus activating obesity networks. Here we found that IRX3 protein is significantly overexpressed in MA cells (5 to 6-fold) as compared to the parental SUM149 cell line, supporting our hypothesis. We also obtained evidence that additional key regulators of energy balance such as ARID5B, IRX5, and CUX1 P200 repressor could potentially help progenitor-like TNBC cells survive in glutamine-free medium. MO-I-500, a pharmacological inhibitor of FTO, significantly (>90%) inhibited survival and/or colony formation of SUM149-MA cells as compared to untreated cells or those treated with a control compound MO-I-100. Curiously, MO-I-500 treatment also led to decreased levels of FTO and IRX3 proteins in the SUM149 cells initially surviving in glutamine-free medium as compared to MO-I-100 treatment. Interestingly, MO-I-500 treatment had a relatively little effect on cell growth of either the SUM149 or SUM149-MA cell line when added to a complete medium containing glutamine that does not pose a metabolic challenge. Importantly, once selected and cultured in glutamine-free medium, SUM149-MA cells were no longer affected by MO-I-500 even in Gln-free medium. We conclude that panresistant MA cells contain interconnected molecular networks that govern developmental status and

Green tea polyphenols reduce body weight in rats by modulating obesity-related genes.

PubMed

Lu, Chuanwen; Zhu, Wenbin; Shen, Chwan-Li; Gao, Weimin

2012-01-01

Beneficial effects of green tea polyphenols (GTP) against obesity have been reported, however, the mechanism of this protection is not clear. Therefore, the objective of this study was to identify GTP-targeted genes in obesity using the high-fat-diet-induced obese rat model. A total of three groups (n = 12/group) of Sprague Dawley (SD) female rats were tested, including the control group (rats fed with low-fat diet), the HF group (rats fed with high-fat diet), and the HF+GTP group (rats fed with high-fat diet and GTP in drinking water). The HF group increased body weight as compared to the control group. Supplementation of GTP in the drinking water in the HF+GTP group reduced body weight as compared to the HF group. RNA from liver samples was extracted for gene expression analysis. A total of eighty-four genes related to obesity were analyzed using PCR array. Compared to the rats in the control group, the rats in the HF group had the expression levels of 12 genes with significant changes, including 3 orexigenic genes (Agrp, Ghrl, and Nr3c1); 7 anorectic genes (Apoa4, Cntf, Ghr, IL-1β, Ins1, Lepr, and Sort); and 2 genes that relate to energy expenditure (Adcyap1r1 and Adrb1). Intriguingly, the HF+GTP group restored the expression levels of these genes in the high-fat-induced obese rats. The protein expression levels of IL-1β and IL-6 in the serum samples from the control, HF, and HF+GTP groups confirmed the results of gene expression. Furthermore, the protein expression levels of superoxide dismutase-1 (SOD1) and catechol-O-methyltransferase (COMT) also showed GTP-regulated protective changes in this obese rat model. Collectively, this study revealed the beneficial effects of GTP on body weight via regulating obesity-related genes, anti-inflammation, anti-oxidant capacity, and estrogen-related actions in high-fat-induced obese rats.

Green Tea Polyphenols Reduce Body Weight in Rats by Modulating Obesity-Related Genes

PubMed Central

Lu, Chuanwen; Zhu, Wenbin; Shen, Chwan-Li; Gao, Weimin

2012-01-01

Beneficial effects of green tea polyphenols (GTP) against obesity have been reported, however, the mechanism of this protection is not clear. Therefore, the objective of this study was to identify GTP-targeted genes in obesity using the high-fat-diet-induced obese rat model. A total of three groups (n = 12/group) of Sprague Dawley (SD) female rats were tested, including the control group (rats fed with low-fat diet), the HF group (rats fed with high-fat diet), and the HF+GTP group (rats fed with high-fat diet and GTP in drinking water). The HF group increased body weight as compared to the control group. Supplementation of GTP in the drinking water in the HF+GTP group reduced body weight as compared to the HF group. RNA from liver samples was extracted for gene expression analysis. A total of eighty-four genes related to obesity were analyzed using PCR array. Compared to the rats in the control group, the rats in the HF group had the expression levels of 12 genes with significant changes, including 3 orexigenic genes (Agrp, Ghrl, and Nr3c1); 7 anorectic genes (Apoa4, Cntf, Ghr, IL-1β, Ins1, Lepr, and Sort); and 2 genes that relate to energy expenditure (Adcyap1r1 and Adrb1). Intriguingly, the HF+GTP group restored the expression levels of these genes in the high-fat-induced obese rats. The protein expression levels of IL-1β and IL-6 in the serum samples from the control, HF, and HF+GTP groups confirmed the results of gene expression. Furthermore, the protein expression levels of superoxide dismutase-1 (SOD1) and catechol-O-methyltransferase (COMT) also showed GTP-regulated protective changes in this obese rat model. Collectively, this study revealed the beneficial effects of GTP on body weight via regulating obesity-related genes, anti-inflammation, anti-oxidant capacity, and estrogen-related actions in high-fat-induced obese rats. PMID:22715380

Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay.

PubMed

Daoud, Hussein; Zhang, Dong; McMurray, Fiona; Yu, Andrea; Luco, Stephanie M; Vanstone, Jason; Jarinova, Olga; Carson, Nancy; Wickens, James; Shishodia, Shifali; Choi, Hwanho; McDonough, Michael A; Schofield, Christopher J; Harper, Mary-Ellen; Dyment, David A; Armour, Christine M

2016-03-01

A homozygous loss-of-function mutation p.(Arg316Gln) in the fat mass and obesity-associated (FTO) gene, which encodes for an iron and 2-oxoglutarate-dependent oxygenase, was previously identified in a large family in which nine affected individuals present with a lethal syndrome characterised by growth retardation and multiple malformations. To date, no other pathogenic mutation in FTO has been identified as a cause of multiple congenital malformations. We investigated a 21-month-old girl who presented distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. We performed targeted next-generation sequencing of 4813 clinically relevant genes in the patient and her parents. We identified a novel FTO homozygous missense mutation (c.956C>T; p.(Ser319Phe)) in the affected individual. This mutation affects a highly conserved residue located in the same functional domain as the previously characterised mutation p.(Arg316Gln). Biochemical studies reveal that p.(Ser319Phe) FTO has reduced 2-oxoglutarate turnover and N-methyl-nucleoside demethylase activity. Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The influence of clinical and genetic factors on the development of obesity in children with type 1 diabetes.

PubMed

Łuczyński, Włodzimierz; Głowińska-Olszewska, Barbara; Bossowski, Artur

2016-10-01

The exact cause of the obesity epidemic remains unknown; however, both environmental and genetic factors are involved. People at risk of developing obesity include children with type 1 diabetes mellitus (T1DM), which in turn increases their cardiovascular disease risk. Here, we discuss the clinical and genetic factors influencing weight in patients with T1DM. In children with T1DM, the presence of obesity depends mainly on sex, metabolic control, and disease duration. However, genetic factors, including the fat mass and obesity-associated (FTO) gene, are also associated with body weight. Indeed, children with the FTO gene rs9939609 obesity-risk allele (homozygous = AA or heterozygous = AT) are predisposed to a higher body mass index and have a greater risk of being overweight or obese. However, in this review, we show that FTO gene polymorphisms only have a small effect on body weight in children, much weaker than the effect of clinical factors. The association between FTO gene polymorphisms and body weight is only statistically significant in children without severe obesity. Moreover, other genetic factors had no effect on weight in patients with T1DM, and further research involving larger populations is required to confirm the genetic basis of diabetes and obesity. Therefore, identifying the clinical features of children with T1DM, such as their initial body mass index, sex, metabolic control, and disease duration, will still have the strongest effect on reducing risk factors for cardiovascular diseases. Physicians should pay close attention to modifiable elements of these relationships, for example, metabolic control and energy and insulin intake, when caring for patients with T1DM. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5

PubMed Central

Huang, Yue; Yan, Jingli; Li, Qi; Li, Jiafei; Gong, Shouzhe; Zhou, Hu; Gan, Jianhua; Jiang, Hualiang; Jia, Gui-Fang; Luo, Cheng; Yang, Cai-Guang

2015-01-01

Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N6-methyladenosine (m6A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m6A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m6A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine. PMID:25452335

Individual genetic variations related to satiety and appetite control increase risk of obesity in preschool-age children in the STRONG kids program.

PubMed

Wang, Yingying; Wang, Anthony; Donovan, Sharon M; Teran-Garcia, Margarita

2013-01-01

The burden of the childhood obesity epidemic is well recognized; nevertheless, the genetic markers and gene-environment interactions associated with the development of common obesity are still unknown. In this study, candidate genes associated to satiety and appetite control pathways with obesity-related traits were tested in Caucasian preschoolers from the STRONG Kids project. Eight genetic variants in genes related to obesity (BDNF, LEPR, FTO, PCSK1, POMC, TUB, LEP, and MC4R) were genotyped in 128 children from the STRONG Kids project (mean age 39.7 months). Data were analyzed for individual associations and to test for genetic predisposition scores (GPSs) with body mass index (BMI) and anthropometric traits (Z-scores, e.g. height-for-age Z-score, HAZ). Covariates included age, sex, and breastfeeding (BF) duration. Obesity and overweight prevalence was 6.3 and 19.5%, respectively, according to age- and sex-specific BMI percentiles. Individual genetic associations of MC4R and LEPR markers with HAZ were strengthened when BF duration was included as a covariate. Our GPSs show that, as the number of risk alleles increased, the risk of higher BMI and HAZ also increased. Overall, the GPSs assembled were able to explain 2-3% of the variability in BMI and HAZ phenotypes. Genetic associations with common obesity-related phenotypes were found in the STRONG Kids project. GPSs assembled for specific candidate genes were associated with BMI and HAZ phenotypes. © 2013 S. Karger AG, Basel.

Relationships between FTO rs9939609, MC4R rs17782313, and PPARγ rs1801282 polymorphisms and the occurrence of selected metabolic and hormonal disorders in middle-aged and elderly men - a preliminary study.

PubMed

Rotter, Iwona; Skonieczna-Żydecka, Karolina; Kosik-Bogacka, Danuta; Adler, Grażyna; Rył, Aleksandra; Laszczyńska, Maria

2016-01-01

Metabolic disorders, including MetS, obesity, and lipid disorders, may be related to genetic factors. Metabolic disorders are associated with decreased TS levels in aging men. The aim of this study was to evaluate the relationship between FTO rs9939609, MC4R rs17782313, and PPARγ rs1801282 polymorphisms and the presence of MetS and its components, the concurrent lipid disorders, as well as sex hormone concentrations. This study involved 272 men of Caucasian descent aged 50-75 years. Lipid profile, including TCh, LDL, HDL, and TG, was evaluated by spectrophotometric method. Anthropometric measurements concerned WC and blood pressure. MetS was diagnosed according to the criteria of the IDF. Sex hormone profile, including TST, FTS, E 2 , DHEAS, and SHBG, was examined using enzyme-linked immunosorbent assay. Polymorphisms within FTO , MC4R , and PPARγ genes were identified using polymerase chain reaction-restriction fragments length polymorphism. This study did not show links between the analyzed genetic polymorphisms and the presence of MetS, T2DM, HT, and obesity. However, higher concentrations of TCh and LDL were found in men with the FTO rs9939609 polymorphism in the recessive mode of inheritance ( P =0.03 and P =0.05, respectively). Lower WC was found to be associated with MC4R rs17782313 gene inherited in the same model ( P =0.005). FTO rs9939609, MC4R rs17782313, and PPARγ rs1801282 polymorphisms seem to have little effect on the incidence of metabolic malfunctions and no effect on androgen-related disorders in the examined middle-aged and elderly men.

m6A demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression.

PubMed

Liu, Jiqin; Ren, Dangli; Du, Zhenhua; Wang, Hekong; Zhang, Hua; Jin, Ying

2018-08-25

N 6 -Methyladenosine (m 6 A) represents the most prevalent internal modification in mammalian mRNAs. Emerging evidences suggest that m 6 A modification is profoundly implicated in many biological processes, including cancer development. However, limited knowledge is available about the functional importance of m 6 A in lung cancer. In this study, by data mining The Cancer Genome Atlas (TCGA) database, we first identified fat mass- and obesity-associated protein (FTO) as a prognostic factor for lung squamous cell carcinoma (LUSC). Then we showed that FTO, but not other m 6 A modification genes including METTL3, METTL14 and ALKBH5, was the major dysregulated factor responsible for aberrant m 6 A modification in LUSC. Loss-of-function studies suggested that FTO knockdown effectively inhibited cell proliferation and invasion, while promoted cell apoptosis of L78 and NCI-H520 cells. Furthermore, overexpression of FTO, but not its mutant form, facilitated the malignant phenotypes of CHLH-1 cells. Mechanistically, FTO enhanced MZF1 expression by reducing m 6 A levels and mRNA stability in MZF1 mRNA transcript, leading to oncogenic functions. Taken together, our study demonstrates the functional importance of FTO in the tumor progression of LUSC and provides a potential therapeutic target for LUSC treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

Association between ACE (rs4646994), FABP2 (rs1799883), MTHFR (rs1801133), FTO (rs9939609) Genes Polymorphism and Type 2 Diabetes with Dyslipidemia.

PubMed

Raza, Syed Tasleem; Abbas, Shania; Siddiqi, Zeba; Mahdi, Farzana

2017-01-01

Diabetic dyslipidemia is one of the leading causes of coronary artery disease (CAD) death. Genetic and environmental factors play an important role in the development of type 2 diabetes mellitus (T2DM) and dyslipidemia. The present study was aimed to investigate the association of ACE (rs4646994), FABP2 (rs1799883), MTHFR (rs1801133) and FTO (rs9939609) genes polymorphism in T2DM with dyslipidemia. Totally, 559 subjects including 221 T2DM cases with dyslipidemia, 158 T2DM without dyslipidemia and 180 controls were enrolled. ACE genes polymorphism was evaluated by polymerase chain reaction (PCR), while MTHFR , FABP2 , FTO genes polymorphisms were evaluated by PCR and restriction fragment length polymorphism (RFLP). Significant association of ACE and MTHFR genes polymorphisms were found in both group of cases [T2DM with dyslipidemia (P<0.001, and P=0.008, respectively) and T2DM without dyslipidemia (P=0.003, and P=0.010, respectively)] while FABP2 and FTO genes polymorphisms were significantly associated with T2DM without dyslipidemia (P=0.038, and P= 0.019, respectively). This study concludes that ACE , FABP2 , FTO and MTHFR genes are associated with T2DM. Additionally, it also seems that ACE and MTHFR genes might be further associated with the development of dyslipidemia in T2DM cases.

Genetic association studies of obesity in Africa: a systematic review.

PubMed

Yako, Y Y; Echouffo-Tcheugui, J B; Balti, E V; Matsha, T E; Sobngwi, E; Erasmus, R T; Kengne, A P

2015-03-01

Obesity is increasing in Africa, but the underlying genetic background largely remains unknown. We assessed existing evidence on genetic determinants of obesity among populations within Africa. MEDLINE and EMBASE were searched and the bibliographies of retrieved articles were examined. Included studies had to report on the association of a genetic marker with obesity indices and the presence/occurrence of obesity/obesity trait. Data were extracted on study design and characteristics, genetic determinants and effect estimates of associations with obesity indices. According to this data, over 300 polymorphisms in 42 genes have been studied in various population groups within Africa mostly through the candidate gene approach. Polymorphisms in genes such as ACE, ADIPOQ, ADRB2, AGRP, AR, CAPN10, CD36, C7orf31, DRD4, FTO, MC3R, MC4R, SGIP1 and LEP were found to be associated with various measures of obesity. Of the 36 polymorphisms previously validated by genome-wide association studies (GWAS) elsewhere, only FTO and MC4R polymorphisms showed significant associations with obesity in black South Africans, Nigerians and Ghanaians. However, these data are insufficient to establish the true nature of genetic susceptibility to obesity in populations within Africa. There has been recent progress in describing the genetic architecture of obesity among populations within Africa. This effort needs to be sustained via GWAS studies. © 2015 World Obesity.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

PubMed

Qi, Qibin; Kilpeläinen, Tuomas O; Downer, Mary K; Tanaka, Toshiko; Smith, Caren E; Sluijs, Ivonne; Sonestedt, Emily; Chu, Audrey Y; Renström, Frida; Lin, Xiaochen; Ängquist, Lars H; Huang, Jinyan; Liu, Zhonghua; Li, Yanping; Asif Ali, Muhammad; Xu, Min; Ahluwalia, Tarunveer Singh; Boer, Jolanda M A; Chen, Peng; Daimon, Makoto; Eriksson, Johan; Perola, Markus; Friedlander, Yechiel; Gao, Yu-Tang; Heppe, Denise H M; Holloway, John W; Houston, Denise K; Kanoni, Stavroula; Kim, Yu-Mi; Laaksonen, Maarit A; Jääskeläinen, Tiina; Lee, Nanette R; Lehtimäki, Terho; Lemaitre, Rozenn N; Lu, Wei; Luben, Robert N; Manichaikul, Ani; Männistö, Satu; Marques-Vidal, Pedro; Monda, Keri L; Ngwa, Julius S; Perusse, Louis; van Rooij, Frank J A; Xiang, Yong-Bing; Wen, Wanqing; Wojczynski, Mary K; Zhu, Jingwen; Borecki, Ingrid B; Bouchard, Claude; Cai, Qiuyin; Cooper, Cyrus; Dedoussis, George V; Deloukas, Panos; Ferrucci, Luigi; Forouhi, Nita G; Hansen, Torben; Christiansen, Lene; Hofman, Albert; Johansson, Ingegerd; Jørgensen, Torben; Karasawa, Shigeru; Khaw, Kay-Tee; Kim, Mi-Kyung; Kristiansson, Kati; Li, Huaixing; Lin, Xu; Liu, Yongmei; Lohman, Kurt K; Long, Jirong; Mikkilä, Vera; Mozaffarian, Dariush; North, Kari; Pedersen, Oluf; Raitakari, Olli; Rissanen, Harri; Tuomilehto, Jaakko; van der Schouw, Yvonne T; Uitterlinden, André G; Zillikens, M Carola; Franco, Oscar H; Shyong Tai, E; Ou Shu, Xiao; Siscovick, David S; Toft, Ulla; Verschuren, W M Monique; Vollenweider, Peter; Wareham, Nicholas J; Witteman, Jacqueline C M; Zheng, Wei; Ridker, Paul M; Kang, Jae H; Liang, Liming; Jensen, Majken K; Curhan, Gary C; Pasquale, Louis R; Hunter, David J; Mohlke, Karen L; Uusitupa, Matti; Cupples, L Adrienne; Rankinen, Tuomo; Orho-Melander, Marju; Wang, Tao; Chasman, Daniel I; Franks, Paul W; Sørensen, Thorkild I A; Hu, Frank B; Loos, Ruth J F; Nettleton, Jennifer A; Qi, Lu

2014-12-20

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Isolation and characterization of Agouti: a diabetes/obesity related gene

DOEpatents

Woychik, Richard P.

1998-01-01

The present invention relates to the cloning and expression of the Agouti gene and analogous genes in transformed, transfected and transgenic mice. The present invention provides an animal model for the study of diabetes, obesity and tumors for the testing of potential therapeutic agents. The present invention provides oligonucleotide probes for the detection of the Agouti gene and mutations in the gene. The present invention also relates to the isolation and recombinant production of the Agouti gene product, production of antibodies to the Agouti gene product and their use as diagnostic and therapeutic agents.

Isolation and characterization of Agouti: a diabetes/obesity related gene

DOEpatents

Woychik, Richard P.

2000-06-27

The present invention relates to the cloning and expression of the Agouti gene and analogous genes in transformed, transfected and transgenic mice. The present invention provides an animal model for the study of diabetes, obesity and tumors for the testing of potential therapeutic agents. The present invention provides oligonucleotide probes for the detection of the Agouti gene and mutations in the gene. The present invention also relates to the isolation and recombinant production of the Agouti gene product, production of antibodies to the Agouti gene product and their use as diagnostic and therapeutic agents.

A High Intake of Saturated Fatty Acids Strengthens the Association between the Fat Mass and Obesity-Associated Gene and BMI123

PubMed Central

Corella, Dolores; Arnett, Donna K.; Tucker, Katherine L.; Kabagambe, Edmond K.; Tsai, Michael; Parnell, Laurence D.; Lai, Chao-Qiang; Lee, Yu-Chi; Warodomwichit, Daruneewan; Hopkins, Paul N.; Ordovas, Jose M.

2011-01-01

Evidence that physical activity (PA) modulates the association between the fat mass and obesity-associated gene (FTO) and BMI is emerging; however, information about dietary factors modulating this association is scarce. We investigated whether fat and carbohydrate intake modified the association of FTO gene variation with BMI in two populations, including participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1069) and in the Boston Puerto Rican Health (BPRHS) study (n = 1094). We assessed energy, nutrient intake, and PA using validated questionnaires. Genetic variability at the FTO locus was characterized by polymorphisms rs9939609 (in the GOLDN) and rs1121980 (in the GOLDN and BPRHS). We found significant interactions between PA and FTO on BMI in the GOLDN but not in the BPRHS. We found a significant interaction between SFA intake and FTO on BMI, which was stronger than that of total fat and was present in both populations (P-interaction = 0.007 in the GOLDN and P-interaction = 0.014 in BPRHS for categorical; and P-interaction = 0.028 in the GOLDN and P-interaction = 0.041 in BPRHS for continuous SFA). Thus, homozygous participants for the FTO-risk allele had a higher mean BMI than the other genotypes only when they had a high-SFA intake (above the population mean: 29.7 ± 0.7 vs. 28.1 ± 0.5 kg/m2; P = 0.037 in the GOLDN and 33.6. ± 0.8 vs. 31.2 ± 0.4 kg/m2; P = 0.006 in BPRHS). No associations with BMI were found at lower SFA intakes. We found no significant interactions with carbohydrate intake. In conclusion, SFA intake modulates the association between FTO and BMI in American populations. PMID:22049296

Interaction between the RGS6 gene and psychosocial stress on obesity-related traits.

PubMed

Kim, Hyun-Jin; Min, Jin-Young; Min, Kyoung-Bok

2017-03-31

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.

Association between the SPRY1 gene polymorphism and obesity-related traits and osteoporosis in Korean women.

PubMed

Jin, Hyun-Seok; Kim, Bo-Young; Kim, Jeonghyun; Hong, Kyung-Won; Jung, Suk-Yul; Lee, Yun-Seok; Huh, Dam; Oh, Bermseok; Chung, Yoon-Sok; Jeong, Seon-Yong

2013-01-01

Emerging evidence has revealed a close relationship between obesity and osteoporosis. It was reported recently that conditional knockout of the Spry1 gene in mice adipocytes causes an increase in body fat and a decrease in bone mass, and that these phenotypes are rescued by Spry1 overexpression in adipose tissue. In this study, we investigated whether genetic variation in the human SPRY1 gene is associated with obesity-related phenotypes and/or osteoporosis in humans. We performed a candidate gene association analysis between the four single nucleotide polymorphisms (SNPs) and 14 imputed SNPs in the SPRY1 gene and obesity-related traits and osteoporosis in a Korean women cohort (3013 subjects). All four SPRY1 gene SNPs were significantly associated with either obesity-related traits or osteoporosis. The TGCC haplotype in the SRPY1 gene showed simultaneous association with an increased risk for obesity-related traits, percentage body fat (p=0.0087) and percentage abdominal fat (p=0.047), and osteoporosis (odds ratio=1.50; p=0.025) in the recessive genetic model. Our results support a previous finding in conditional Spry1 gene knockout mice and suggest that the SPRY1 gene is an important genetic factor for determining the risk of both obesity and osteoporosis in humans. Copyright © 2012 Elsevier Inc. All rights reserved.

Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults

PubMed Central

Mirza, S. S.; Zhao, J. H.; Chasman, D. I.; Fischer, K.; Qi, Q.; Smith, A. V.; Thinggaard, M.; Jarczok, M. N.; Nalls, M. A.; Trompet, S.; Timpson, N. J.; Schmidt, B.; Jackson, A. U.; Lyytikäinen, L. P.; Verweij, N.; Mueller-Nurasyid, M.; Vikström, M.; Marques-Vidal, P.; Wong, A.; Meidtner, K.; Middelberg, R. P.; Strawbridge, R. J.; Christiansen, L.; Kyvik, K. O.; Hamsten, A.; Jääskeläinen, T.; Tjønneland, A.; Eriksson, J. G.; Whitfield, J. B.; Boeing, H.; Hardy, R.; Vollenweider, P.; Leander, K.; Peters, A.; van der Harst, P.; Kumari, M.; Lehtimäki, T.; Meirhaeghe, A.; Tuomilehto, J.; Jöckel, K.-H.; Ben-Shlomo, Y.; Sattar, N.; Baumeister, S. E.; Smith, G. Davey; Casas, J. P.; Houston, D. K.; März, W.; Christensen, K.; Gudnason, V.; Hu, F. B.; Metspalu, A.; Ridker, P. M.; Wareham, N. J.; Loos, R. J. F.; Tiemeier, H.; Sonestedt, E.; Sørensen, T. I. A.

2015-01-01

Summary Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m−2; 95% CI 0.28–0.32, P < 1 × 10−32), WC (n = 152,631; 0.76 cm; 0.68–0.84, P < 1 × 10−32) and FMI (n = 48,192; 0.17 kg m−2; 0.13–0.22, P = 1.0 × 10−13). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00–1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98–1.03, P = 0.662) and for FMI (HR: 1.00; 0.96–1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes. PMID:25752329

[Obesity studies in candidate genes].

PubMed

Ochoa, María del Carmen; Martí, Amelia; Martínez, J Alfredo

2004-04-17

There are more than 430 chromosomic regions with gene variants involved in body weight regulation and obesity development. Polymorphisms in genes related to energy expenditure--uncoupling proteins (UCPs), related to adipogenesis and insulin resistance--hormone-sensitive lipase (HLS), peroxisome proliferator-activated receptor gamma (PPAR gamma), beta adrenergic receptors (ADRB2,3), and alfa tumor necrosis factor (TNF-alpha), and related to food intake--ghrelin (GHRL)--appear to be associated with obesity phenotypes. Obesity risk depends on two factors: a) genetic variants in candidate genes, and b) biographical exposure to environmental risk factors. It is necessary to perform new studies, with appropriate control groups and designs, in order to reach relevant conclusions with regard to gene/environmental (diet, lifestyle) interactions.

Association of fat mass and obesity-associated and retinitis pigmentosa guanosine triphosphatase (GTPase) regulator-interacting protein-1 like polymorphisms with body mass index in Chinese women.

PubMed

Chen, Boyu; Li, Zhiqiang; Chen, Jianhua; Ji, Jue; Shen, Jingyi; Xu, Yufeng; Zhao, Yingying; Liu, Danping; Shen, Yinhuan; Zhang, Weijie; Shen, Jiawei; Wang, Yonggang; Shi, Yongyong

2018-04-14

Body mass index (BMI) is the most commonly used quantitative measure of adiposity. It is a kind of complex genetic diseases which are caused by multiple susceptibility genes. The first intron of fat mass and obesity-associated (FTO) has been widely discovered to be associated with BMI. Retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L) is located in the upstream region of FTO and has been proved to be linked with obesity through functional tests. We carried out a genetic association analysis to figure out the role of the FTO gene and the RPGRIP1L gene in BMI. A quantitative traits study with 6,102 Chinese female samples, adjusted for age, was performed during our project. Among the twelve SNPs, rs1421085, rs1558902, rs17817449, rs8050136, rs9939609, rs7202296, rs56137030, rs9930506 and rs12149832 in the FTO gene were significantly associated with BMI after Bonferroni correction. Meanwhile, rs9934800 in the RPGRIP1L gene showed significance with BMI before Bonferroni correction, but this association was eliminated after Bonferroni correction. Our results suggested that genetic variants in the FTO gene were strongly associated with BMI in Chinese women, which may serve as targets of pharmaceutical research and development concerning BMI. Meanwhile, we didn't found the significant association between RPGRIP1L and BMI in Chinese women.

Familial risk for alcohol dependence and developmental changes in BMI: the moderating influence of addiction and obesity genes.

PubMed

Lichenstein, Sarah D; Jones, Bobby L; O'Brien, Jessica W; Zezza, Nicholas; Stiffler, Scott; Holmes, Brian; Hill, Shirley Y

2014-07-01

Familial loading for alcohol dependence (AD) and variation in genes reported to be associated with AD or BMI were tested in a longitudinal study. Growth curve analyses of BMI data collected at approximately yearly intervals and obesity status (BMI > 30) were examined. High-risk males were found to have higher BMI than low-risk males, beginning at age 15 years (2.0 kg/m(2) difference; p = 0.046), persisting through age 19 years (3.3 kg/m(2) difference; p = 0.005). CHRM2 genotypic variance predicted longitudinal BMI and obesity status. Interactions with risk status and sex were also observed for DRD2 and FTO gene variation. Variation at loci implicated in addiction may be influential in determining susceptibility to increased BMI in childhood and adolescence.

Epigenomic elements analyses for promoters identify ESRRG as a new susceptibility gene for obesity-related traits.

PubMed

Dong, S-S; Guo, Y; Zhu, D-L; Chen, X-F; Wu, X-M; Shen, H; Chen, X-D; Tan, L-J; Tian, Q; Deng, H-W; Yang, T-L

2016-07-01

With ENCODE epigenomic data and results from published genome-wide association studies (GWASs), we aimed to find regulatory signatures of obesity genes and discover novel susceptibility genes. Obesity genes were obtained from public GWAS databases and their promoters were annotated based on the regulatory element information. Significantly enriched or depleted epigenomic elements in the promoters of obesity genes were evaluated and all human genes were then prioritized according to the existence of the selected elements to predict new candidate genes. Top-ranked genes were subsequently applied to validate their associations with obesity-related traits in three independent in-house GWAS samples. We identified RAD21 and EZH2 as over-represented, and STAT2 (signal transducer and activator of transcription 2) and IRF3 (interferon regulatory transcription factor 3) as depleted transcription factors. Histone modification of H3K9me3 and chromatin state segmentation of 'poised promoter' and 'repressed' were over-represented. All genes were prioritized and we selected the top five genes for validation at the population level. Combining results from the three GWAS samples, rs7522101 in ESRRG (estrogen-related receptor-γ) remained significantly associated with body mass index after multiple testing corrections (P=7.25 × 10(-5)). It was also associated with β-cell function (P=1.99 × 10(-3)) and fasting glucose level (P<0.05) in the meta-analyses of glucose and insulin-related traits consortium (MAGIC) data set.Cnoclusions:In summary, we identified epigenomic characteristics for obesity genes and suggested ESRRG as a novel obesity-susceptibility gene.

FTO Is Associated with Aortic Valve Stenosis in a Gender Specific Manner of Heterozygote Advantage: A Population-Based Case-Control Study.

PubMed

Thron, Cindy; Akhyari, Payam; Godehardt, Erhard; Lichtenberg, Artur; Rüther, Ulrich; Seehaus, Stefanie

2015-01-01

Single nucleotide polymorphisms (SNPs) within the Fat mass and obesity associated (FTO) gene have been linked with increased body weight. However, the data on an association of FTO with cardiovascular diseases remains conflicting. Therefore, we ascertained whether FTO is associated with aortic valve stenosis (AVS), one of the most frequent cardiovascular diseases in the Western world. In this population-based case-control study the FTO SNP rs9939609 was analyzed in 300 German patients with AVS and 429 German controls of the KORA survey S4, representing a random population. Blood samples were collected prior to aortic valve replacement in AVS cases and FTO rs9939609 was genotyped via ARMS-PCR. Genotype frequencies differed significantly between AVS cases and KORA controls (p = 0.004). Separate gender-analyses uncovered an association of FTO with AVS exclusively in males; homozygote carriers for the risk-allele (A) had a higher risk to develop AVS (p = 0.017, odds ratio (OR) 1.727; 95% confidence interval (CI) 1.087-2.747, recessive model), whereas heterozygote carriers for the risk-allele showed a lower risk (p = 0.002, OR 0.565, 95% CI 0.384-0.828, overdominant model). After adjustment for multiple co-variables, the odds ratios of heterozygotes remained significant for an association with AVS (p = 0.008, OR 0.565, 95% CI 0.369-0.861). This study revealed an association of FTO rs9939609 with AVS. Furthermore, this association was restricted to men, with heterozygotes having a significantly lower chance to develop AVS. Lastly, the association between FTO and AVS was independent of BMI and other variables such as diabetes mellitus.

FTO variant, energy intake, physical activity and basal metabolic rate in Caucasians. The HAPIEE study.

PubMed

Hubáček, J A; Pikhart, H; Peasey, A; Kubínová, R; Bobák, M

2011-01-01

The FTO gene variants are the most important genetic determinants of body weight and obesity known so far, but the mechanism of their effect remains unclear. We have analyzed FTO rs17817449 variant (G>T in first intron) in 6024 adults aged 45-69 years to assess the potential mediating role of diet and physical activity. Diet was assessed by a 140-item food frequency questionnaire. Physical activity was measured by hours spent during a typical week by sport, walking and other activities outside of work requiring heavy and medium physical activity. Basal metabolic rate was calculated according Schofield formula. The FTO variant was significantly associated with body mass index (means in GG, GT and TT carriers were 28.7, 28.2 and 27.8 kg/m(2), p<0.001) and basal metabolic rate (BMR) (means in GG, GT and TT were 1603, 1588 and 1576 kcal per day, respectively, p<0.008) but it was not associated with physical activity, total energy intake or with energy intakes from fat, carbohydrates, proteins or alcohol. Results were essentially similar in men and women and the adjustment for physical activity or dietary energy intake did not reduce the effect of the FTO polymorphism. Means of BMR per kg of body weight was lowest in GG carriers (20.09, 20.21 for GT and 20.30 for TT, p<0.006) and this effect was more pronounced in females. These results suggest that the effect of the FTO rs17817449 variant on BMI in Caucasian adults is not mediated by energy intake or physical activity, but some effect on BMR per kg of body weight is possible.

Epigenomic Elements Analyses for Promoters Identify ESRRG as a New Susceptibility Gene for Obesity-related Traits

PubMed Central

Dong, Shan-Shan; Guo, Yan; Zhu, Dong-Li; Chen, Xiao-Feng; Wu, Xiao-Ming; Shen, Hui; Chen, Xiang-Ding; Tan, Li-Jun; Tian, Qing; Deng, Hong-Wen; Yang, Tie-Lin

2016-01-01

OBJECTIVES With ENCODE epigenomic data and results from published genome-wide association studies (GWASs), we aimed to find regulatory signatures of obesity genes and discover novel susceptibility genes. METHODS Obesity genes were obtained from public GWASs databases and their promoters were annotated based on the regulatory elements information. Significantly enriched or depleted epigenomic elements in the promoters of obesity genes were evaluated and all human genes were then prioritized according to the existence of the selected elements to predict new candidate genes. Top ranked genes were subsequently applied to validate their associations with obesity-related traits in three independent in-house GWASs samples. RESULTS We identified RAD21 and EZH2 as over-represented, STAT2 and IRF3 as depleted transcription factors. Histone modification of H3K9me3 and chromatin state segmentation of “poised promoter” and “repressed” were overrepresented. All genes were prioritized and we selected the top five genes for validation at population level. Combined results from the three GWASs samples, rs7522101 in ESRRG remained significantly associated with BMI after multiple testing corrections (P = 7.25 × 10−5). It was also associated with β-cell function (P = 1.99 × 10−3) and fasting glucose level (P < 0.05) in the meta-analyses of glucose and insulin-related traits consortium (MAGIC) dataset. CONCLUSIONS In summary, we identified epigenomic characteristics for obesity genes and suggested ESRRG as a novel obesity susceptibility gene. PMID:27113491

Gene Polymorphism Association with Type 2 Diabetes and Related Gene-Gene and Gene-Environment Interactions in a Uyghur Population

PubMed Central

Xiao, Shan; Zeng, Xiaoyun; Fan, Yong; Su, Yinxia; Ma, Qi; Zhu, Jun; Yao, Hua

2016-01-01

Background We investigated the association between 8 single-nucleotide polymorphisms (SNPs) at 3 genetic loci (CDKAL1, CDKN2A/2B and FTO) with type 2 diabetes (T2D) in a Uyghur population. Material/Methods A case-control study of 879 Uyghur patients with T2D and 895 non-diabetic Uyghur controls was conducted at the Hospital of Xinjiang Medical University between 2010 and 2013. Eight SNPs in CDKAL1, CDKN2A/2B and FTO were analyzed using Sequenom MassARRAY®SNP genotyping. Factors associated with T2D were assessed by logistic regression analyses. Gene-gene and gene-environment interactions were analyzed by generalized multifactor dimensionality reduction. Results Genotype distributions of rs10811661 (CDKN2A/2B), rs7195539, rs8050136, and rs9939609 (FTO) and allele frequencies of rs8050136 and rs9939609 differed significantly between diabetes and control groups (all P<0.05). While rs10811661, rs8050136, and rs9939609 were eliminated after adjusting for covariates (P>0.05), rs7195539 distribution differed significantly in co-dominant and dominant models (P<0.05). In gene-gene interaction analysis, after adjusting for covariates the two-locus rs10811661-rs7195539 interaction model had a cross-validation consistency of 10/10 and the highest balanced accuracy of 0.5483 (P=0.014). In gene-environment interaction analysis, the 3-locus interaction model TG-HDL-family history of diabetes had a cross-validation consistency of 10/10 and the highest balanced accuracy of 0.7072 (P<0.001). The 4-locus interaction model, rs7195539-TG-HDL-family history of diabetes had a cross-validation consistency of 8/10 (P<0.001). Conclusions Polymorphisms in CDKN2A/2B and FTO, but not CDKAL1, may be associated with T2D, and alleles rs8050136 and rs9939609 are likely risk alleles for T2D in this population. There were potential interactions among CDKN2A/2B (rs10811661) – FTO (rs7195539) or FTO (rs7195539)-TG-HDL-family history of diabetes in the pathogenesis of T2D in a Uyghur population. PMID

FTO Is Associated with Aortic Valve Stenosis in a Gender Specific Manner of Heterozygote Advantage: A Population-Based Case-Control Study

PubMed Central

Thron, Cindy; Akhyari, Payam; Godehardt, Erhard; Lichtenberg, Artur; Rüther, Ulrich; Seehaus, Stefanie

2015-01-01

Background Single nucleotide polymorphisms (SNPs) within the Fat mass and obesity associated (FTO) gene have been linked with increased body weight. However, the data on an association of FTO with cardiovascular diseases remains conflicting. Therefore, we ascertained whether FTO is associated with aortic valve stenosis (AVS), one of the most frequent cardiovascular diseases in the Western world. Methods and Findings In this population-based case-control study the FTO SNP rs9939609 was analyzed in 300 German patients with AVS and 429 German controls of the KORA survey S4, representing a random population. Blood samples were collected prior to aortic valve replacement in AVS cases and FTO rs9939609 was genotyped via ARMS-PCR. Genotype frequencies differed significantly between AVS cases and KORA controls (p = 0.004). Separate gender-analyses uncovered an association of FTO with AVS exclusively in males; homozygote carriers for the risk-allele (A) had a higher risk to develop AVS (p = 0.017, odds ratio (OR) 1.727; 95% confidence interval (CI) 1.087–2.747, recessive model), whereas heterozygote carriers for the risk-allele showed a lower risk (p = 0.002, OR 0.565, 95% CI 0.384–0.828, overdominant model). After adjustment for multiple co-variables, the odds ratios of heterozygotes remained significant for an association with AVS (p = 0.008, OR 0.565, 95% CI 0.369–0.861). Conclusions This study revealed an association of FTO rs9939609 with AVS. Furthermore, this association was restricted to men, with heterozygotes having a significantly lower chance to develop AVS. Lastly, the association between FTO and AVS was independent of BMI and other variables such as diabetes mellitus. PMID:26431034

Gender-Dependent Association of FTO Polymorphisms with Body Mass Index in Mexicans

PubMed Central

Saldaña-Alvarez, Yolanda; Salas-Martínez, María Guadalupe; García-Ortiz, Humberto; Luckie-Duque, Angélica; García-Cárdenas, Gustavo; Vicenteño-Ayala, Hermenegildo; Cordova, Emilio J.; Esparza-Aguilar, Marcelino; Contreras-Cubas, Cecilia; Carnevale, Alessandra; Chávez-Saldaña, Margarita; Orozco, Lorena

2016-01-01

To evaluate the associations between six single-nucleotide polymorphisms (SNPs) in intron 1 of FTO and body mass index (BMI), a case-control association study of 2314 unrelated Mexican-Mestizo adult subjects was performed. The association between each SNP and BMI was tested using logistic and linear regression adjusted for age, gender, and ancestry and assuming additive, recessive, and dominant effects of the minor allele. Association analysis after BMI stratification showed that all five FTO SNPs (rs1121980, rs17817449, rs3751812, rs9930506, and rs17817449), were significantly associated with obesity class II/III under an additive model (P<0.05). Interestingly, we also documented a genetic model-dependent influence of gender on the effect of FTO variants on increased BMI. Two SNPs were specifically associated in males under a dominant model, while the remainder were associated with females under additive and recessive models (P<0.05). The SNP rs9930506 showed the highest increased in obesity risk in females (odds ratio = 4.4). Linear regression using BMI as a continuous trait also revealed differential FTO SNP contributions. Homozygous individuals for the risk alleles of rs17817449, rs3751812, and rs9930506 were on average 2.18 kg/m2 heavier than homozygous for the wild-type alleles; rs1121980 and rs8044769 showed significant but less-strong effects on BMI (1.54 kg/m2 and 0.9 kg/m2, respectively). Remarkably, rs9930506 also exhibited positive interactions with age and BMI in a gender-dependent manner. Women carrying the minor allele of this variant have a significant increase in BMI by year (0.42 kg/m2, P = 1.17 x 10−10). Linear regression haplotype analysis under an additive model, confirmed that the TGTGC haplotype harboring all five minor alleles, increased the BMI of carriers by 2.36 kg/m2 (P = 1.15 x 10−5). Our data suggest that FTO SNPs make differential contributions to obesity risk and support the hypothesis that gender differences in the mechanisms

An integrative systems genetics approach reveals potential causal genes and pathways related to obesity.

PubMed

Kogelman, Lisette J A; Zhernakova, Daria V; Westra, Harm-Jan; Cirera, Susanna; Fredholm, Merete; Franke, Lude; Kadarmideen, Haja N

2015-10-20

Obesity is a multi-factorial health problem in which genetic factors play an important role. Limited results have been obtained in single-gene studies using either genomic or transcriptomic data. RNA sequencing technology has shown its potential in gaining accurate knowledge about the transcriptome, and may reveal novel genes affecting complex diseases. Integration of genomic and transcriptomic variation (expression quantitative trait loci [eQTL] mapping) has identified causal variants that affect complex diseases. We integrated transcriptomic data from adipose tissue and genomic data from a porcine model to investigate the mechanisms involved in obesity using a systems genetics approach. Using a selective gene expression profiling approach, we selected 36 animals based on a previously created genomic Obesity Index for RNA sequencing of subcutaneous adipose tissue. Differential expression analysis was performed using the Obesity Index as a continuous variable in a linear model. eQTL mapping was then performed to integrate 60 K porcine SNP chip data with the RNA sequencing data. Results were restricted based on genome-wide significant single nucleotide polymorphisms, detected differentially expressed genes, and previously detected co-expressed gene modules. Further data integration was performed by detecting co-expression patterns among eQTLs and integration with protein data. Differential expression analysis of RNA sequencing data revealed 458 differentially expressed genes. The eQTL mapping resulted in 987 cis-eQTLs and 73 trans-eQTLs (false discovery rate < 0.05), of which the cis-eQTLs were associated with metabolic pathways. We reduced the eQTL search space by focusing on differentially expressed and co-expressed genes and disease-associated single nucleotide polymorphisms to detect obesity-related genes and pathways. Building a co-expression network using eQTLs resulted in the detection of a module strongly associated with lipid pathways. Furthermore, we

Anti-obesity effect of radix Angelica sinensis and candidate causative genes in transcriptome analyses of adipose tissues in high-fat diet-induced mice.

PubMed

Zhong, Tao; Zhang, Hao; Duan, Xiaoyue; Hu, Jiangtao; Wang, Linjie; Li, Li; Zhang, Hongping; Niu, Lili

2017-01-30

We have previously reported that radix Angelica sinensis (RAS) suppressed body weight and altered the expression of the fat mass and obesity associated (FTO) gene in mice with high fat diet (HFD)-induced obesity. In the present study we performed RNA sequencing-mediated transcriptome analysis to elucidate the molecular mechanisms underlying the anti-obesogenic effects of RAS in mice. The results revealed that 36 differentially-expressed genes (DEGs) were identified in adipose tissues from the RAS supplementation group (DH) and control group (HC). These 36 DEGs were clustered into 297 functional gene ontology (GO) categories, among which several GO annotations and signaling pathways were associated with lipid homeostasis. Six out of the 36 DEGs were identified to be involved in lipid metabolism, with the APOA2 gene a potential anti-obesogenic influence. The expression pattern revealed by RNA-Seq was identical to the results of quantitative real-time PCR (qPCR). Therefore, RAS supplementation in HFD-induced obese mice was associated with an anti-obesogenic global transcriptomic response. This study provides insight into potential applications of RAS in obesity therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m6A-YTHDF2-dependent manner.

PubMed

Wu, Ruifan; Yao, Yongxi; Jiang, Qin; Cai, Min; Liu, Qing; Wang, Yizhen; Wang, Xinxia

2018-05-24

N 6 -methyladenosine (m 6 A) modification of mRNA plays a role in regulating adipogenesis. However, its underlying mechanism remains largely unknown. Epigallocatechin gallate (EGCG), the most abundant catechin in green tea, plays a critical role in anti-obesity and anti-adipogenesis. High-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (HPLC-QqQ-MS/MS) was performed to determine the m 6 A levels in 3T3-L1 preadipocytes. The effects of EGCG on the m 6 A levels in specific genes were determined by methylated RNA immunoprecipitation coupled with quantitative real-time PCR (meRIP-qPCR). Several adipogenesis makers and cell cycle genes were analyzed by quantitative real-time PCR (qPCR) and western blotting. Lipid accumulation was evaluated by oil red O staining. All measurements were performed at least for three times. Here we showed that EGCG inhibited adipogenesis by blocking the mitotic clonal expansion (MCE) at the early stage of adipocyte differentiation. Exposing 3T3-L1 cells to EGCG reduced the expression of fat mass and obesity-associated (FTO) protein, an m 6 A demethylase, which led to increased overall levels of RNA m 6 A methylation. Cyclin A2 (CCNA2) and cyclin dependent kinase 2 (CDK2) play vital roles in MCE. The m 6 A levels of CCNA2 and CDK2 mRNA were dramatically enhanced by EGCG. Interestingly, EGCG increased the expression of YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2), which recognized and decayed methylated mRNAs, resulting in decreased protein levels of CCNA2 and CDK2. As a result, MCE was blocked and adipogenesis was inhibited. FTO overexpression and YTHDF2 knockdown in 3T3-L1 cells significantly increased CCNA2 and CDK2 protein levels and ameliorated the EGCG-induced adipogenesis inhibition. Thus, m 6 A-dependent CCNA2 and CDK2 expressions mediated by FTO and YTHDF2 contributed to EGCG-induced adipogenesis inhibition. Our findings provide mechanistic insights into how m 6 A is involved in the

Gene-gene interactions among genetic variants from obesity candidate genes for nonobese and obese populations in type 2 diabetes.

PubMed

Lin, Eugene; Pei, Dee; Huang, Yi-Jen; Hsieh, Chang-Hsun; Wu, Lawrence Shih-Hsin

2009-08-01

Recent studies indicate that obesity may play a key role in modulating genetic predispositions to type 2 diabetes (T2D). This study examines the main effects of both single-locus and multilocus interactions among genetic variants in Taiwanese obese and nonobese individuals to test the hypothesis that obesity-related genes may contribute to the etiology of T2D independently and/or through such complex interactions. We genotyped 11 single nucleotide polymorphisms for 10 obesity candidate genes including adrenergic beta-2-receptor surface, adrenergic beta-3-receptor surface, angiotensinogen, fat mass and obesity associated gene, guanine nucleotide binding protein beta polypeptide 3 (GNB3), interleukin 6 receptor, proprotein convertase subtilisin/kexin type 1 (PCSK1), uncoupling protein 1, uncoupling protein 2, and uncoupling protein 3. There were 389 patients diagnosed with T2D and 186 age- and sex-matched controls. Single-locus analyses showed significant main effects of the GNB3 and PCSK1 genes on the risk of T2D among the nonobese group (p = 0.002 and 0.047, respectively). Further, interactions involving GNB3 and PCSK1 were suggested among the nonobese population using the generalized multifactor dimensionality reduction method (p = 0.001). In addition, interactions among angiotensinogen, fat mass and obesity associated gene, GNB3, and uncoupling protein 3 genes were found in a significant four-locus generalized multifactor dimensionality reduction model among the obese population (p = 0.001). The results suggest that the single nucleotide polymorphisms from the obesity candidate genes may contribute to the risk of T2D independently and/or in an interactive manner according to the presence or absence of obesity.

Dog obesity--the need for identifying predisposing genetic markers.

PubMed

Switonski, M; Mankowska, M

2013-12-01

Incidence of overweight and obesity in dogs exceeds 30%, and several breeds are predisposed to this heritable phenotype. Rapid progress of canine genomics and advanced knowledge on the genetic background of human obesity bring a unique opportunity to perform such studies in dogs. Natural candidate genes for obesity are these encoding adipokines. Extended studies in humans indicated that polymorphisms of three of them, i.e. ADIPOQ, IL1 and TNF, are associated with predisposition to obesity. On the other hand, the use of genome-wide association studies revealed an association between human obesity and polymorphism of more than 50 other genes. Until now only few preliminary reports on polymorphism of canine FTO, MC4R, MC3R and PPARG genes have been published. Since the dog is a valuable model organism for human diseases one can foresee that such studies may also contribute to an in-depth understanding of human obesity pathogenesis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Genetic association analysis of 30 genes related to obesity in a European American population.

PubMed

Li, P; Tiwari, H K; Lin, W-Y; Allison, D B; Chung, W K; Leibel, R L; Yi, N; Liu, N

2014-05-01

Obesity, which is frequently associated with diabetes, hypertension and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). We reanalyzed 355 common genetic variants of 30 candidate genes in seven molecular pathways related to obesity in 1982 unrelated European Americans from the New York Cancer Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates, including age, age(2), gender and diabetes status. The single-nucleotide polymorphisms (SNPs) were modeled as additive effects. With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: ghrelin (GHRL; rs35683), agouti-related peptide (AGRP; rs5030980), carboxypeptidase E (CPE; rs1946816 and rs4481204), glucagon-like peptide-1 receptor (GLP1R; rs2268641), serotonin receptors (HTR2A; rs912127), neuropeptide Y receptor (NPY5R;Y5R1c52), suppressor of cytokine signaling 3 (SOCS3; rs4969170) and signal transducer and activator of transcription 3 (STAT3; rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake, and thus these associations are mechanistically plausible in this context.

Fat mass- and obesity-associated genotype, dietary intakes and anthropometric measures in European adults: the Food4Me study.

PubMed

Livingstone, Katherine M; Celis-Morales, Carlos; Navas-Carretero, Santiago; San-Cristobal, Rodrigo; Forster, Hannah; O'Donovan, Clare B; Woolhead, Clara; Marsaux, Cyril F M; Macready, Anna L; Fallaize, Rosalind; Kolossa, Silvia; Tsirigoti, Lydia; Lambrinou, Christina P; Moschonis, George; Godlewska, Magdalena; Surwiłło, Agnieszka; Drevon, Christian A; Manios, Yannis; Traczyk, Iwona; Gibney, Eileen R; Brennan, Lorraine; Walsh, Marianne C; Lovegrove, Julie A; Martinez, J Alfredo; Saris, Wim H M; Daniel, Hannelore; Gibney, Mike; Mathers, John C

2016-02-14

The interplay between the fat mass- and obesity-associated (FTO) gene variants and diet has been implicated in the development of obesity. The aim of the present analysis was to investigate associations between FTO genotype, dietary intakes and anthropometrics among European adults. Participants in the Food4Me randomised controlled trial were genotyped for FTO genotype (rs9939609) and their dietary intakes, and diet quality scores (Healthy Eating Index and PREDIMED-based Mediterranean diet score) were estimated from FFQ. Relationships between FTO genotype, diet and anthropometrics (weight, waist circumference (WC) and BMI) were evaluated at baseline. European adults with the FTO risk genotype had greater WC (AA v. TT: +1·4 cm; P=0·003) and BMI (+0·9 kg/m2; P=0·001) than individuals with no risk alleles. Subjects with the lowest fried food consumption and two copies of the FTO risk variant had on average 1·4 kg/m2 greater BMI (Ptrend=0·028) and 3·1 cm greater WC (Ptrend=0·045) compared with individuals with no copies of the risk allele and with the lowest fried food consumption. However, there was no evidence of interactions between FTO genotype and dietary intakes on BMI and WC, and thus further research is required to confirm or refute these findings.

Genetic Association Analysis of 30 Genes Related to Obesity in a European American Population

PubMed Central

Li, Peng; Tiwari, Hemant K.; Lin, Wan-Yu; Allison, David B.; Chung, Wendy K.; Leibel, Rudolph L.; Yi, Nengjun; Liu, Nianjun

2013-01-01

Objective Obesity, which is frequently associated with diabetes, hypertension, and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). Methods We re-analyzed 355 common genetic variants of 30 candidate genes in 7 molecular pathways related to obesity in 1,982 unrelated European Americans from the New York Health Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates including age, age2, gender, and diabetes status. The single nucleotide polymorphisms (SNPs) were modeled as additive effects. Results With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: GHRL (rs35683), AGRP (rs5030980), CPE (rs1946816 and rs4481204), GLP1R (rs2268641), HTR2A (rs912127), NPY5R (Y5R1c52), SOCS3 (rs4969170), and STAT3 (rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. Conclusion Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3, and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake and thus these associations are mechanistically plausible in this context. PMID:23900445

Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study.

PubMed

Ruiz, Jonatan R; Labayen, Idoia; Ortega, Francisco B; Legry, Vanessa; Moreno, Luis A; Dallongeville, Jean; Martínez-Gómez, David; Bokor, Szilvia; Manios, Yannis; Ciarapica, Donatella; Gottrand, Frederic; De Henauw, Stefaan; Molnár, Denes; Sjöström, Michael; Meirhaeghe, Aline

2010-04-01

To examine whether physical activity attenuates the effect of the FTO rs9939609 polymorphism on body fat estimates in adolescents. Cross-sectional study. Athens, Greece; Dortmund, Germany; Ghent, Belgium; Heraklion, Greece; Lille, France; Pécs, Hungary; Rome, Italy; Stockholm, Sweden; Vienna, Austria; and Zaragoza, Spain, from October 2006 to December 2007. Adolescents from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (n = 752). Physical activity. The FTO rs9939609 polymorphism was genotyped. Physical activity was assessed by accelerometry. We measured weight, height, waist circumference, and triceps and subscapular skinfolds; body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) and body fat percentage were calculated. The A allele of the FTO polymorphism was significantly associated with higher BMI (+0.42 per risk allele), higher body fat percentage (+1.03% per risk allele), and higher waist circumference (+0.85 cm per risk allele). We detected significant or borderline gene x physical activity interactions for the studied body fat estimates (for interaction, P = .02, .06, and .10 for BMI, body fat percentage, and waist circumference, respectively). Indeed, the effect of the FTO rs9939609 polymorphism on these body fat parameters was much lower in adolescents who met the daily physical activity recommendations (ie, >/=60 min/d of moderate to vigorous physical activity) compared with those who did not: +0.17 vs +0.65 per risk allele in BMI, respectively; +0.40% vs +1.70% per risk allele in body fat percentage, respectively; and +0.60 vs +1.15 cm per risk allele in waist circumference, respectively. Adolescents meeting the daily physical activity recommendations may overcome the effect of the FTO rs9939609 polymorphism on obesity-related traits.

Macronutrient intake as a mediator with FTO to increase body mass index.

PubMed

Hardy, Dale S; Racette, Susan B; Hoelscher, Deanna M

2014-01-01

The fat mass and obesity-associated (FTO) single nucleotide polymorphisms (SNPs; rs1421085, rs17817449, rs9939609, rs8050136) and macronutrient intake (carbohydrate, protein, fat, total calories) are associated with body mass index (BMI). However, the mechanism for this relationship has not been fully elucidated. This study examined whether macronutrient intake mediates the association between FTO SNPs and BMI. Baseline cross-sectional data from the Atherosclerosis Risk in Communities (ARIC) study of whites (n = 10,176) and African Americans (n = 3641) aged 45 to 64 years were analyzed. In linear regression models with BMI as the dependent variable, FTO SNPs were significantly associated with higher BMI after adjusting for covariates. The addition of energy-adjusted macronutrients attenuated the FTO effect estimates, indicating partial mediation. In whites, β ranged from 0.40 (95% confidence interval [CI], 0.20, 0.60) for rs17817449 heterozygous carriers to 0.93 (95% CI, 0.64, 122) for rs8050136 homozygous carriers; for African Americans rs17817449 homozygous carriers β was 0.65 (95% CI, 0.03, 1.27). In models with macronutrient intake as the dependent variable, all FTO SNPs were associated with higher protein intake for homozygous carriers after adjusting for BMI and other covariates. Among whites, β ranged from 1.44 (95% CI, 0.51, 2.37) for rs8050136 to 1.73 (95% CI, 0.85, 2.61) for rs17817449; among African American rs8050136 homozygous carriers β was 2.46 (95% CI, 0.77, 4.14). In mediation analysis, in whites only, FTO high-risk alleles were associated with higher BMI partly through their small effects on carbohydrate and protein intake. These findings suggest that in adults, the relationship between FTO variants and BMI is not primarily through mediation of food intake.

Electric field induced metal-insulator transition in VO2 thin film based on FTO/VO2/FTO structure

NASA Astrophysics Data System (ADS)

Hao, Rulong; Li, Yi; Liu, Fei; Sun, Yao; Tang, Jiayin; Chen, Peizu; Jiang, Wei; Wu, Zhengyi; Xu, Tingting; Fang, Baoying

2016-03-01

A VO2 thin film has been prepared using a DC magnetron sputtering method and annealing on an F-doped SnO2 (FTO) conductive glass substrate. The FTO/VO2/FTO structure was fabricated using photolithography and a chemical etching process. The temperature dependence of the I-V hysteresis loop for the FTO/VO2/FTO structure has been analyzed. The threshold voltage decreases with increasing temperature, with a value of 9.2 V at 20 °C. The maximum transmission modulation value of the FTO/VO2/FTO structure is 31.4% under various temperatures and voltages. Optical modulation can be realized in the structure by applying an electric field.

Genome-wide association studies of obesity and metabolic syndrome.

PubMed

Fall, Tove; Ingelsson, Erik

2014-01-25

Until just a few years ago, the genetic determinants of obesity and metabolic syndrome were largely unknown, with the exception of a few forms of monogenic extreme obesity. Since genome-wide association studies (GWAS) became available, large advances have been made. The first single nucleotide polymorphism robustly associated with increased body mass index (BMI) was in 2007 mapped to a gene with for the time unknown function. This gene, now known as fat mass and obesity associated (FTO) has been repeatedly replicated in several ethnicities and is affecting obesity by regulating appetite. Since the first report from a GWAS of obesity, an increasing number of markers have been shown to be associated with BMI, other measures of obesity or fat distribution and metabolic syndrome. This systematic review of obesity GWAS will summarize genome-wide significant findings for obesity and metabolic syndrome and briefly give a few suggestions of what is to be expected in the next few years. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Potential Susceptibility Loci Identified for Renal Cell Carcinoma by Targeting Obesity-Related Genes.

PubMed

Shu, Xiang; Purdue, Mark P; Ye, Yuanqing; Tu, Huakang; Wood, Christopher G; Tannir, Nizar M; Wang, Zhaoming; Albanes, Demetrius; Gapstur, Susan M; Stevens, Victoria L; Rothman, Nathaniel; Chanock, Stephen J; Wu, Xifeng

2017-09-01

Background: Obesity is an established risk factor for renal cell carcinoma (RCC). Although genome-wide association studies (GWAS) of RCC have identified several susceptibility loci, additional variants might be missed due to the highly conservative selection. Methods: We conducted a multiphase study utilizing three independent genome-wide scans at MD Anderson Cancer Center (MDA RCC GWAS and MDA RCC OncoArray) and National Cancer Institute (NCI RCC GWAS), which consisted of a total of 3,530 cases and 5,714 controls, to investigate genetic variations in obesity-related genes and RCC risk. Results: In the discovery phase, 32,946 SNPs located at ±10 kb of 2,001 obesity-related genes were extracted from MDA RCC GWAS and analyzed using multivariable logistic regression. Proxies ( R 2 > 0.8) were searched or imputation was performed if SNPs were not directly genotyped in the validation sets. Twenty-one SNPs with P < 0.05 in both MDA RCC GWAS and NCI RCC GWAS were subsequently evaluated in MDA RCC OncoArray. In the overall meta-analysis, significant ( P < 0.05) associations with RCC risk were observed for SNP mapping to IL1RAPL2 [rs10521506-G: OR meta = 0.87 (0.81-0.93), P meta = 2.33 × 10 -5 ], PLIN2 [rs2229536-A: OR meta = 0.87 (0.81-0.93), P meta = 2.33 × 10 -5 ], SMAD3 [rs4601989-A: OR meta = 0.86 (0.80-0.93), P meta = 2.71 × 10 -4 ], MED13L [rs10850596-A: OR meta = 1.14 (1.07-1.23), P meta = 1.50 × 10 -4 ], and TSC1 [rs3761840-G: OR meta = 0.90 (0.85-0.97), P meta = 2.47 × 10 -3 ]. We did not observe any significant cis-expression quantitative trait loci effect for these SNPs in the TCGA KIRC data. Conclusions: Taken together, we found that genetic variation of obesity-related genes could influence RCC susceptibility. Impact: The five identified loci may provide new insights into disease etiology that reveal importance of obesity-related genes in RCC development. Cancer Epidemiol Biomarkers Prev; 26(9); 1436-42. ©2017 AACR . ©2017 American Association for

3D FTO/FTO-Nanocrystal/TiO2 Composite Inverse Opal Photoanode for Efficient Photoelectrochemical Water Splitting.

PubMed

Wang, Zhiwei; Li, Xianglin; Ling, Han; Tan, Chiew Kei; Yeo, Loo Pin; Grimsdale, Andrew Clive; Tok, Alfred Iing Yoong

2018-05-01

A 3D fluorine-doped SnO 2 (FTO)/FTO-nanocrystal (NC)/TiO 2 inverse opal (IO) structure is designed and fabricated as a new "host and guest" type of composite photoanode for efficient photoelectrochemical (PEC) water splitting. In this novel photoanode design, the highly conductive and porous FTO/FTO-NC IO acts as the "host" skeleton, which provides direct pathways for faster electron transport, while the conformally coated TiO 2 layer acts as the "guest" absorber layer. The unique composite IO structure is fabricated through self-assembly of colloidal spheres template, a hydrothermal method and atomic layer deposition (ALD). Owing to its large surface area and efficient charge collection, the FTO/FTO-NC/TiO 2 composite IO photoanode shows excellent photocatalytic properties for PEC water splitting. With optimized dimensions of the SnO 2 nanocrystals and the thickness of the ALD TiO 2 absorber layers, the 3D FTO/FTO-NC/TiO 2 composite IO photoanode yields a photocurrent density of 1.0 mA cm -2 at 1.23 V versus reversible hydrogen electrode (RHE) under AM 1.5 illumination, which is four times higher than that of the FTO/TiO 2 IO reference photoanode. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Relationship of age and body mass index to the expression of obesity and osteoarthritis-related genes in human meniscus.

PubMed

Rai, M F; Sandell, L J; Cheverud, J M; Brophy, R H

2013-09-01

Aging and obesity contribute to the initiation and progression of osteoarthritis with little information on their relation to gene expression in joint tissues, particularly the meniscus. Here, we test the hypothesis that patient age and body mass index (BMI) correlate with the expression of osteoarthritis- and obesity-related gene signatures in the meniscus. Meniscus was obtained from patients (N=68) undergoing arthroscopic partial meniscectomy. The mRNA expression of 24 osteoarthritis-related and 4 obesity-related genes in meniscus was assessed by quantitative real-time PCR. The relationship between gene expression and patient age and BMI was analyzed using Spearman's rank-order correlation. Hierarchical cluster dendrogram and heat map were generated to study inter-gene associations. Age was negatively correlated (P<0.05) with the expression of MMP-1 (r=-0.447), NFκB2 (r=-0.361), NFκBIA (r=-0.312), IκBA (r=-0.308), IL-8 (r=-0.305), ADAMTS-4 (r=-0.294), APLN (apelin) (r=-0.250) and IL-6 (r=-0.244). Similarly, BMI was negatively correlated with the expression of APLN (r=-0.328), ACAN (r=-0.268) and MMP-1 (r=-0.261). After adjusting for the correlation between age and BMI (r=0.310; P=0.008), the only independent effect of BMI on gene expression was for APLN (r=-0.272). However, age had an independent effect on the expression on ADAMTS-4 (r=-0.253), MMP-1 (r=-0.399), IL-8 (r=-0.327), COL1A1 (r=-0.287), NFκBIA (r=-0.278), NFκB2 (r=-0.312) and IκBA (r=-0.299). The gene correlation analysis identified four clusters of potentially relevant genes: transcription factors, matrix-degrading enzymes, cytokines and chemokines, and obesity genes. Age and BMI were negatively correlated with several osteoarthritis- and obesity-related genes. Although the bulk of these changes appeared to be driven by age, expression of APLN was related to BMI. Inter-gene correlation analysis implicated a common role for strongly correlated genes. Although age-related variations in gene

Wide Bandgap Transparent Conducting Electrode of FTO/Ag/FTO Structure for Ultraviolet Light-Emitting Diodes.

PubMed

Yohn, Gyu-Jae; Jeong, Soae; Kang, Soo-Hyun; Kim, Si-Won; Noh, Beom-Rae; Oh, Semi; Jeong, Bong-Yong; Kim, Kyoung-Kook

2018-09-01

We investigated the effect of the Ag interlayer thickness on the structural, electrical and optical properties of FTO/Ag/FTO structures designed for use in wide bandgap transparent conducting electrodes. The top and bottom FTO layers were deposited on α-Al2O3 (0001) substrates via RF magnetron sputtering at 300 °C and Ag interlayers were deposited using an e-beam evaporator system. We optimized the figure of merit by changing the thickness of the inserted Ag interlayer from 10 nm to 14 nm, achieving a maximum value of 2.46 × 10-3 Ω-1 and a resistivity of 6.4 × 10-4 Ω · cm using an FTO (70 nm)/Ag (14 nm)/FTO (40 nm) structure. Furthermore, the average optical transmittance in the deep UV range (300 to 330 nm) was 82.8%.

A preliminary candidate genotype-intermediate phenotype study of satiation and gastric motor function in obesity.

PubMed

Papathanasopoulos, Athanasios; Camilleri, Michael; Carlson, Paula J; Vella, Adrian; Nord, Sara J Linker; Burton, Duane D; Odunsi, Suwebatu T; Zinsmeister, Alan R

2010-06-01

Stomach motility contributes significantly to fullness sensation while eating and cessation of food intake in humans. Genes controlling adrenergic and serotonergic mechanisms (ADRA2A, GNB3, and SLC6A4) affect gastric emptying (GE), volume (GV), and satiation. Fat mass and obesity-associated gene (FTO) is linked with satiety. Our aim was to examine the association of these candidate genes with stomach functions that signal postprandial fullness: GE, GV, and maximum tolerated volume (MTV). These biomarkers constitute a component of the intermediate phenotype of satiation. A total of 62 overweight or obese participants underwent genotyping of the candidate genes, and validated measurements of GE of solids and liquids by scintigraphy, fasting and postprandial change in GV by SPECT (single photon emission computed tomography), and MTV by nutrient drink test. These markers of satiation were compared for 38 genetic variants in ADRA2A, ADR2C, ADRB3, uncoupling protein (UCP)-2 and -3, GNB3, FTO, and SLC6A4 using a recessive model of inheritance. ADRA2A, ADR2C, UCP-3, GNB3, and FTO loci were significantly associated with the intermediate phenotype markers of satiation: ADR2C (Ins-Del322_325) with accelerated GE; GNB3 (rs1047776) with delayed GE; ADRA2A (rs491589 and rs553668) and GNB3 (rs2269355, rs10849527, and rs3759348) with decreased postprandial GV; ADRA2A (rs3750625) and GNB3 (rs4963517 and rs1129649) with increased postprandial GV; UCP-3 (rs1685356) with increased MTV, and FTO (rs9939609) decreased MTV. Genetic susceptibility to postprandial satiation can be identified through intermediate phenotype markers. With independent validation, these markers may guide patient selection of weight-loss therapies directed at gastric motor functions.

The FTO A/T Polymorphism and Elite Athletic Performance: A Study Involving Three Groups of European Athletes

PubMed Central

Eynon, Nir; Nasibulina, Emiliya S.; Banting, Lauren K.; Cieszczyk, Pawel; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Bondareva, Elvira A.; Shagimardanova, Roza R.; Raz, Maytal; Sharon, Yael; Williams, Alun G.; Ahmetov, Ildus I.

2013-01-01

Objective The FTO A/T polymorphism (rs9939609) is a strong candidate to influence obesity-related traits. Elite athletes from many different sporting disciplines are characterized by low body fat. Therefore, the aim of this study was to assess whether athletic status is associated with the FTO A/T polymorphism. Subjects and Methods A large cohort of European Caucasians from Poland, Russia and Spain were tested to examine the association between FTO A/T polymorphism (rs9939609) and athletic status. A total of 551 athletes were divided by type of sport (endurance athletes, n = 266 vs. sprint/power athletes, n = 285) as well as by level of competition (elite-level vs. national-level). The control group consisted of 1,416 ethnically-matched, non-athletic participants, all Europeans. Multinomial logistic regression analyses were conducted to assess the association between FTO A/T genotypes and athletic status/competition level. Results There were no significantly greater/lesser odds of harbouring any type of genotype when comparing across athletic status (endurance athletes, sprint/power athletes or control participants). These effects were observed after controlling for sex and nationality. Furthermore, no significantly greater/lesser odds ratios were observed for any of the genotypes in respect to the level of competition (elite-level vs. national-level). Conclusion The FTO A/T polymorphism is not associated with elite athletic status in the largest group of elite athletes studied to date. Large collaborations and data sharing between researchers, as presented here, are strongly recommended to enhance the research in the field of exercise genomics. PMID:23573268

FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β-catenin through mRNA demethylation.

PubMed

Zhou, Shun; Bai, Zhou-Lan; Xia, Di; Zhao, Zhi-Jun; Zhao, Ren; Wang, Yan-Yang; Zhe, Hong

2018-05-01

The role of N 6 -methyladenosine (m 6 A) demethylase fat mass and obesity-associated protein (FTO) in the regulation of chemo-radiotherapy resistance remains largely unknown. Here, we show that the mRNA level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo-radiotherapy resistance both in vitro and in vivo through regulating expression of β-catenin by reducing m 6 A levels in its mRNA transcripts and in turn increases excision repair cross-complementation group 1 (ERCC1) activity. Clinically, the prognostic value of FTO for overall survival is found to be dependent on β-catenin expression in human CSCC samples. Taken together, these findings uncover a critical function for FTO and its substrate m 6 A in the regulation of chemo-radiotherapy resistance, which may bear potential clinical implications for CSCC treatment. © 2018 Wiley Periodicals, Inc.

[Current trends in nutrigenomics of obesity].

PubMed

Lapik, I A; Gapparova, K M; Chekhonina, Yu G; Sorikina, E Yu; Borodina, S V

2016-01-01

One of the most general chronic illness in the world is obesity, which lead to progression of cardiovascular diseases, diabetes mellitus type 2, metabolic syndrome and other diseases. Slow body weight gain, that leads to overweight, is a long-term aftereffect of a long-term positive energy balance, which occurs as a result of physical activity reduction and calorie intake increasing. Trend in the reduction of physical activity and increasing the caloric value of food intake is probably the main reason of increasing patients with obesity, but it's necessary to mention that this tendency occurs because of genetic variation in population. The volume of scientific information, relevant to the problem of genetic predisposition testing to obesity, is highly increasing. This article provides an overview of recent data on the genetics of obesity and the role of genetic testing of candidate genes polymorphisms, as well as genes associated with carbohydrate and lipid metabolism disorders (FTO, ADRB2, ADRB3, PPARG and a number of others). The role of nutrigenomics in personalization of diet treatment for obesity.

Meta-analysis of genome-wide linkage studies in BMI and obesity.

PubMed

Saunders, Catherine L; Chiodini, Benedetta D; Sham, Pak; Lewis, Cathryn M; Abkevich, Victor; Adeyemo, Adebowale A; de Andrade, Mariza; Arya, Rector; Berenson, Gerald S; Blangero, John; Boehnke, Michael; Borecki, Ingrid B; Chagnon, Yvon C; Chen, Wei; Comuzzie, Anthony G; Deng, Hong-Wen; Duggirala, Ravindranath; Feitosa, Mary F; Froguel, Philippe; Hanson, Robert L; Hebebrand, Johannes; Huezo-Dias, Patricia; Kissebah, Ahmed H; Li, Weidong; Luke, Amy; Martin, Lisa J; Nash, Matthew; Ohman, Miina; Palmer, Lyle J; Peltonen, Leena; Perola, Markus; Price, R Arlen; Redline, Susan; Srinivasan, Sathanur R; Stern, Michael P; Stone, Steven; Stringham, Heather; Turner, Stephen; Wijmenga, Cisca; Collier, David A

2007-09-01

The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.

Role of the Polymorphisms of Uncoupling Protein Genes in Childhood Obesity and Their Association with Obesity-Related Disturbances.

PubMed

Gul, Ali; Ateş, Ömer; Özer, Samet; Kasap, Tuba; Ensari, Emel; Demir, Osman; Sönmezgöz, Ergün

2017-09-01

Obesity, one of the most common disorders observed in clinical practice, has been associated with energy metabolism-related protein genes such as uncoupling proteins (UCPs). Herein, we evaluated UCPs as candidate genes for obesity and its morbidities. A total of 268 obese and 185 nonobese children and adolescents were enrolled in this study. To determine dyslipidemia, hypertension, and insulin resistance, laboratory tests were derived from fasting blood samples. UCP1-3826 A/G, UCP2 exon 8 deletion/insertion (del/ins), and UCP3-55C/T variants were also genotyped, and the relationships among the polymorphisms of these UCPs and obesity morbidities were investigated. The mean ages of the obese and control groups were 11.61 ± 2.83 and 10.74 ± 3.36 years, respectively. The respective genotypic frequencies of the AA, AG, and GG genotypes of UCP1 were 46.3%, 33.2%, and 20.5% in obese subjects and 46.5%, 42.2%, and 11.4% in the controls (p = 0.020). G alleles were more frequent in obese subjects with hypertriglyceridemia (42.9%; p = 0.048) than in those without, and the GG genotype presented an odds ratio for obesity of 2.02 (1.17-3.47; p = 0.010). The polymorphisms of UCP2 exon 8 del/ins and UCP3-55C/T did not influence obesity risk (p > 0.05). The I (ins) allele was associated with low HDL cholesterolemia (p = 0.023). The GG genotype of the UCP1-3826 A/G polymorphism appears to contribute to the onset of childhood obesity in Turkish children. The GG genotype of UCP1, together with the del/del genotype of the UCP2 polymorphism, may increase the risk of obesity with synergistic effects. The ins allele of the UCP2 exon 8 del/ins polymorphism may contribute to low HDL cholesterolemia.

The FTO variant is associated with chronic complications of diabetes mellitus in Czech population.

PubMed

Hubacek, Jaroslav A; Dlouha, Dana; Klementova, Marta; Lanska, Vera; Neskudla, Tomas; Pelikanova, Terezie

2018-02-05

Genome-wide association studies have resulted in the identification of the FTO gene as an important genetic determinant of diabetes mellitus. The aim of this study was to confirm the role of this gene in the development of DM in the Czech-Slavonic population and to analyse whether this gene is associated with common DM complications. Two groups of patients (814 with T1DM and 848 with T2DM) and a group of healthy controls (2339 individuals) - both of Czech origin - were genotyped for the FTO rs17817449 SNP. ANOVA and logistic regression were used for the statistical evaluations. The frequency of the GG genotype was significantly higher in T2DM (25.4% vs. 16.7%, P<0.0005) but not in T1DM patients (19.3% vs. 16.7%, P=0.20) than in controls. The increased risk of development of diabetic nephropathy was observed both for T1DM patients (GG vs. TT homozygotes, P<0.01) and T2DM patients (G carriers vs. TT homozygotes, P<0.05). FTO genotype predicted the development of diabetic neuropathy (GG vs. TT comparison; P<0.01) in the T2DM patients only. No association between FTO genotype and development of retinopathy was detected. All presented values are after adjustment for age, sex, BMI and duration of diabetes. We confirm the association between the FTO rs17817449 SNP and susceptibility to T2DM in the Czech-Slavonic population. The same variant is associated with a spectrum of chronic complications in both types of diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

PubMed Central

Scherag, André; Dina, Christian; Hinney, Anke; Vatin, Vincent; Scherag, Susann; Vogel, Carla I. G.; Müller, Timo D.; Grallert, Harald; Wichmann, H.-Erich; Balkau, Beverley; Heude, Barbara; Jarvelin, Marjo-Riitta; Hartikainen, Anna-Liisa; Levy-Marchal, Claire; Weill, Jacques; Delplanque, Jérôme; Körner, Antje; Kiess, Wieland; Kovacs, Peter; Rayner, Nigel W.; Prokopenko, Inga; McCarthy, Mark I.; Schäfer, Helmut; Jarick, Ivonne; Boeing, Heiner; Fisher, Eva; Reinehr, Thomas; Heinrich, Joachim; Rzehak, Peter; Berdel, Dietrich; Borte, Michael; Biebermann, Heike; Krude, Heiko; Rosskopf, Dieter; Rimmbach, Christian; Rief, Winfried; Fromme, Tobias; Klingenspor, Martin; Schürmann, Annette; Schulz, Nadja; Nöthen, Markus M.; Mühleisen, Thomas W.; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Boes, Tanja; Illig, Thomas; Froguel, Philippe; Hebebrand, Johannes; Meyre, David

2010-01-01

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between

The Association of Polymorphisms in Leptin/Leptin Receptor Genes and Ghrelin/Ghrelin Receptor Genes With Overweight/Obesity and the Related Metabolic Disturbances: A Review

PubMed Central

Ghalandari, Hamid; Hosseini-Esfahani, Firoozeh; Mirmiran, Parvin

2015-01-01

Context: Leptin and ghrelin are two important appetite and energy balance-regulating peptides. Common polymorphisms in the genes coding these peptides and their related receptors are shown to be associated with body weight, different markers of obesity and metabolic abnormalities. This review article aims to investigate the association of common polymorphisms of these genes with overweight/obesity and the metabolic disturbances related to it. Evidence Acquisition: The keywords leptin, ghrelin, polymorphism, single-nucleotide polymorphism (SNP), obesity, overweight, Body Mass Index, metabolic syndrome, and type 2 diabetes mellitus (T2DM) (MeSH headings) were used to search in the following databases: Pubmed, Sciencedirect (Elsevier), and Google scholar. Overall, 24 case-control studies, relevant to our topic, met the criteria and were included in the review. Results: The most prevalent leptin/leptin receptor genes (LEP/LEPR) and ghrelin/ghrelin receptor genes (GHRL/GHSR) single nucleotide polymorphisms studied were LEP G-2548A, LEPR Q223R, and Leu72Met, respectively. Nine studies of the 17 studies on LEP/LEPR, and three studies of the seven studies on GHRL/GHSR showed significant relationships. Conclusions: In general, our study suggests that the association between LEP/LEPR and GHRL/GHSR with overweight/obesity and the related metabolic disturbances is inconclusive. These results may be due to unidentified gene-environment interactions. More investigations are needed to further clarify this association. PMID:26425125

The Association of Polymorphisms in Leptin/Leptin Receptor Genes and Ghrelin/Ghrelin Receptor Genes With Overweight/Obesity and the Related Metabolic Disturbances: A Review.

PubMed

Ghalandari, Hamid; Hosseini-Esfahani, Firoozeh; Mirmiran, Parvin

2015-07-01

Leptin and ghrelin are two important appetite and energy balance-regulating peptides. Common polymorphisms in the genes coding these peptides and their related receptors are shown to be associated with body weight, different markers of obesity and metabolic abnormalities. This review article aims to investigate the association of common polymorphisms of these genes with overweight/obesity and the metabolic disturbances related to it. The keywords leptin, ghrelin, polymorphism, single-nucleotide polymorphism (SNP), obesity, overweight, Body Mass Index, metabolic syndrome, and type 2 diabetes mellitus (T2DM) (MeSH headings) were used to search in the following databases: Pubmed, Sciencedirect (Elsevier), and Google scholar. Overall, 24 case-control studies, relevant to our topic, met the criteria and were included in the review. The most prevalent leptin/leptin receptor genes (LEP/LEPR) and ghrelin/ghrelin receptor genes (GHRL/GHSR) single nucleotide polymorphisms studied were LEP G-2548A, LEPR Q223R, and Leu72Met, respectively. Nine studies of the 17 studies on LEP/LEPR, and three studies of the seven studies on GHRL/GHSR showed significant relationships. In general, our study suggests that the association between LEP/LEPR and GHRL/GHSR with overweight/obesity and the related metabolic disturbances is inconclusive. These results may be due to unidentified gene-environment interactions. More investigations are needed to further clarify this association.

Fat brains, greedy genes, and parent power: a biobehavioural risk model of child and adult obesity.

PubMed

Carnell, Susan; Kim, Yale; Pryor, Katherine

2012-06-01

We live in a world replete with opportunities to overeat highly calorific, palatable foods - yet not everyone becomes obese. Why? We propose that individuals show differences in appetitive traits (e.g. food cue responsiveness, satiety sensitivity) that manifest early in life and predict their eating behaviours and weight trajectories. What determines these traits? Parental feeding restriction is associated with higher child adiposity, pressure to eat with lower adiposity, and both strategies with less healthy eating behaviours, while authoritative feeding styles coincide with more positive outcomes. But, on the whole, twin and family studies argue that nature has a greater influence than nurture on adiposity and eating behaviour, and behavioural investigations of genetic variants that are robustly associated with obesity (e.g. FTO) confirm that genes influence appetite. Meanwhile, a growing body of neuroimaging studies in adults, children and high risk populations suggests that structural and functional variation in brain networks associated with reward, emotion and control might also predict appetite and obesity, and show genetic influence. Together these different strands of evidence support a biobehavioural risk model of obesity development. Parental feeding recommendations should therefore acknowledge the powerful - but modifiable - contribution of genetic and neurological influences to children's eating behaviour.

Extreme obesity is associated with variation in genes related to the circadian rhythm of food intake and hypothalamic signaling.

PubMed

Mariman, Edwin C M; Bouwman, Freek G; Aller, Erik E J G; van Baak, Marleen A; Wang, Ping

2015-06-01

The hypothalamus is important for regulation of energy intake. Mutations in genes involved in the function of the hypothalamus can lead to early-onset severe obesity. To look further into this, we have followed a strategy that allowed us to identify rare and common gene variants as candidates for the background of extreme obesity from a relatively small cohort. For that we focused on subjects with a well-selected phenotype and on a defined gene set and used a rich source of genetic data with stringent cut-off values. A list of 166 genes functionally related to the hypothalamus was generated. In those genes complete exome sequence data from 30 extreme obese subjects (60 genomes) were screened for novel rare indel, nonsense, and missense variants with a predicted negative impact on protein function. In addition, (moderately) common variants in those genes were analyzed for allelic association using the general population as reference (false discovery rate<0.05). Six novel rare deleterious missense variants were found in the genes for BAIAP3, NBEA, PRRC2A, RYR1, SIM1, and TRH, and a novel indel variant in LEPR. Common variants in the six genes for MBOAT4, NPC1, NPW, NUCB2, PER1, and PRRC2A showed significant allelic association with extreme obesity. Our findings underscore the complexity of the genetic background of extreme obesity involving rare and common variants of genes from defined metabolic and physiologic processes, in particular regulation of the circadian rhythm of food intake and hypothalamic signaling. Copyright © 2015 the American Physiological Society.

Phyllodulcin, a Natural Sweetener, Regulates Obesity-Related Metabolic Changes and Fat Browning-Related Genes of Subcutaneous White Adipose Tissue in High-Fat Diet-Induced Obese Mice.

PubMed

Kim, Eunju; Lim, Soo-Min; Kim, Min-Soo; Yoo, Sang-Ho; Kim, Yuri

2017-09-21

Phyllodulcin is a natural sweetener found in Hydrangea macrophylla var. thunbergii . This study investigated whether phyllodulcin could improve metabolic abnormalities in high-fat diet (HFD)-induced obese mice. Animals were fed a 60% HFD for 6 weeks to induce obesity, followed by 7 weeks of supplementation with phyllodulcin (20 or 40 mg/kg body weight (b.w.)/day). Stevioside (40 mg/kg b.w./day) was used as a positive control. Phyllodulcin supplementation reduced subcutaneous fat mass, levels of plasma lipids, triglycerides, total cholesterol, and low-density lipoprotein cholesterol and improved the levels of leptin, adiponectin, and fasting blood glucose. In subcutaneous fat tissues, supplementation with stevioside or phyllodulcin significantly decreased mRNA expression of lipogenesis-related genes, including CCAAT/enhancer-binding protein α ( C/EBPα ), peroxisome proliferator activated receptor γ ( PPARγ ), and sterol regulatory element-binding protein-1C ( SREBP-1c ) compared to the high-fat group. Phyllodulcin supplementation significantly increased the expression of fat browning-related genes, including PR domain containing 16 ( Prdm16 ), uncoupling protein 1 ( UCP1 ), and peroxisome proliferator-activated receptor γ coactivator 1-α ( PGC-1α ), compared to the high-fat group. Hypothalamic brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) signaling was upregulated by phyllodulcin supplementation. In conclusion, phyllodulcin is a potential sweetener that could be used to combat obesity by regulating levels of leptin, fat browning-related genes, and hypothalamic BDNF-TrkB signaling.

Meta-analysis indicates that SNP rs9939609 within FTO is not associated with major depressive disorder (MDD) in Asian population.

PubMed

Yao, Yao; Wen, Yueqiang; Du, Tingfu; Sun, Ning; Deng, Hong; Ryan, Joanne; Rao, Shuquan

2016-03-15

Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses with heritability of up to 38%. The fat mass- and obesity-associated (FTO) gene, in particular the single nucleotide polymorphism (SNP) rs9939609, has been identified as a genetic risk loci associated with MDD. However, most prior studies have involved European and American populations. Whether rs9939609 is an true risk SNP for MDD in Asian populations remains inconclusive. In the present study, we conducted a meta-analysis of the association between rs9939609 and MDD in Asian populations by combining 5 available case-control samples totaling 6531 cases and 12,359 controls. Our meta-analysis suggests that rs9939609 is not a risk SNP for MDD in Asian populations by fixed effect model (Z=1.04, P=0.30, OR=0.96, 95% CI=0.90-1.03). The age distribution and gender ratios were not matched well in the combined samples of cases and controls. Publication bias might be also considered with only a relatively small number of association studies of FTO rs9939609 with MDD in Asian populations. The absence of association of rs9939609 with MDD in our Asian populations suggests a potential genetic heterogeneity in the susceptibility of MDD on this locus. Copyright © 2015 Elsevier B.V. All rights reserved.

Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty.

PubMed

Howard, Sasha R; Guasti, Leonardo; Poliandri, Ariel; David, Alessia; Cabrera, Claudia P; Barnes, Michael R; Wehkalampi, Karoliina; O'Rahilly, Stephen; Aiken, Catherine E; Coll, Anthony P; Ma, Marcella; Rimmington, Debra; Yeo, Giles S H; Dunkel, Leo

2018-02-01

Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity-associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/- mice. We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/- mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP. Copyright © 2017 Endocrine Society

Using molecular functional networks to manifest connections between obesity and obesity-related diseases

PubMed Central

Yang, Jialiang; Qiu, Jing; Wang, Kejing; Zhu, Lijuan; Fan, Jingjing; Zheng, Deyin; Meng, Xiaodi; Yang, Jiasheng; Peng, Lihong; Fu, Yu; Zhang, Dahan; Peng, Shouneng; Huang, Haiyun; Zhang, Yi

2017-01-01

Obesity is a primary risk factor for many diseases such as certain cancers. In this study, we have developed three algorithms including a random-walk based method OBNet, a shortest-path based method OBsp and a direct-overlap method OBoverlap, to reveal obesity-disease connections at protein-interaction subnetworks corresponding to thousands of biological functions and pathways. Through literature mining, we also curated an obesity-associated disease list, by which we compared the methods. As a result, OBNet outperforms other two methods. OBNet can predict whether a disease is obesity-related based on its associated genes. Meanwhile, OBNet identifies extensive connections between obesity genes and genes associated with a few diseases at various functional modules and pathways. Using breast cancer and Type 2 diabetes as two examples, OBNet identifies meaningful genes that may play key roles in connecting obesity and the two diseases. For example, TGFB1 and VEGFA are inferred to be the top two key genes mediating obesity-breast cancer connection in modules associated with brain development. Finally, the top modules identified by OBNet in breast cancer significantly overlap with modules identified from TCGA breast cancer gene expression study, revealing the power of OBNet in identifying biological processes involved in the disease. PMID:29156709

The Role of Aldosterone in Obesity-Related Hypertension

PubMed Central

Kawarazaki, Wakako

2016-01-01

Obese subjects often have hypertension and related cardiovascular and renal diseases, and this has become a serious worldwide health problem. In obese subjects, impaired renal-pressure natriuresis causes sodium retention, leading to the development of salt-sensitive hypertension. Physical compression of the kidneys by visceral fat and activation of the sympathetic nervous system, renin–angiotensin systems (RAS), and aldosterone/mineralocorticoid receptor (MR) system are involved in this mechanism. Obese subjects often exhibit hyperaldosteronism, with increased salt sensitivity of blood pressure (BP). Adipose tissue excretes aldosterone-releasing factors, thereby stimulating aldosterone secretion independently of the systemic RAS, and aldosterone/MR activation plays a key role in the development of hypertension and organ damage in obesity. In obese subjects, both salt sensitivity of BP, enhanced by obesity-related metabolic disorders including aldosterone excess, and increased dietary sodium intake are closely related to the incidence of hypertension. Some salt sensitivity-related gene variants affect the risk of obesity, and together with salt intake, its combination is possibly associated with the development of hypertension in obese subjects. With high salt levels common in modern diets, salt restriction and weight control are undoubtedly important. However, not only MR blockade but also new diagnostic modalities and therapies targeting and modifying genes that are related to salt sensitivity, obesity, or RAS regulation are expected to prevent obesity and obesity-related hypertension. PMID:26927805

Age-related obesity and type 2 diabetes dysregulate neuronal associated genes and proteins in humans

PubMed Central

Daghighi, Mojtaba; Özcan, Behiye; Akbarkhanzadeh, Vishtaseb; Sheedfar, Fareeba; Amini, Marzyeh; Mazza, Tommaso; Pazienza, Valerio; Motazacker, Mahdi M.; Mahmoudi, Morteza; De Rooij, Felix W. M.; Sijbrands, Eric; Peppelenbosch, Maikel P.; Rezaee, Farhad

2015-01-01

Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs. PMID:26337083

Genetic variants within obesity-related genes are associated with tumor recurrence in patients with stages II/III colon cancer.

PubMed

Sebio, Ana; Gerger, Armin; Matsusaka, Satoshi; Yang, Dongyun; Zhang, Wu; Stremitzer, Stefan; Stintzing, Sebastian; Sunakawa, Yu; Yamauchi, Shinichi; Ning, Yan; Fujimoto, Yoshiya; Ueno, Masashi; Lenz, Heinz-Josef

2015-01-01

Obesity is an established risk factor for colorectal cancer (CRC) incidence and it is also linked to CRC recurrence and survival. Polymorphisms located in obesity-related genes are associated with an increased risk of developing several cancer types including CRC. We evaluated whether single-nucleotide polymorphisms in obesity-related genes may predict tumor recurrence in colon cancer patients. Genotypes were obtained from germline DNA from 207 patients with stage II or III colon cancer at the Norris Comprehensive Cancer Center. Nine polymorphisms in eight obesity-related genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA, and DSCR1) were evaluated. The primary endpoint of the study was the 3-year recurrence rate. Positive associations were also tested in an independent Japanese cohort of 350 stage III CRC patients. In univariate analysis, for PPARrs1801282, patients with a CC genotype had significantly lower recurrence probability (29 ± 4% SE) compared with patients with a CG genotype (48 ± 8% SE) [hazard ratio (HR): 1.77; 95% confidence interval (CI), 1.01-3.10; P = 0.040]. For DSCR1rs6517239, patients with an AA genotype had higher recurrence probability than patients carrying at least one allele G (37 ± 4% SE vs. 15 ± 6% SE) (HR: 0.51; 95% CI, 0.27-0.94; P = 0.027). This association was stronger in the patients bearing a left-sided tumor (HR: 0.34; 95% CI, 0.13-0.88; P = 0.018). In the Japanese cohort, no associations were found. This hypothesis-generating study suggests a potential influence of polymorphisms within obesity-related genes in the recurrence probability of colon cancer. These interesting results should be evaluated further.

Analysis of Genes Involved in Body Weight Regulation by Targeted Re-Sequencing.

PubMed

Volckmar, Anna-Lena; Han, Chung Ting; Pütter, Carolin; Haas, Stefan; Vogel, Carla I G; Knoll, Nadja; Struve, Christoph; Göbel, Maria; Haas, Katharina; Herrfurth, Nikolas; Jarick, Ivonne; Grallert, Harald; Schürmann, Annette; Al-Hasani, Hadi; Hebebrand, Johannes; Sauer, Sascha; Hinney, Anke

2016-01-01

Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing. We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) ≥ 99th percentile and 176 lean adults (BMI ≤ 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults. We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (pTDT = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.

R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

PubMed

Su, Rui; Dong, Lei; Li, Chenying; Nachtergaele, Sigrid; Wunderlich, Mark; Qing, Ying; Deng, Xiaolan; Wang, Yungui; Weng, Xiaocheng; Hu, Chao; Yu, Mengxia; Skibbe, Jennifer; Dai, Qing; Zou, Dongling; Wu, Tong; Yu, Kangkang; Weng, Hengyou; Huang, Huilin; Ferchen, Kyle; Qin, Xi; Zhang, Bin; Qi, Jun; Sasaki, Atsuo T; Plas, David R; Bradner, James E; Wei, Minjie; Marcucci, Guido; Jiang, Xi; Mulloy, James C; Jin, Jie; He, Chuan; Chen, Jianjun

2018-01-11

R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N 6 -methyladenosine (m 6 A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m 6 A/MYC/CEBPA signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Obesity: genes, glands or gluttony?

PubMed

Chisholm, D J; Samaras, K; Markovic, T; Carey, D; Lapsys, N; Campbell, L V

1998-01-01

Distribution as well as amount of fat has health implications; central abdominal fat seems to be the major contributor to insulin resistance and risk of diabetes, hypertension and cardiovascular disease. Physical activity and diet affect overall adiposity; moreover, exercise specifically reduces visceral fat. The sexes differ in fat distribution; in particular, pre-menopausal women, despite greater overall adiposity, have much less visceral fat than men. There is a strong genetic determination of overall obesity and central abdominal adiposity. Genes regulating obesity (e.g. Ob) could modulate appetite, satiety, metabolic rate or physical activity. Moderate obesity probably results from interaction between genetic predisposition and an environment of abundant calories and reduced physical activity. Single gene mutations are being identified in a few morbidly obese people; however, the common genetic predisposition for obesity may relate to more subtle variations in regulatory controls. Diet and exercise are effective for some, but the response is often disappointing. Definition of pathways controlling appetite, metabolic rate and lipid metabolism may generate improved pharmacological compounds. Education and availability of lower-energy foods may help, but more radical approaches may be needed, such as environmental restructuring to increase physical activity. The problem is great, but failure will mean intolerably increased health costs.

Meta-review of protein network regulating obesity between validated obesity candidate genes in the white adipose tissue of high-fat diet-induced obese C57BL/6J mice.

PubMed

Kim, Eunjung; Kim, Eun Jung; Seo, Seung-Won; Hur, Cheol-Goo; McGregor, Robin A; Choi, Myung-Sook

2014-01-01

Worldwide obesity and related comorbidities are increasing, but identifying new therapeutic targets remains a challenge. A plethora of microarray studies in diet-induced obesity models has provided large datasets of obesity associated genes. In this review, we describe an approach to examine the underlying molecular network regulating obesity, and we discuss interactions between obesity candidate genes. We conducted network analysis on functional protein-protein interactions associated with 25 obesity candidate genes identified in a literature-driven approach based on published microarray studies of diet-induced obesity. The obesity candidate genes were closely associated with lipid metabolism and inflammation. Peroxisome proliferator activated receptor gamma (Pparg) appeared to be a core obesity gene, and obesity candidate genes were highly interconnected, suggesting a coordinately regulated molecular network in adipose tissue. In conclusion, the current network analysis approach may help elucidate the underlying molecular network regulating obesity and identify anti-obesity targets for therapeutic intervention.

A common variant near BDNF is associated with dietary calcium intake in adolescents.

PubMed

Dušátková, Lenka; Zamrazilová, Hana; Aldhoon-Hainerová, Irena; Sedláčková, Barbora; Včelák, Josef; Hlavatý, Petr; Bendlová, Běla; Kunešová, Marie; Hainer, Vojtěch

2015-09-01

Specific targets for most obesity candidate genes discovered by genomewide association studies remain unknown. Such genes are often highly expressed in the hypothalamus, indicating their role in energy homeostasis. We aimed to evaluate the associations of selected gene variants with adiposity and dietary traits. Anthropometric parameters, fat mass, dietary intake (total energy, fat, protein, carbohydrate, fiber, and calcium) and 10 gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R and FTO) were analyzed in 1953 Czech individuals aged 10.0 to 18.0 years (1035 nonoverweight and 918 overweight: body mass index [BMI] ≥90th percentile). Obesity risk alleles of TMEM18 rs7561317, SEC16B rs10913469, and FTO rs9939609 were related to increased body weight and BMI (P < .005). The FTO variant also showed a significant positive association with waist circumference and fat mass (P < .001). Overweight adolescents had a lower total energy intake (P < .001) but a higher percentage of fat (P = .009) and protein intake (P < .001) than the nonoverweight subjects. There was also a lower calcium intake in the overweight group (P < .001). An association with at least one component of dietary intake was found in 3 of 10 studied gene variants. The MC4R rs17782313 was associated negatively with protein (P = .012) and positively associated with fiber (P = .032) intakes. The obesity risk alleles of BDNF rs925946 and FTO rs9939609 were related to a lower calcium intake (P = .001 and .037). The effects of FTO and MC4R variants, however, disappeared after corrections for multiple testing. Our results suggest that the common BDNF variant may influence dietary calcium intake independent of BMI. Copyright © 2015 Elsevier Inc. All rights reserved.

Polymorphisms in genes related to inflammation and obesity and colorectal adenoma risk.

PubMed

Huang, Brian Z; Tsilidis, Konstantinos K; Smith, Michael W; Hoffman-Bolton, Judith; Visvanathan, Kala; Platz, Elizabeth A; Joshu, Corinne E

2018-05-26

We previously investigated the association between single nucleotide polymorphisms (SNPs) in genes related to obesity and inflammation and colorectal cancer in the CLUE II cohort. However, the relationships between these SNPs and colorectal adenomas have not been well evaluated. In a nested case-control study of 135 incident adenoma cases and 269 matched controls in the CLUE II cohort (1989-2000), we genotyped 17 candidate SNPs in 12 genes (PPARG, TCF7L2, ADIPOQ, LEP, IL10, CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and 19 tagSNPs in three genes (IL10, CRP, and TLR4). Conditional logistic regression was used to calculate odds ratios (OR) for adenomas (overall and by size, histology, location, number). Polymorphisms in the inflammatory-related genes CRP, ADIPOQ, IL6, and TLR4 were observed to be associated with adenoma risk. At rs1205 in CRP, T (minor allele) carriers had a higher risk (OR 1.67, 95%CI 1.07-2.60; reference: CC) of adenomas overall and adenomas with aggressive characteristics. At rs1201299 in ADIPOQ, the AC genotype had a higher risk (OR 1.58, 95%CI 1.00-2.49) of adenomas, while the minor AA genotype had a borderline inverse association (OR 0.44, 95%CI 0.18-1.08; reference: CC). At rs1800797 in IL6, the AA genotype had a borderline inverse association (OR 0.53, 95%CI 0.27-1.05; reference: GG). Three TLR4 tagSNPs (rs10116253, rs1927911, rs7873784) were associated with adenomas among obese participants. None of these SNPs were associated with colorectal cancer in our prior study in CLUE II, possibly suggesting a different genetic etiology for early colorectal neoplasia. © 2018 Wiley Periodicals, Inc.

Maternal BMI as a predictor of methylation of obesity-related genes in saliva samples from preschool-age Hispanic children at-risk for obesity.

PubMed

Oelsner, Kathryn Tully; Guo, Yan; To, Sophie Bao-Chieu; Non, Amy L; Barkin, Shari L

2017-01-09

The study of epigenetic processes and mechanisms present a dynamic approach to assess complex individual variation in obesity susceptibility. However, few studies have examined epigenetic patterns in preschool-age children at-risk for obesity despite the relevance of this developmental stage to trajectories of weight gain. We hypothesized that salivary DNA methylation patterns of key obesogenic genes in Hispanic children would 1) correlate with maternal BMI and 2) allow for identification of pathways associated with children at-risk for obesity. Genome-wide DNA methylation was conducted on 92 saliva samples collected from Hispanic preschool children using the Infinium Illumina HumanMethylation 450 K BeadChip (Illumina, San Diego, CA, USA), which interrogates >484,000 CpG sites associated with ~24,000 genes. The analysis was limited to 936 genes that have been associated with obesity in a prior GWAS Study. Child DNA methylation at 17 CpG sites was found to be significantly associated with maternal BMI, with increased methylation at 12 CpG sites and decreased methylation at 5 CpG sites. Pathway analysis revealed methylation at these sites related to homocysteine and methionine degradation as well as cysteine biosynthesis and circadian rhythm. Furthermore, eight of the 17 CpG sites reside in genes (FSTL1, SORCS2, NRF1, DLC1, PPARGC1B, CHN2, NXPH1) that have prior known associations with obesity, diabetes, and the insulin pathway. Our study confirms that saliva is a practical human tissue to obtain in community settings and in pediatric populations. These salivary findings indicate potential epigenetic differences in Hispanic preschool children at risk for pediatric obesity. Identifying early biomarkers and understanding pathways that are epigenetically regulated during this critical stage of child development may present an opportunity for prevention or early intervention for addressing childhood obesity. The clinical trial protocol is available at Clinical

Changes in gene expression in PBMCs profiles of PPARα target genes in obese and non-obese individuals during fasting.

PubMed

Felicidade, Ingrid; Marcarini, Juliana Cristina; Carreira, Clísia Mara; Amarante, Marla Karine; Afman, Lydia A; Mantovani, Mário Sérgio; Ribeiro, Lúcia Regina

2015-01-01

The prevalence of obesity has risen dramatically and the World Health Organization estimates that 700 million people will be obese worldwide by 2015. Approximately, 50% of the Brazilian population above 20 years of age is overweight, and 16% is obese. This study aimed to evaluate the differences in the expression of PPARα target genes in human peripheral blood mononuclear cells (PBMCs) and free fatty acids (FFA) in obese and non-obese individuals after 24 h of fasting. We first presented evidence that Brazilian people exhibit expression changes in PPARα target genes in PBMCs under fasting conditions. Q-PCR was utilized to assess the mRNA expression levels of target genes. In both groups, the FFA concentrations increased significantly after 24 h of fasting. The basal FFA mean concentration was two-fold higher in the obese group compared with the non-obese group. After fasting, all genes evaluated in this study showed increased expression levels compared with basal expression in both groups. However, our results reveal no differences in gene expression between the obese and non-obese, more studies are necessary to precisely delineate the associated mechanisms, particularly those that include groups with different degrees of obesity and patients with diabetes mellitus type 2 because the expression of the main genes that are involved in β-oxidation and glucose level maintenance are affected by these factors. © 2014 S. Karger AG, Basel.

Multilocus analyses of seven candidate genes suggest interacting pathways for obesity-related traits in Brazilian populations.

PubMed

Angeli, Cláudia B; Kimura, Lilian; Auricchio, Maria T; Vicente, João P; Mattevi, Vanessa S; Zembrzuski, Verônica M; Hutz, Mara H; Pereira, Alexandre C; Pereira, Tiago V; Mingroni-Netto, Regina C

2011-06-01

We investigated whether variants in major candidate genes for food intake and body weight regulation contribute to obesity-related traits under a multilocus perspective. We studied 375 Brazilian subjects from partially isolated African-derived populations (quilombos). Seven variants displaying conflicting results in previous reports and supposedly implicated in the susceptibility of obesity-related phenotypes were investigated: β2-adrenergic receptor (ADRB2) (Arg16Gly), insulin induced gene 2 (INSIG2) (rs7566605), leptin (LEP) (A19G), LEP receptor (LEPR) (Gln223Arg), perilipin (PLIN) (6209T > C), peroxisome proliferator-activated receptor-γ (PPARG) (Pro12Ala), and resistin (RETN) (-420 C > G). Regression models as well as generalized multifactor dimensionality reduction (GMDR) were employed to test the contribution of individual effects and higher-order interactions to BMI and waist-hip ratio (WHR) variation and risk of overweight/obesity. The best multilocus association signal identified in the quilombos was further examined in an independent sample of 334 Brazilian subjects of European ancestry. In quilombos, only the PPARG polymorphism displayed significant individual effects (WHR variation, P = 0.028). No association was observed either with the risk of overweight/obesity (BMI ≥ 25 kg/m2), risk of obesity alone (BMI ≥ 30 kg/m2) or BMI variation. However, GMDR analyses revealed an interaction between the LEPR and ADRB2 polymorphisms (P = 0.009) as well as a third-order effect involving the latter two variants plus INSIG2 (P = 0.034) with overweight/obesity. Assessment of the LEPR-ADRB2 interaction in the second sample indicated a marginally significant association (P = 0.0724), which was further verified to be limited to men (P = 0.0118). Together, our findings suggest evidence for a two-locus interaction between the LEPR Gln223Arg and ADRB2 Arg16Gly variants in the risk of overweight/obesity, and highlight further the importance of multilocus effects in

Kernel machine SNP set analysis provides new insight into the association between obesity and polymorphisms located on the chromosomal 16q.12.2 region: Tehran Lipid and Glucose Study.

PubMed

Javanrouh, Niloufar; Daneshpour, Maryam S; Soltanian, Ali Reza; Tapak, Leili

2018-06-05

Obesity is a serious health problem that leads to low quality of life and early mortality. To the purpose of prevention and gene therapy for such a worldwide disease, genome wide association study is a powerful tool for finding SNPs associated with increased risk of obesity. To conduct an association analysis, kernel machine regression is a generalized regression method, has an advantage of considering the epistasis effects as well as the correlation between individuals due to unknown factors. In this study, information of the people who participated in Tehran cardio-metabolic genetic study was used. They were genotyped for the chromosomal region, evaluation 986 variations located at 16q12.2; build 38hg. Kernel machine regression and single SNP analysis were used to assess the association between obesity and SNPs genotyped data. We found that associated SNP sets with obesity, were almost in the FTO (P = 0.01), AIKTIP (P = 0.02) and MMP2 (P = 0.02) genes. Moreover, two SNPs, i.e., rs10521296 and rs11647470, showed significant association with obesity using kernel regression (P = 0.02). In conclusion, significant sets were randomly distributed throughout the region with more density around the FTO, AIKTIP and MMP2 genes. Furthermore, two intergenic SNPs showed significant association after using kernel machine regression. Therefore, more studies have to be conducted to assess their functionality or precise mechanism. Copyright © 2018 Elsevier B.V. All rights reserved.

Identification of genes whose expression is altered by obesity throughout the arterial tree.

PubMed

Padilla, Jaume; Jenkins, Nathan T; Thorne, Pamela K; Martin, Jeffrey S; Rector, R Scott; Davis, J Wade; Laughlin, M Harold

2014-11-15

We used next-generation RNA sequencing (RNA-Seq) technology on the whole transcriptome to identify genes whose expression is consistently affected by obesity across multiple arteries. Specifically, we examined transcriptional profiles of the iliac artery as well as the feed artery, first, second, and third branch order arterioles in the soleus, gastrocnemius, and diaphragm muscles from obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats. Within the gastrocnemius and soleus muscles, the number of genes differentially expressed with obesity tended to increase with increasing branch order arteriole number (i.e., decreasing size of the artery). This trend was opposite in the diaphragm. We found a total of 15 genes that were consistently upregulated with obesity (MIS18A, CTRB1, FAM151B, FOLR2, PXMP4, OAS1B, SREBF2, KLRA17, SLC25A44, SNX10, SLFN3, MEF2BNB, IRF7, RAD23A, LGALS3BP) and five genes that were consistently downregulated with obesity (C2, GOLGA7, RIN3, PCP4, CYP2E1). A small fraction (∼9%) of the genes affected by obesity was modulated across all arteries examined. In conclusion, the present study identifies a select number of genes (i.e., 20 genes) whose expression is consistently altered throughout the arterial network in response to obesity and provides further insight into the heterogeneous vascular effects of obesity. Although there is no known direct function of the majority of 20 genes related to vascular health, the obesity-associated upregulation of SREBF2, LGALS3BP, IRF7, and FOLR2 across all arteries is suggestive of an unfavorable vascular phenotypic alteration with obesity. These data may serve as an important resource for identifying novel therapeutic targets against obesity-related vascular complications.

Identification of genes whose expression is altered by obesity throughout the arterial tree

PubMed Central

Jenkins, Nathan T.; Thorne, Pamela K.; Martin, Jeffrey S.; Rector, R. Scott; Davis, J. Wade; Laughlin, M. Harold

2014-01-01

We used next-generation RNA sequencing (RNA-Seq) technology on the whole transcriptome to identify genes whose expression is consistently affected by obesity across multiple arteries. Specifically, we examined transcriptional profiles of the iliac artery as well as the feed artery, first, second, and third branch order arterioles in the soleus, gastrocnemius, and diaphragm muscles from obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats. Within the gastrocnemius and soleus muscles, the number of genes differentially expressed with obesity tended to increase with increasing branch order arteriole number (i.e., decreasing size of the artery). This trend was opposite in the diaphragm. We found a total of 15 genes that were consistently upregulated with obesity (MIS18A, CTRB1, FAM151B, FOLR2, PXMP4, OAS1B, SREBF2, KLRA17, SLC25A44, SNX10, SLFN3, MEF2BNB, IRF7, RAD23A, LGALS3BP) and five genes that were consistently downregulated with obesity (C2, GOLGA7, RIN3, PCP4, CYP2E1). A small fraction (∼9%) of the genes affected by obesity was modulated across all arteries examined. In conclusion, the present study identifies a select number of genes (i.e., 20 genes) whose expression is consistently altered throughout the arterial network in response to obesity and provides further insight into the heterogeneous vascular effects of obesity. Although there is no known direct function of the majority of 20 genes related to vascular health, the obesity-associated upregulation of SREBF2, LGALS3BP, IRF7, and FOLR2 across all arteries is suggestive of an unfavorable vascular phenotypic alteration with obesity. These data may serve as an important resource for identifying novel therapeutic targets against obesity-related vascular complications. PMID:25271210

Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population.

PubMed

Nikitin, Aleksey G; Potapov, Viktor Y; Brovkina, Olga I; Koksharova, Ekaterina O; Khodyrev, Dmitry S; Philippov, Yury I; Michurova, Marina S; Shamkhalova, Minara S; Vikulova, Olga K; Smetanina, Svetlana A; Suplotova, Lyudmila A; Kononenko, Irina V; Kalashnikov, Viktor Y; Smirnova, Olga M; Mayorov, Alexander Y; Nosikov, Valery V; Averyanov, Alexander V; Shestakova, Marina V

2017-01-01

The association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes. The study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA- β were used to measure insulin resistance and β -cell secretory function, respectively. The analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871 , rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired β -cell function. In the Russian population, genes, which affect insulin synthesis and secretion in the β -cells of the pancreas, play a central role in the development of T2DM.

Influence of Adiposity-Related Genetic Markers in a Population of Saudi Arabians Where Other Variables Influencing Obesity May Be Reduced

PubMed Central

Alharbi, Khalid K.; Khan, Imran Ali; Syed, Rabbani; Mohammed, Abdul Khader; Gaunt, Tom R.; Tamimi, Waleed; Al-Daghri, Nasser M.; Day, Ian N. M.

2014-01-01

Large scale studies in Europeans have clearly identified common polymorphism affecting BMI and obesity. We undertook a genotype study to examine the impact of variants, known to influence obesity, in a sample from the Saudi Arabian population, notable for its profound combination of low mean physical activity indices and high energy intake. Anthropometry measures and genotypes were obtained for 367 Saudis, taken from King Saud University and Biomarker Screening Project in Riyadh (Riyadh Cohort). We observed large effect sizes with obesity for rs10767664 (BDNF) (OR = 1.923, P = 0.00072) and rs3751812 (FTO) (OR = 1.523, P = 0.016) in our sample and, using weighted genetic risk scores, we found strong evidence of a cumulative effect using 11 SNPs taken predominantly from loci principally affecting appetite (OR = 2.57, P = 0.00092). We used conditional analyses to discern which of our three highly correlated FTO SNPs were responsible for the observed signal, although we were unable to determine with confidence which best marked the causal site. Our analysis indicates that markers located in loci known to influence fat mass through increased appetite affect obesity in Saudi Arabians to an extent possibly greater than in Europeans. Larger scale studies will be necessary to obtain a precise comparison. PMID:25484485

Exome sequencing in Thai patients with familial obesity.

PubMed

Kaewsutthi, S; Santiprabhob, J; Phonrat, B; Tungtrongchitr, A; Lertrit, P; Tungtrongchitr, R

2016-07-14

Obesity is a major worldwide health issue, with increasing prevalence in adults and children from developed and developing countries. Obesity causes several chronic diseases, including cardiovascular and respiratory diseases, osteoarthritis, hypertension, stroke, type II diabetes, obstructive sleep apnea, and several types of cancer. Previous genome-wide association studies have identified several genes associated with obesity, including LEP, LEPR, POMC, PCSK1, FTO, MC3R, MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B, SIM1, and TNKS/MSRA. However, most of these variants are found in the intronic or intergenic regions, making it difficult to elucidate the underlying mechanisms. Therefore, in this study, we performed a whole exome sequencing of the protein-coding regions in the total genome (exome) of two obese and one normal subject belonging to the same Thai family to identify the genes responsible for obesity. We identified 709 functional variants that were differentially expressed between obese and normal subjects; of these, 65 were predicted to be deleterious to protein structure or function. The minor allele frequency of 14 of these genes (ALOX5AP, COL9A2, DEFB126, GDPD4, HCRTR1, MLL3, OPLAH, OR4C45, PRIM2, RXFP2, TIGD6, TRPM8, USP49, and ZNF596) was low, indicating causal variants that could be associated with complex traits or diseases. Genotyping revealed HCRTR1, COL9A2, and TRPM8 to be associated with the regulation of feeding behavior and energy expenditure. These genes constituted a network of pathways, including lipid metabolism, signaling transduction, immune, membrane transport, and gene regulation pathways, and seemed to play important roles in obesity.

Mitochondrial ATPase Subunit 6 and Cytochrome B Gene Variations in Obese Turkish Children

PubMed Central

Demir, Durkadın; Türkkahraman, Doğa; Samur, Anıl Aktaş; Lüleci, Güven; Akçurin, Sema; M. Alper, Özgül

2014-01-01

Objective: Due to the importance of energy metabolism in mitochondria, mitochondrial genome variations are evaluated in energy-related diseases such as obesity. To date, several nuclear genes were found to be related to obesity. Our aim in this study was to investigate the presence of polymorphisms in mitochondrial ATPase subunit 6 (mt-ATP6) and cytochrome b (mt-CytB) genes that may be associated with childhood obesity. Methods: The mt-ATP6 and mt-CytB genes were amplified and entirely sequenced in a series of 100 obese and in an equal number of healthy Turkish children aged between 6-14 years. Results: A total of 118 synonymous and nonsynonymous variations were detected in the obese and control groups. Only two previously reported synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene were found to be significantly higher in the obese group compared to the control group (p<0.05). In the mt-ATP6 gene, one novel nonsynonymous substitution (mt.8726C>T) and one novel synonymous substitution (mt.9108A>T) were found. In the mt-CytB gene, one nonsynonymous substitution (mt.14880T>C) and two synonymous substitutions (mt.14891C>T and mt.15091C>T) were novel substitutions. Conclusion: Two synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene may be associated with childhood obesity. Our study provides the first data about mitochondrial genome variations in a Turkish obese population and also the first in obese children. More cases should be screened in obese groups in order to understand the effects of mitochondrial polymorphisms in the development of obesity. PMID:25541891

Expression of Selenoprotein Genes Is Affected by Obesity of Pigs Fed a High-Fat Diet.

PubMed

Zhao, Hua; Li, Ke; Tang, Jia-Yong; Zhou, Ji-Chang; Wang, Kang-Ning; Xia, Xin-Jie; Lei, Xin Gen

2015-07-01

Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear. This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs. Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy-based control diet or that diet containing 3-7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables. The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29-42% and affected (P < 0.05-0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA. The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue thyroid hormone activity, endoplasmic reticulum protein degradation

Identification of co-expression gene networks, regulatory genes and pathways for obesity based on adipose tissue RNA Sequencing in a porcine model.

PubMed

Kogelman, Lisette J A; Cirera, Susanna; Zhernakova, Daria V; Fredholm, Merete; Franke, Lude; Kadarmideen, Haja N

2014-09-30

Obesity is a complex metabolic condition in strong association with various diseases, like type 2 diabetes, resulting in major public health and economic implications. Obesity is the result of environmental and genetic factors and their interactions, including genome-wide genetic interactions. Identification of co-expressed and regulatory genes in RNA extracted from relevant tissues representing lean and obese individuals provides an entry point for the identification of genes and pathways of importance to the development of obesity. The pig, an omnivorous animal, is an excellent model for human obesity, offering the possibility to study in-depth organ-level transcriptomic regulations of obesity, unfeasible in humans. Our aim was to reveal adipose tissue co-expression networks, pathways and transcriptional regulations of obesity using RNA Sequencing based systems biology approaches in a porcine model. We selected 36 animals for RNA Sequencing from a previously created F2 pig population representing three extreme groups based on their predicted genetic risks for obesity. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to detect clusters of highly co-expressed genes (modules). Additionally, regulator genes were detected using Lemon-Tree algorithms. WGCNA revealed five modules which were strongly correlated with at least one obesity-related phenotype (correlations ranging from -0.54 to 0.72, P < 0.001). Functional annotation identified pathways enlightening the association between obesity and other diseases, like osteoporosis (osteoclast differentiation, P = 1.4E-7), and immune-related complications (e.g. Natural killer cell mediated cytotoxity, P = 3.8E-5; B cell receptor signaling pathway, P = 7.2E-5). Lemon-Tree identified three potential regulator genes, using confident scores, for the WGCNA module which was associated with osteoclast differentiation: CCR1, MSR1 and SI1 (probability scores respectively 95.30, 62.28, and 34.58). Moreover, detection

Evaluation of weight loss and adipocytokines levels after two hypocaloric diets with different macronutrient distribution in obese subjects with rs9939609 gene variant.

PubMed

de Luis, Daniel Antonio; Aller, Rocío; Izaola, Olatz; de la Fuente, Beatriz; Conde, Rosa; Sagrado, Manuel Gonzalez; Primo, David

2012-11-01

Common polymorphisms of the fat mass and obesity associated gene (FTO) have been linked to obesity in some populations. One of these genetic variants (rs9939609) has been related to an increased risk of obesity. Our aim was to evaluate weight loss and adipocytokine levels after two hypocaloric diets with different macronutrient distribution in obese subjects with RS9939609 gene variant. 305 obese patients were enrolled in a prospective way. In the basal visit, patients were randomly allocated during 3 months to low carbohydrates and low fat. After treatment with both diets and in both genotypes, weight, fat mass, waist circumference and systolic blood pressures decreased. With the diet type I and in TT genotype, insulin (-6.6 ± 9.8 IU/L) and homeostasis model assessment (-2.9 ± 6.1 units) decreased. With the diet type II and in both genotypes (wild and mutant type), insulin (-5.2 ± 6.1 vs. -3.8 ± 6.1 IU/L; p < 0.05) and homeostasis model assessment (-2.4 ± 4.8 vs. -1.1 ± 3.8 kg; p < 0.05) decreased. In the A allele group, a significant decrease was detected in total cholesterol levels (-11.5 ± 20.1 mg/dL), low density lipoprotein cholesterol levels (-13.2 ± 20.9 mg/dL) and c-reactive protein levels (-1.3 ± 3.8 mg/dL) secondary to weight loss after treatment with diet II. The decrease of leptin levels was higher in mutant type group than wild type group with low fat diet (-10.3 ± 36.1 vs. -28.6 ± 53.7 ng/mL; p < 0.05). Metabolic improvement secondary to weight loss was better in A carriers with a low fat hypocaloric diet. Copyright © 2012 John Wiley & Sons, Ltd.

Moderate effects of apple juice consumption on obesity-related markers in obese men: impact of diet-gene interaction on body fat content.

PubMed

Barth, Stephan W; Koch, Tatiana C L; Watzl, Bernhard; Dietrich, Helmut; Will, Frank; Bub, Achim

2012-10-01

The effect of polyphenol-rich cloudy apple juice (CloA) consumption on plasma parameters related to the obesity phenotype and potential effects of interactions between CloA and allelic variants in obesity candidate genes were assessed in obese men. In this controlled, randomized, and parallel study, n = 68, non-smoking, non-diabetic men with a BMI ≥27 kg/m(2) received 750 mL/day CloA (802.5 mg polyphenols) or 750 mL/day control beverage (CB, isocaloric equivalent to CloA) for 4 weeks. Further, study participants were genotyped for single-nucleotide polymorphisms in PPARγ (rs1801282), UCP3 (rs1800849), IL-6 (rs1800795), FABP2 (rs1799883), INSIG2 (rs7566605), and PGC1 (rs8192678) genes. At the beginning and at the end of intervention plasma lipids, distinct adipokines and cytokines as well as anthropometric parameters were determined. CloA compared to CB had no significant effect on plasma lipids, plasma adipokine and cytokine levels, BMI, and waist circumference. However, CloA consumption significantly reduced percent body fat compared to CB (∆ % body fat: CloA: -1.0 ± 1.3 vs. CB: -0.2 ± 0.9, p < 0.05). The IL-6-174 G/C polymorphism showed an interaction with body fat reduction induced by CloA. Solely in C/C, but not in G/C or G/G variants, a significant reduction in body fat after 4 weeks of CloA intervention was detectable. The observed diet-gene interaction might be a first indication for the impact of individual genetic background on CloA-mediated bioactivity on obesity-associated comorbidities.

[STUDY RELATIVE EXPRESSION OF GENES THAT CONTROL GLUCOSE METABOLISM IN THE LIVER IN MICE WITH DEVELOPMENT OF MELANOCORTIN OBESITY].

PubMed

Baklanov, A V; Bazhan, N M

2015-06-01

The relative gene expressions of glucose-6-phosphatase (G6P), phosphoenolpyruvate carbo- xykinase (PEPCK)--markers of gluconeogenesis, glucokinase (GK)--a marker of glycolysis, glucose transporter type 2 (GLUT2)--a marker of input and output of glucose in the liver were measured during the development of melanocortin (MC) obesity in male mice of C57BL/6J strain with mutation yellow in the Agouti locus (Ay/a mice). The mutation decreases MC receptor activity and induces hyperphagia and MC obesity. The males of the same line with mutation nonagouti were used as control. Tissue samples were taken at age 10 (before obesity), 15 (moderate obesity) and 30 (developed obesity) weeks. It has been shown that Ay/a mice had decreased glucose tolerance since 10-week age. There were age-related changes in mRNA levels in the liver of Ay/a mice, unlike a/a mice. In Ay/a mice the mRNA GLUT2 levels at the age of 10 weeks, mRNA GK levels at the age of 15 weeks, and mRNA G6P levels at the age of 3O weeks were higher than those in Ada mice of other ages. InAYfa mice the mRNA GK levels at the age of 15 weeks and mRNA G6F levels at the age of 30 weeks were increased relatively to those in a/a mice. Thus, Ay/a mice before the development of MK obesity had changes in the mRNA levels genes of proteins that regulate hepatic glucose metabolism, which may contribute to the compensation of glucose metabolism disorders caused by a hereditary decrease of MK system activity

Association of variants in genes related to the immune response and obesity with BPH in CLUE II.

PubMed

Lopez, D S; Peskoe, S B; Tsilidis, K K; Hoffman-Bolton, J; Helzlsouer, K J; Isaacs, W B; Smith, M W; Platz, E A

2014-12-01

Chronic inflammation and obesity may contribute to the genesis or progression of BPH and BPH-associated lower urinary tract symptoms (LUTS). The influence of variants in genes related to these states on BPH has not been studied extensively. Thus, we evaluated the association of 17 single-nucleotide polymorphisms (SNPs) in immune response genes (IL1B, IL6, IL8, IL10, TNF, CRP, TLR4 and RNASEL) and genes involved in obesity, including insulin regulation (LEP, ADIPOQ, PPARG and TCF7L2), with BPH. BPH cases (N = 568) and age-frequency matched controls (N=568) were selected from among adult male CLUE II cohort participants who responded in 2000 to a mailed questionnaire. BPH was defined as BPH surgery, use of BPH medications or symptomatic BPH (American Urological Association Symptom Index Score ⩾ 15). Controls were men who had not had BPH surgery, did not use BPH medications and whose symptom score was ⩽ 7. Age-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. None of the candidate SNPs was statistically significantly associated with BPH. However, we could not rule out possible weak associations for CRP rs1205 (1082C>T), ADIPOQ rs1501299 (276C>A), PPARG rs1801282 (-49C>G) and TCF7L2 rs7903146 (47833T>C). After summing risk alleles, men with ⩾ 4 had an increased BPH risk compared with those with ⩽ 1 (OR, 1.78; 95% CI, 1.10-2.89; P(trend) = 0.006). SNPs in genes related to immune response and obesity, especially in combination, may be associated with BPH.

A targeted genotyping approach enhances identification of variants in taste receptor and appetite/reward genes of potential functional importance for obesity-related porcine traits.

PubMed

Cirera, S; Clop, A; Jacobsen, M J; Guerin, M; Lesnik, P; Jørgensen, C B; Fredholm, M; Karlskov-Mortensen, P

2018-04-01

Taste receptors (TASRs) and appetite and reward (AR) mechanisms influence eating behaviour, which in turn affects food intake and risk of obesity. In a previous study, we used next generation sequencing to identify potentially functional mutations in TASR and AR genes and found indications for genetic associations between identified variants and growth and fat deposition in a subgroup of animals (n = 38) from the UNIK resource pig population. This population was created for studying obesity and obesity-related diseases. In the present study we validated results from our previous study by investigating genetic associations between 24 selected single nucleotide variants in TASR and AR gene variants and 35 phenotypes describing obesity and metabolism in the entire UNIK population (n = 564). Fifteen variants showed significant association with specific obesity-related phenotypes after Bonferroni correction. Six of the 15 genes, namely SIM1, FOS, TAS2R4, TAS2R9, MCHR2 and LEPR, showed good correlation between known biological function and associated phenotype. We verified a genetic association between potentially functional variants in TASR/AR genes and growth/obesity and conclude that the combination of identification of potentially functional variants by next generation sequencing followed by targeted genotyping and association studies is a powerful and cost-effective approach for increasing the power of genetic association studies. © 2018 Stichting International Foundation for Animal Genetics.

Can Thrifty Gene(s) or Predictive Fetal Programming for Thriftiness Lead to Obesity?

PubMed Central

Baig, Ulfat; Belsare, Prajakta; Watve, Milind; Jog, Maithili

2011-01-01

Obesity and related disorders are thought to have their roots in metabolic “thriftiness” that evolved to combat periodic starvation. The association of low birth weight with obesity in later life caused a shift in the concept from thrifty gene to thrifty phenotype or anticipatory fetal programming. The assumption of thriftiness is implicit in obesity research. We examine here, with the help of a mathematical model, the conditions for evolution of thrifty genes or fetal programming for thriftiness. The model suggests that a thrifty gene cannot exist in a stable polymorphic state in a population. The conditions for evolution of thrifty fetal programming are restricted if the correlation between intrauterine and lifetime conditions is poor. Such a correlation is not observed in natural courses of famine. If there is fetal programming for thriftiness, it could have evolved in anticipation of social factors affecting nutrition that can result in a positive correlation. PMID:21773010

Expression of Selenoprotein Genes Is Affected by Obesity of Pigs Fed a High-Fat Diet123

PubMed Central

Zhao, Hua; Li, Ke; Tang, Jia-Yong; Zhou, Ji-Chang; Wang, Kang-Ning; Xia, Xin-Jie; Lei, Xin Gen

2015-01-01

Background: Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear. Objective: This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs. Methods: Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy–based control diet or that diet containing 3–7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables. Results: The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29–42% and affected (P < 0.05–0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA. Conclusions: The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue

Identification of active miRNA and transcription factor regulatory pathways in human obesity-related inflammation.

PubMed

Zhang, Xi-Mei; Guo, Lin; Chi, Mei-Hua; Sun, Hong-Mei; Chen, Xiao-Wen

2015-03-07

Obesity-induced chronic inflammation plays a fundamental role in the pathogenesis of metabolic syndrome (MS). Recently, a growing body of evidence supports that miRNAs are largely dysregulated in obesity and that specific miRNAs regulate obesity-associated inflammation. We applied an approach aiming to identify active miRNA-TF-gene regulatory pathways in obesity. Firstly, we detected differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs) from mRNA and miRNA expression profiles, respectively. Secondly, by mapping the DEGs and DEmiRs to the curated miRNA-TF-gene regulatory network as active seed nodes and connect them with their immediate neighbors, we obtained the potential active miRNA-TF-gene regulatory subnetwork in obesity. Thirdly, using a Breadth-First-Search (BFS) algorithm, we identified potential active miRNA-TF-gene regulatory pathways in obesity. Finally, through the hypergeometric test, we identified the active miRNA-TF-gene regulatory pathways that were significantly related to obesity. The potential active pathways with FDR < 0.0005 were considered to be the active miRNA-TF regulatory pathways in obesity. The union of the active pathways is visualized and identical nodes of the active pathways were merged. We identified 23 active miRNA-TF-gene regulatory pathways that were significantly related to obesity-related inflammation.

ROLE OF RS9939609 FTO GENE VARIANT IN WEIGHT LOSS, INSULIN RESISTANCE AND METABOLIC PARAMETERS AFTER A HIGH MONOUNSATURATED VS A HIGH POLYUNSATURATED FAT HYPOCALORIC DIETS.

PubMed

De Luis, Daniel Antonio; Aller, Rocío; Izaola, Olatz; Pacheco, D

2015-07-01

common polymorphisms (rs9939609) of the fat mass and obesity associated gene (FTO) have been linked to obesity. our aim was to investigate the role of this polymorphism on insulin resistance, metabolic changes and weight loss secondary to a high monounsaturated fat vs a high polyunsaturated fat hypocaloric diets. a sample of 233 obese subjects was enrolled in a prospective way. In the basal visit, patients were randomly allocated during 3 months to; Diet M (high monounsaturated fat hypocaloric diet) or Diet P (high polyunsaturated fat hypocaloric diet). after treatment with two diets and in both genotypes, weight, fat mass and waist circumference decreased. Lower levels of body mass index (BMI), weight and fat mass were detected after Diet P in A allele carriers than TT genotype subjects. With the diet type P and in both genotypes (TT and AT + AA), total cholesterol levels (-15.3 + 35.1 mg/dl vs -11.6 + 32.1 mg/dl: p > 0.05) and LDL cholesterol levels (-11.5 + 34.1 mg/dl vs -8.5 + 30.1 mg/dl: p > 0.05) decreased. In A allele carriers a significant decreased was detected in insulin levels (-2.8 + 2.1 UI/L vs -1.3 + 8.0 UI/L: p < 0.05) and HOMA index (-1.0 + 1.3 vs -0.2 + 2.1: p > 0.05), too. With the diet M and in both genotype groups, leptin levels (-8.0 + 17.1 ng/ ml vs -4.9 + 18.7 ng/ml: p > 0.05) decreased. Conclusiones: metabolic improvement secondary to weight loss was better in A carriers with a high polyunsaturated fat hypocaloric diet. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Study of seven single-nucleotide polymorphisms identified in East Asians for association with obesity in a Taiwanese population.

PubMed

Huang, Wei-Hsin; Hwang, Lee-Ching; Chan, Hsin-Lung; Lin, Hsiang-Yu; Lin, Yung-Hsiang

2016-08-10

This study aimed to examine single-nucleotide polymorphisms (SNPs) of seven previously reported obesity genes in East Asians and to analyse their associations and synergistic effects on obesity in the Taiwanese population. Cross-sectional study. One medical centre in northern Taiwan. A total of 323 non-obese and 264 obese participants were recruited. The threshold for obesity in this study was a body mass index of ≥27 kg/m(2), as defined by the Ministry of Health and Welfare in Taiwan. The study was performed with the approval of the institutional review board of MacKay Memorial Hospital, Taipei, Taiwan (application number 12MMHIS106). We analysed the genotype distributions of seven SNPs localising to the PPARγ2, GNB3, SDC3, ADRB2, FTO, PPARγ and ESR1 genes in obese and non-obese groups and then paired obesity-related SNPs to determine if they have synergistic effects on obesity. Analysis of the genotype distributions in obese and non-obese groups revealed only a significant positive correlation between an SNP in rs2282440-syndecan 3 (SDC3) and obesity in the Taiwanese population (p=0.006). In addition, the T/T genotype of SDC3 was significantly associated with a larger waist and hip circumference, higher body fat percentage and lower high-density lipoprotein cholesterol. Moreover, the combination of the rs2282440-SDC3T/T genotype with the rs1801282-peroxisome proliferator-activated receptor-gamma2 gene (PPARγ2) G carrier genotype was strongly associated with obesity (OR=6.77). We found that the rs2282440-SDC3T/T genotype is associated with obesity in the Taiwanese population. Furthermore, there is a synergistic effect of the high-risk alleles of the SDC3 and PPARγ2 genes on the obese phenotype in the Taiwanese population. 12MMHIS106; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Association of melanocortin-4 receptor gene polymorphisms with obesity-related parameters in Malaysian Malays.

PubMed

Apalasamy, Yamunah Devi; Ming, Moy Foong; Rampal, Sanjay; Bulgiba, Awang; Mohamed, Zahurin

2013-01-01

Melanocortin-4 receptor (MC4R) is an important regulator of body weight and energy intake. Genetic polymorphisms of the MC4R gene have been found to be linked to obesity in many recent studies across the globe. This study aimed to examine the effects of MC4R polymorphisms on obesity parameters, Linkage disequilibrium (LD) pattern and haplotypes in Malaysian Malays. The study subjects were 652 Malaysian Malays. Genomic DNA was extracted from buccal swabs. Genotyping was performed using Sequenom MassARRAY® iPLEX platform. Anthropometric and blood lipid profiles were measured. MC4R rs571312 SNP was associated with logBMI (p = 0.008) and systolic blood pressure (p = 0.005), while MC4R rs2229616 SNP was associated with total cholesterol (TC) levels (p = 0.016). The MC4R rs7227255 SNP did not show any association with obesity parameters. The strength of LD of the MC4R gene region is low and the haplotypes were not associated with obesity in Malaysian Malays.

Leptin and leptin receptor-related monogenic obesity.

PubMed

Dubern, Beatrice; Clement, Karine

2012-10-01

The studies based on candidate genes and encoded proteins known to cause severe obesity in rodents, have shown that these genes also contribute to human early-onset obesity especially for those involved in the leptin pathway: the leptin (LEP) and leptin receptor (LEPR) genes. Since 1997, less than 20 individuals carrying a LEP gene mutation have been identified. Patients are mostly characterized by severe early-onset obesity with severe hyperphagia and associated phenotype such hypogonadotrophic hypogonadism, high rate of infection associated with a deficiency in T cell and abnormalities of sympathetic nerve function. Therapeutic option (subcutaneous daily injection of leptin) is available for patients with LEP deficiency. It results in weight loss, mainly of fat mass, with a major effect on reducing food intake and on other dysfunctions including immunity and induction of puberty even in adults. In LEPR deficient subjects, phenotypic similarities with the LEP-deficient subjects were noticed, especially the exhibited rapid weight gain in the first few months of life, with severe hyperphagia and the endocrine abnormalities (hypogonadotrophic hypogonadism, insufficient somatotrophic or thyreotropic secretion). Leptin treatment is useless in the LEPR deficient subjects. Factors that could possibly bypass normal leptin delivery systems are being developed but are not yet currently available for the treatment of these patients. Measurement of circulating leptin may help for the diagnosis of such obesity: it is undetectable in LEP mutation carriers or extremely elevated in LEPR mutation carriers. Thus, LEPR gene screening might be also considered in subjects with the association of severe obesity with endocrine dysfunctions such as hypogonadism and with leptin related to corpulence level. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Association of HS6ST3 gene polymorphisms with obesity and triglycerides: gene x gender interaction.

PubMed

Wang, Ke-Sheng; Wang, Liang; Liu, Xuefeng; Zeng, Min

2013-12-01

The heparan sulfate 6-O-sulfotransferase 3 (HS6ST3) gene is involved in heparan sulphate and heparin metabolism, and has been reported to be associated with diabetic retinopathy in type 2 diabetes.We hypothesized that HS6ST3 gene polymorphisms might play an important role in obesity and related phenotypes (such as triglycerides). We examined genetic associations of 117 single-nucleotide polymorphisms (SNPs) within the HS6ST3 gene with obesity and triglycerides using two Caucasian samples: the Marshfield sample (1442 obesity cases and 2122 controls), and the Health aging and body composition (Health ABC) sample (305 cases and 1336 controls). Logistic regression analysis of obesity as a binary trait and linear regression analysis of triglycerides as a continuous trait, adjusted for age and sex, were performed using PLINK. Single marker analysis showed that six SNPs in the Marshfield sample and one SNP in the Health ABC sample were associated with obesity (P < 0.05). SNP rs535812 revealed a stronger association with obesity in meta-analysis of these two samples (P = 0.0105). The T-A haplotype from rs878950 and rs9525149 revealed significant association with obesity in the Marshfield sample (P = 0.012). Moreover, nine SNPs showed associations with triglycerides in the Marshfield sample (P < 0.05) and the best signal was rs1927796 (P = 0.00858). In addition, rs7331762 showed a strong gene x gender interaction (P = 0.00956) for obesity while rs1927796 showed a strong gene x gender interaction (P = 0.000625) for triglycerides in the Marshfield sample. These findings contribute new insights into the pathogenesis of obesity and triglycerides and demonstrate the importance of gender differences in the aetiology.

Association of Nuclear Factor-Erythroid 2-Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase-1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients.

PubMed

Jiménez-Osorio, Angélica Saraí; González-Reyes, Susana; García-Niño, Wylly Ramsés; Moreno-Macías, Hortensia; Rodríguez-Arellano, Martha Eunice; Vargas-Alarcón, Gilberto; Zúñiga, Joaquín; Barquera, Rodrigo; Pedraza-Chaverri, José

2016-01-01

The nuclear factor-erythroid 2- (NF-E2-) related factor 2 (Nrf2) is abated and its ability to reduce oxidative stress is impaired in type 2 diabetes and obesity. Thus, the aim of this study was to explore if polymorphisms in Nrf2 and target genes are associated with diabetes and obesity in Mexican mestizo subjects. The rs1800566 of quinone oxidoreductase 1 (NQO1) gene, rs7211 of thioredoxin interacting protein (TXNIP) gene, rs2071749 of heme oxygenase-1 (HMOX1) gene, and the rs6721961 and the rs2364723 from Nrf2 gene were genotyped in 627 diabetic subjects and 1020 controls. The results showed that the rs7211 polymorphism is a protective factor against obesity in nondiabetic subjects (CC + CT versus TT, OR = 0.40, P = 0.005) and in women (CC versus CT + TT, OR = 0.7, P = 0.016). TT carriers had lower high-density lipoprotein cholesterol levels and lower body mass index. The rs2071749 was positively associated with obesity (AA versus AG + GG, OR = 1.25, P = 0.026). Finally, the rs6721961 was negatively associated with diabetes in men (CC versus CA + AA, OR = 0.62, P = 0.003). AA carriers showed lower glucose concentrations. No association was found for rs1800566 and rs2364723 polymorphisms. In conclusion, the presence of Nrf2 and related genes polymorphisms are associated with diabetes and obesity in Mexican patients.

Gene-Diet Interaction and Precision Nutrition in Obesity

PubMed Central

Heianza, Yoriko; Qi, Lu

2017-01-01

The rapid rise of obesity during the past decades has coincided with a profound shift of our living environment, including unhealthy dietary patterns, a sedentary lifestyle, and physical inactivity. Genetic predisposition to obesity may have interacted with such an obesogenic environment in determining the obesity epidemic. Growing studies have found that changes in adiposity and metabolic response to low-calorie weight loss diets might be modified by genetic variants related to obesity, metabolic status and preference to nutrients. This review summarized data from recent studies of gene-diet interactions, and discussed integration of research of metabolomics and gut microbiome, as well as potential application of the findings in precision nutrition. PMID:28387720

Polymorphism and methylation of the MC4R gene in obese and non-obese dogs.

PubMed

Mankowska, Monika; Nowacka-Woszuk, Joanna; Graczyk, Aneta; Ciazynska, Paulina; Stachowiak, Monika; Switonski, Marek

2017-08-01

The dog is considered to be a useful biomedical model for human diseases and disorders, including obesity. One of the numerous genes associated with human polygenic obesity is MC4R, encoding the melanocortin 4 receptor. The aim of our study was to analyze polymorphisms and methylation of the canine MC4R in relation to adiposity. Altogether 270 dogs representing four breeds predisposed to obesity: Labrador Retriever (n = 187), Golden Retriever (n = 38), Beagle (n = 28) and Cocker Spaniel (n = 17), were studied. The dogs were classified into three groups: lean, overweight and obese, according to the 5-point Body Condition Score (BCS) scale. In the cohort of Labradors a complete phenotypic data (age, sex, neutering status, body weight and BCS) were collected for 127 dogs. The entire coding sequence as well as 5' and 3'-flanking regions of the studied gene were sequenced and six polymorphic sites were reported. Genotype frequencies differed considerably between breeds and Labrador Retrievers appeared to be the less polymorphic. Moreover, distribution of some polymorphic variants differed significantly (P < 0.05) between small cohorts with diverse BCS in Golden Retrievers (c.777T>C, c.868C>T and c.*33C>G) and Beagles (c.-435T>C and c.637G>T). On the contrary, in Labradors no association between the studied polymorphisms and BCS or body weight was observed. Methylation analysis, using bisulfite DNA conversion followed by Sanger sequencing, was carried out for 12 dogs with BCS = 3 and 12 dogs with BCS = 5. Two intragenic CpG islands, containing 19 cytosines, were analyzed and the methylation profile did not differ significantly between lean and obese animals. We conclude that an association of the MC4R gene polymorphism with dog obesity or body weight is unlikely, in spite of the fact that some associations were found in small cohorts of Beagles and Golden Retrievers. Also methylation level of this gene is not related with dog adiposity.

Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer: a GWAS data analysis.

PubMed

Tang, Hongwei; Wei, Peng; Duell, Eric J; Risch, Harvey A; Olson, Sara H; Bueno-de-Mesquita, H Bas; Gallinger, Steven; Holly, Elizabeth A; Petersen, Gloria M; Bracci, Paige M; McWilliams, Robert R; Jenab, Mazda; Riboli, Elio; Tjønneland, Anne; Boutron-Ruault, Marie Christine; Kaaks, Rudolf; Trichopoulos, Dimitrios; Panico, Salvatore; Sund, Malin; Peeters, Petra H M; Khaw, Kay-Tee; Amos, Christopher I; Li, Donghui

2014-01-01

Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level. Using genome-wide association studies (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by using the likelihood-ratio test nested in logistic regression models and Ingenuity Pathway Analysis (IPA). After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10(-6)) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10(-4)) in modifying the risk of pancreatic cancer were observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1, and GNAS. None of the individual genes or single-nucleotide polymorphism (SNP) except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10(-7)) at a false discovery rate of 6%. Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity- and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets. A gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.

What model organisms and interactomics can reveal about the genetics of human obesity.

PubMed

Williams, Michael J; Almén, Markus S; Fredriksson, Robert; Schiöth, Helgi B

2012-11-01

Genome-wide association studies have identified a number of genes associated with human body weight. While some of these genes are large fields within obesity research, such as MC4R, POMC, FTO and BDNF, the majority do not have a clearly defined functional role explaining why they may affect body weight. Here, we searched biological databases and discovered 33 additional genes associated with human obesity (CADM2, GIPR, GPCR5B, LRP1B, NEGR1, NRXN3, SH2B1, FANCL, GNPDA2, HMGCR, MAP2K5, NUDT3, PRKD1, QPCTL, TNNI3K, MTCH2, DNAJC27, SLC39A8, MTIF3, RPL27A, SEC16B, ETV5, HMGA1, TFAP2B, TUB, ZNF608, FAIM2, KCTD15, LINGO2, POC5, PTBP2, TMEM18, TMEM160). We find that the majority have orthologues in distant species, such as D. melanogaster and C. elegans, suggesting that they are important for the biology of most bilateral species. Intriguingly, signalling cascade genes and transcription factors are enriched among these obesity genes, and several of the genes show properties that could be useful for potential drug discovery. In this review, we demonstrate how information from several distant model species, interactomics and signalling pathway analysis represents an important way to better understand the functional diversity of the surprisingly high number of molecules that seem to be important for human obesity.

Effective anodic oxidation of naproxen by platinum nanoparticles coated FTO glass.

PubMed

Chin, Ching-Ju Monica; Chen, Tsan-Yao; Lee, Menshan; Chang, Chiung-Fen; Liu, Yu-Ting; Kuo, Yu-Tsun

2014-07-30

This study investigated applications of the electrochemical anodic oxidation process with Pt-FTO and Pt/MWCNTs-FTO glasses as anodes on the treatment of one of the most important emerging contaminants, naproxen. The anodes used in this study have been synthesized using commercial FTO, MWCNTs and Pt nanoparticles (PtNP). XRD patterns of Pt nanoparticles coated on FTO and MWCNTs revealed that MWCNTs can prevent the surface of PtNPs from sintering and thus provide a greater reaction sites density to interact with naproxen, which have also been confirmed by higher degradation and mineralization efficiencies in the Pt/MWCNTs-FTO system. Results from the CV analysis showed that the Pt-FTO and Pt/MWCNTs-FTO electrodes possessed dual functions of decreasing activation energy and interactions between hydroxyl radicals to effectively degrade naproxen. The lower the solution pH value, the better the degradation efficiency. The existence of humic acid indeed inhibited the degradation ability of naproxen due to the competitions in the multiple-component system. The electrochemical degradation processes were controlled by diffusion mechanism and two major intermediates of 2-acetyl-6-methoxynaphthalene and 2-(6-Hydroxy-2-naphthyl)propanoic acid were identified. This study has successfully demonstrated new, easy, flexible and effective anodic materials which can be feasibly applied to the electrochemical oxidation of naproxen. Copyright © 2014 Elsevier B.V. All rights reserved.

Adipose genes down-regulated during experimental endotoxemia are also suppressed in obesity.

PubMed

Shah, Rachana; Hinkle, Christine C; Haris, Lalarukh; Shah, Rhia; Mehta, Nehal N; Putt, Mary E; Reilly, Muredach P

2012-11-01

Adipose inflammation is a crucial link between obesity and its metabolic complications. Human experimental endotoxemia is a controlled model for the study of inflammatory cardiometabolic responses in vivo. We hypothesized that adipose genes down-regulated during endotoxemia would approximate changes observed with obesity-related inflammation and reveal novel candidates in cardiometabolic disease. Healthy volunteers (n = 14) underwent a 3 ng/kg endotoxin challenge; adipose biopsies were taken at 0, 4, 12, and 24 h for mRNA microarray. A priority list of highly down-regulated and biologically relevant genes was validated by RT-PCR in an independent sample of adipose from healthy subjects (n = 7) undergoing a subclinical 0.6 ng/kg endotoxemia protocol. Expression of validated genes was screened in adipose of lean and severely obese individuals (n = 11 per group), and cellular source was probed in cultured adipocytes and macrophages. Endotoxemia (3 ng/kg) suppressed expression of 353 genes (to <67% of baseline; P < 1 × 10(-5)) of which 68 candidates were prioritized for validation. In low-dose (0.6 ng/kg) endotoxin validation, 22 (32%) of these 68 genes were confirmed. Functional classification revealed that many of these genes are involved in cell development and differentiation. Of validated genes, 59% (13 of 22) were down-regulated more than 1.5-fold in primary human adipocytes after treatment with endotoxin. In human macrophages, 59% (13 of 22) were up-regulated during differentiation to inflammatory M1 macrophages whereas 64% (14 of 22) were down-regulated during transition to homeostatic M2 macrophages. Finally, in obese vs. lean adipose, 91% (20 of 22) tended to have reduced expression (χ(2) = 10.72, P < 0.01) with 50% (11 of 22) reaching P < 0.05 (χ(2) = 9.28, P < 0.01). Exploration of down-regulated mRNA in adipose during human endotoxemia revealed suppression of genes involved in cell development and differentiation. A majority of candidates were also

Expression of epigenetic machinery genes is sensitive to maternal obesity and weight loss in relation to fetal growth in mice.

PubMed

Panchenko, Polina E; Voisin, Sarah; Jouin, Mélanie; Jouneau, Luc; Prézelin, Audrey; Lecoutre, Simon; Breton, Christophe; Jammes, Hélène; Junien, Claudine; Gabory, Anne

2016-01-01

Maternal obesity impacts fetal growth and pregnancy outcomes. To counteract the deleterious effects of obesity on fertility and pregnancy issue, preconceptional weight loss is recommended to obese women. Whether this weight loss is beneficial/detrimental for offspring remains poorly explored. Epigenetic mechanisms could be affected by maternal weight changes, perturbing expression of key developmental genes in the placenta or fetus. Our aim was to investigate the effects of chronic maternal obesity on feto-placental growth along with the underlying epigenetic mechanisms. We also tested whether preconceptional weight loss could alleviate these effects. Female mice were fed either a control diet (CTRL group), a high-fat diet (obese (OB) group), or a high-fat diet switched to a control diet 2 months before conception (weight loss (WL) group). At mating, OB females presented an obese phenotype while WL females normalized metabolic parameters. At embryonic day 18.5 (E18.5), fetuses from OB females presented fetal growth restriction (FGR; -13 %) and 28 % of the fetuses were small for gestational age (SGA). Fetuses from WL females normalized this phenotype. The expression of 60 epigenetic machinery genes and 32 metabolic genes was measured in the fetal liver, placental labyrinth, and junctional zone. We revealed 23 genes altered by maternal weight trajectories in at least one of three tissues. The fetal liver and placental labyrinth were more responsive to maternal obesity than junctional zone. One third (18/60) of the epigenetic machinery genes were differentially expressed between at least two maternal groups. Interestingly, genes involved in the histone acetylation pathway were particularly altered (13/18). In OB group, lysine acetyltransferases and Bromodomain-containing protein 2 were upregulated, while most histone deacetylases were downregulated. In WL group, the expression of only a subset of these genes was normalized. This study highlights the high

A novel MC4R deletion coexisting with FTO and MC1R gene variants, causes severe early onset obesity.

PubMed

Neocleous, Vassos; Shammas, Christos; Phelan, Marie M; Fanis, Pavlos; Pantelidou, Maria; Skordis, Nicos; Mantzoros, Christos; Phylactou, Leonidas A; Toumba, Meropi

2016-07-01

Heterozygous mutations on the melanocortin-4-receptor gene (MC4R) are the most frequent cause of monogenic obesity. We describe a novel MC4R deletion in a girl with severe early onset obesity, tall stature, pale skin and red hair. Clinical and hormonal parameters were evaluated in a girl born full-term by non-consanguineous parents. Her body mass index (BMI) at presentation (3 years) was 30 kg/m 2 (z-score: +4.5SDS). By the age of 5.2 years, she exhibited extreme linear growth acceleration and developed hyperinsulinemia. Direct sequencing of the MC4R, MC1Rand for the knownFTOsingle nucleotide polymorphism (SNP) rs9939609was performed for the patient and her family. A novel heterozygous MC4R p.Met215del (c.643_645delATG) deletion was identified in the patient, her father and her brother, both of whom exhibited a milder phenotype. 3D structural dynamic simulation studies investigated the conformational changes induced by the p.Met215del. The patient and her mother were also found to be carriers of the obesity risk associated FTOrs9939609SNP. Finally, the identification of the known p.Arg160Trp MC1Rvariant in the patient accounts for the red hair and pale skin phenotypic features. The p.Met215del causes global conformational and functional changes as it is localized at the alpha-helical transmembrane regions and the membrane spanning regions of the beta-barrel. This novel mutation produces a severe overgrowth phenotype that is apparent as from infancy and is progressive in childhood. The additional negative effect of environmental and unhealthy lifestyle habits as well as a possible co-interaction of FTOrs9939609 SNP may worsen the phenotype.

Deregulation of obesity-relevant genes is associated with progression in BMI and the amount of adipose tissue in pigs.

PubMed

Mentzel, Caroline M Junker; Cardoso, Tainã Figueiredo; Pipper, Christian Bressen; Jacobsen, Mette Juul; Jørgensen, Claus Bøttcher; Cirera, Susanna; Fredholm, Merete

2018-02-01

The aim of this study was to elucidate the relative impact of three phenotypes often used to characterize obesity on perturbation of molecular pathways involved in obesity. The three obesity-related phenotypes are (1) body mass index (BMI), (2) amount of subcutaneous adipose tissue (SATa), and (3) amount of retroperitoneal adipose tissue (RPATa). Although it is generally accepted that increasing amount of RPATa is 'unhealthy', a direct comparison of the relative impact of the three obesity-related phenotypes on gene expression has, to our knowledge, not been performed previously. We have used multiple linear models to analyze altered gene expression of selected obesity-related genes in tissues collected from 19 female pigs phenotypically characterized with respect to the obesity-related phenotypes. Gene expression was assessed by high-throughput qPCR in RNA from liver, skeletal muscle and abdominal adipose tissue. The stringent statistical approach used in the study has increased the power of the analysis compared to the classical approach of analysis in divergent groups of individuals. Our approach led to the identification of key components of cellular pathways that are modulated in the three tissues in association with changes in the three obesity-relevant phenotypes (BMI, SATa and RPATa). The deregulated pathways are involved in biosynthesis and transcript regulation in adipocytes, in lipid transport, lipolysis and metabolism, and in inflammatory responses. Deregulation seemed more comprehensive in liver (23 genes) compared to abdominal adipose tissue (10 genes) and muscle (3 genes). Notably, the study supports the notion that excess amount of intra-abdominal adipose tissue is associated with a greater metabolic disease risk. Our results provide molecular support for this notion by demonstrating that increasing amount of RPATa has a higher impact on perturbation of cellular pathways influencing obesity and obesity-related metabolic traits compared to increase

Single nucleotide polymorphisms in obesity-related genes and the risk of esophageal cancers.

PubMed

Doecke, James D; Zhao, Zhen Zhen; Stark, Mitchell S; Green, Adèle C; Hayward, Nicholas K; Montgomery, Grant W; Webb, Penelope M; Whiteman, David C

2008-04-01

Rates of adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJAC) have been rising rapidly in recent decades, in contrast to the declining rates of esophageal squamous cell carcinomas (ESCC). Obesity is a major risk factor for both EAC and EGJAC, but not ESCC, and there is speculation that obesity promotes adenocarcinoma development through endocrine and related pathways. We therefore compared the prevalence of 12 single nucleotide polymorphisms (SNPs) in nine candidate genes previously implicated in obesity pathways (LEP, LEPR, ADIPOQ, POMC, PPARalpha, PPARgamma, RXRgamma, GHRL, and INSIG2) in a large Australian case-control study comprising DNA samples from 260 EAC cases, 301 EGJAC cases, 213 ESCC cases, and 1,352 population controls. No SNPs were associated with EGJAC or ESCC. Although several SNPs seemed to be associated with EAC on crude analysis [ADIPOQ (rs1501299), LEP (5'-untranslated region), PPARgamma (H447H), and GHRL (M72L)], effect sizes were modest and none of the associations was significant after correcting for multiple comparisons. Further, we found no consistent evidence that any of the genotypes were associated with risk of EAC or EGJAC within strata of body mass index (<25.0 kg/m(2), 25.0-29.9 kg/m(2), >30 kg/m(2)). In conclusion, our data suggest that these SNPs do not play a major role in esophageal carcinogenesis.

Copy number variations in "classical" obesity candidate genes are not frequently associated with severe early-onset obesity in children.

PubMed

Windholz, Jan; Kovacs, Peter; Schlicke, Marina; Franke, Christin; Mahajan, Anubha; Morris, Andrew P; Lemke, Johannes R; Klammt, Jürgen; Kiess, Wieland; Schöneberg, Torsten; Pfäffle, Roland; Körner, Antje

2017-05-01

Obesity is genetically heterogeneous and highly heritable, although polymorphisms explain the phenotype in only a small proportion of obese children. We investigated the presence of copy number variations (CNVs) in "classical" genes known to be associated with (monogenic) early-onset obesity in children. In 194 obese Caucasian children selected for early-onset and severe obesity from our obesity cohort we screened for deletions and/or duplications by multiplex ligation-dependent probe amplification reaction (MLPA). As we found one MLPA probe to interfere with a polymorphism in SIM1 we investigated its association with obesity and other phenotypic traits in our extended cohort of 2305 children. In the selected subset of most severely obese children, we did not find CNV with MLPA in POMC, LEP, LEPR, MC4R, MC3R or MC2R genes. However, one SIM1 probe located at exon 9 gave signals suggestive for SIM1 insufficiency in 52 patients. Polymerase chain reaction (PCR) analysis identified this as a false positive result due to interference with single nucleotide polymorphism (SNP) rs3734354/rs3734355. We, therefore, investigated for associations of this polymorphism with obesity and metabolic traits in our extended cohort. We found rs3734354/rs3734355 to be associated with body mass index-standard deviation score (BMI-SDS) (p = 0.003), but not with parameters of insulin metabolism, blood pressure or food intake. In our modest sample of severely obese children, we were unable to find CNVs in well-established monogenic obesity genes. Nevertheless, we found an association of rs3734354 in SIM1 with obesity of early-onset type in children, although not with obesity-related traits.

Can genetic-based advice help you lose weight? Findings from the Food4Me European randomized controlled trial.

PubMed

Celis-Morales, Carlos; Marsaux, Cyril Fm; Livingstone, Katherine M; Navas-Carretero, Santiago; San-Cristobal, Rodrigo; Fallaize, Rosalind; Macready, Anna L; O'Donovan, Clare; Woolhead, Clara; Forster, Hannah; Kolossa, Silvia; Daniel, Hannelore; Moschonis, George; Mavrogianni, Christina; Manios, Yannis; Surwillo, Agnieszka; Traczyk, Iwona; Drevon, Christian A; Grimaldi, Keith; Bouwman, Jildau; Gibney, Mike J; Walsh, Marianne C; Gibney, Eileen R; Brennan, Lorraine; Lovegrove, Julie A; Martinez, J Alfredo; Saris, Wim Hm; Mathers, John C

2017-05-01

Background: There has been limited evidence about whether genotype-tailored advice provides extra benefits in reducing obesity-related traits compared with the benefits of conventional one-size-fits-all advice. Objective: We determined whether the disclosure of information on fat-mass and obesity-associated ( FTO ) genotype risk had a greater effect on a reduction of obesity-related traits in risk carriers than in nonrisk carriers across different levels of personalized nutrition. Design: A total of 683 participants (women: 51%; age range: 18-73 y) from the Food4Me randomized controlled trial were included in this analysis. Participants were randomly assigned to 4 intervention arms as follows: level 0, control group; level 1, dietary group; level 2, phenotype group; and level 3, genetic group. FTO (single nucleotide polymorphism rs9939609) was genotyped at baseline in all participants, but only subjects who were randomly assigned to level 3 were informed about their genotypes. Level 3 participants were stratified into risk carriers (AA/AT) and nonrisk carriers (TT) of the FTO gene for analyses. Height, weight, and waist circumference (WC) were self-measured and reported at baseline and months 3 and 6. Results: Changes in adiposity markers were greater in participants who were informed that they carried the FTO risk allele (level 3 AT/AA carriers) than in the nonpersonalized group (level 0) but not in the other personalized groups (level 1 and 2). Mean reductions in weight and WC at month 6 were greater for FTO risk carriers than for noncarriers in the level 3 group [-2.28 kg (95% CI: -3.06, -1.48 kg) compared with -1.99 kg (-2.19, -0.19 kg), respectively ( P = 0.037); and -4.34 cm (-5.63, -3.08 cm) compared with -1.99 cm (-4.04, -0.05 cm), respectively, ( P = 0.048)]. Conclusions: There are greater body weight and WC reductions in risk carriers than in nonrisk carriers of the FTO gene. This trial was registered at clinicaltrials.gov as NCT01530139. © 2017 American

'Obesity' is healthy for cetaceans? Evidence from pervasive positive selection in genes related to triacylglycerol metabolism.

PubMed

Wang, Zhengfei; Chen, Zhuo; Xu, Shixia; Ren, Wenhua; Zhou, Kaiya; Yang, Guang

2015-09-18

Cetaceans are a group of secondarily adapted marine mammals with an enigmatic history of transition from terrestrial to fully aquatic habitat and subsequent adaptive radiation in waters around the world. Numerous physiological and morphological cetacean characteristics have been acquired in response to this drastic habitat transition; for example, the thickened blubber is one of the most striking changes that increases their buoyancy, supports locomotion, and provides thermal insulation. However, the genetic basis underlying the blubber thickening in cetaceans remains poorly explored. Here, 88 candidate genes associated with triacylglycerol metabolism were investigated in representative cetaceans and other mammals to test whether the thickened blubber matched adaptive evolution of triacylglycerol metabolism-related genes. Positive selection was detected in 41 of the 88 candidate genes, and functional characterization of these genes indicated that these are involved mainly in triacylglycerol synthesis and lipolysis processes. In addition, some essential regulatory genes underwent significant positive selection in cetacean-specific lineages, whereas no selection signal was detected in the counterpart terrestrial mammals. The extensive occurrence of positive selection in triacylglycerol metabolism-related genes is suggestive of their essential role in secondary adaptation to an aquatic life, and further implying that 'obesity' might be an indicator of good health for cetaceans.

Interactome of Obesity: Obesidome : Genetic Obesity, Stress Induced Obesity, Pathogenic Obesity Interaction.

PubMed

Geronikolou, Styliani A; Pavlopoulou, Athanasia; Cokkinos, Dennis; Chrousos, George

2017-01-01

Obesity is a chronic disease of increasing prevalence reaching epidemic proportions. Genetic defects as well as epigenetic effects contribute to the obesity phenotype. Investigating gene (e.g. MC4R defects)-environment (behavior, infectious agents, stress) interactions is a relative new field of great research interest. In this study, we have made an effort to create an interactome (henceforth referred to as "obesidome"), where extrinsic stressors response, intrinsic predisposition, immunity response to inflammation and autonomous nervous system implications are integrated. These pathways are presented in one interactome network for the first time. In our study, obesity-related genes/gene products were found to form a complex interactions network.

Adipose Genes Down-Regulated During Experimental Endotoxemia Are Also Suppressed in Obesity

PubMed Central

Hinkle, Christine C.; Haris, Lalarukh; Shah, Rhia; Mehta, Nehal N.; Putt, Mary E.; Reilly, Muredach P.

2012-01-01

Context: Adipose inflammation is a crucial link between obesity and its metabolic complications. Human experimental endotoxemia is a controlled model for the study of inflammatory cardiometabolic responses in vivo. Objective: We hypothesized that adipose genes down-regulated during endotoxemia would approximate changes observed with obesity-related inflammation and reveal novel candidates in cardiometabolic disease. Design, Subjects, and Intervention: Healthy volunteers (n = 14) underwent a 3 ng/kg endotoxin challenge; adipose biopsies were taken at 0, 4, 12, and 24 h for mRNA microarray. A priority list of highly down-regulated and biologically relevant genes was validated by RT-PCR in an independent sample of adipose from healthy subjects (n = 7) undergoing a subclinical 0.6 ng/kg endotoxemia protocol. Expression of validated genes was screened in adipose of lean and severely obese individuals (n = 11 per group), and cellular source was probed in cultured adipocytes and macrophages. Results: Endotoxemia (3 ng/kg) suppressed expression of 353 genes (to <67% of baseline; P < 1 × 10−5) of which 68 candidates were prioritized for validation. In low-dose (0.6 ng/kg) endotoxin validation, 22 (32%) of these 68 genes were confirmed. Functional classification revealed that many of these genes are involved in cell development and differentiation. Of validated genes, 59% (13 of 22) were down-regulated more than 1.5-fold in primary human adipocytes after treatment with endotoxin. In human macrophages, 59% (13 of 22) were up-regulated during differentiation to inflammatory M1 macrophages whereas 64% (14 of 22) were down-regulated during transition to homeostatic M2 macrophages. Finally, in obese vs. lean adipose, 91% (20 of 22) tended to have reduced expression (χ2 = 10.72, P < 0.01) with 50% (11 of 22) reaching P < 0.05 (χ2 = 9.28, P < 0.01). Conclusions: Exploration of down-regulated mRNA in adipose during human endotoxemia revealed suppression of genes involved in

Penetrance of Polygenic Obesity Susceptibility Loci across the Body Mass Index Distribution.

PubMed

Abadi, Arkan; Alyass, Akram; Robiou du Pont, Sebastien; Bolker, Ben; Singh, Pardeep; Mohan, Viswanathan; Diaz, Rafael; Engert, James C; Yusuf, Salim; Gerstein, Hertzel C; Anand, Sonia S; Meyre, David

2017-12-07

A growing number of single-nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effects of these obesity-susceptibility loci are uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI-associated SNPs in 75,230 adults of European ancestry across BMI percentiles by using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of nine SNPs (24%)-rs1421085 (FTO; p = 8.69 × 10 -15 ), rs6235 (PCSK1; p = 7.11 × 10 -6 ), rs7903146 (TCF7L2; p = 9.60 × 10 -6 ), rs11873305 (MC4R; p = 5.08 × 10 -5 ), rs12617233 (FANCL; p = 5.30 × 10 -5 ), rs11672660 (GIPR; p = 1.64 × 10 -4 ), rs997295 (MAP2K5; p = 3.25 × 10 -4 ), rs6499653 (FTO; p = 6.23 × 10 -4 ), and rs3824755 (NT5C2; p = 7.90 × 10 -4 )-increased significantly across the sample BMI distribution. We showed that such increases stemmed from unadjusted gene interactions that enhanced the effects of SNPs in persons with a high BMI. When 125 height-associated SNPs were analyzed for comparison, only one (<1%), rs6219 (IGF1, p = 1.80 × 10 -4 ), showed effects that varied significantly across height percentiles. Cumulative gene scores of these SNPs (GS-BMI and GS-height) showed that only GS-BMI had effects that increased significantly across the sample distribution (BMI: p = 7.03 × 10 -37 ; height: p = 0.499). Overall, these findings underscore the importance of gene-gene and gene-environment interactions in shaping the genetic architecture of BMI and advance a method for detecting such interactions by using only the sample outcome distribution. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Vertical growth of ZnO nanorods on ZnO seeded FTO substrate for dye sensitized solar cells

NASA Astrophysics Data System (ADS)

Marimuthu, T.; Anandhan, N.

2018-04-01

Zinc oxide (ZnO) nanorods (NRs) were electrochemically grown on fluorine doped tin oxide (FTO) and ZnO seeded FTO substrates. X-ray diffraction (XRD) patterns, Raman spectra and photoluminescence (PL) spectra reveal that the hexagonal wurtzite structured ZnO grown on a seeded FTO substrate has a high crystallinity, crystal quality and less atomic defects. Felid emission scanning electron microscope (FE-SEM) images display a high growth density of NRs grown on seeded FTO substrate compared to NRs grown on FTO substrate. The efficiency of the DSSCs based on NRs grown on FTO and seeded FTO substrates is 0.85 and 1.52 %, respectively. UV-Vis absorption spectra and electrochemical impedance spectra depict that the NRs grown on seeded FTO photoanode have higher dye absorption and charge recombination resistance than that of the NRs grown on FTO substrate.

Leptin gene promoter DNA methylation in WNIN obese mutant rats

PubMed Central

2014-01-01

Background Obesity has become an epidemic in worldwide population. Leptin gene defect could be one of the causes for obesity. Two mutant obese rats WNIN/Ob and WNIN/GROb, isolated at National Centre for Laboratory Animal Sciences (NCLAS), Hyderabad, India, were found to be leptin resistant. The present study aims to understand the regulatory mechanisms underlying the resistance by promoter DNA methylation of leptin gene in these mutant obese rats. Methods Male obese mutant homozygous, carrier and heterozygous rats of WNIN/Ob and WNIN/GROb strain of 6 months old were studied to check the leptin gene expression (RT-PCR) and promoter DNA methylation (MassARRAY Compact system, SEQUENOM) of leptin gene by invivo and insilico approach. Results Homozygous WNIN/Ob and WNIN/GROb showed significantly higher leptin gene expression compared to carrier and lean counterparts. Leptin gene promoter DNA sequence region was analyzed ranging from transcription start site (TSS) to-550 bp length and found four CpGs in this sequence among them only three CpG loci (-309, -481, -502) were methylated in these WNIN mutant rat phenotypes. Conclusion The increased percentage of methylation in WNIN mutant lean and carrier phenotypes is positively correlated with transcription levels. Thus genetic variation may have effect on methylation percentages and subsequently on the regulation of leptin gene expression which may lead to obesity in these obese mutant rat strains. PMID:24495350

The role of established East Asian obesity-related loci on pediatric leptin levels highlights a neuronal influence on body weight regulation in Chinese children and adolescents: the BCAMS study.

PubMed

Fu, Junling; Li, Ge; Li, Lujiao; Yin, Jinhua; Cheng, Hong; Han, Lanwen; Zhang, Qian; Li, Naishi; Xiao, Xinhua; Grant, Struan F A; Li, Mingyao; Gao, Shan; Mi, Jie; Li, Ming

2017-11-07

Genome-wide association studies have identified multiple variants associated with adult obesity, mostly in European-ancestry populations. We aimed to systematically assess the contribution of key loci, which had been previously shown to be associated in East Asian adults, to childhood obesity, related adipokine profiles and metabolic traits in a Chinese pediatric population. Twelve single-nucleotide polymorphisms (SNPs) plus metabolic profiles and levels of five adipokines (leptin, adiponectin, resistin, fibroblast growth factor 21 and retinol binding protein 4) were evaluated in 3,506 Chinese children and adolescents aged 6-18. After correction for multiple comparisons, six of these SNPs were robustly associated with childhood obesity: FTO -rs1558902 ( P =5.6×10 -5 ), MC4R -rs2331841 ( P =4.4×10 -4 ), GNPDA2 -rs16858082 ( P = 3.4×10 -4 ), PCSK1 -rs261967 ( P = 0.001), SEC16B -rs516636 ( P = 0.004) and MAP2K5 -rs4776970 ( P = 0.004), with odds ratios ranging from 1.211 to 1.421; while ITIH4 -rs2535633 and BDNF -rs2030323 yielded nominal association with the same trait ( P < 0.05). Moreover, the risk alleles of six SNPs displayed significant ( P < 0.004) or nominal ( P < 0.05) association with leptin levels, namely at in/near PCSK1, MC4R, FTO, MAP2K5, GNPDA2 and BDNF plus their cumulative genetic score yielded stronger association with increased leptin levels ( P = 6.2×10 -11 ). Our results reveal that key obesity-associated loci previously reported in Europeans, but also associated with East Asian adults, are also associated with obesity and/or metabolic quantitative traits in Chinese children. These associations coincide with six brain-expressed loci that correlate with leptin levels, thus may point to an important neuronal influence on body weight regulation in the pediatric setting.

Population differentiation in allele frequencies of obesity-associated SNPs.

PubMed

Mao, Linyong; Fang, Yayin; Campbell, Michael; Southerland, William M

2017-11-10

Obesity is emerging as a global health problem, with more than one-third of the world's adult population being overweight or obese. In this study, we investigated worldwide population differentiation in allele frequencies of obesity-associated SNPs (single nucleotide polymorphisms). We collected a total of 225 obesity-associated SNPs from a public database. Their population-level allele frequencies were derived based on the genotype data from 1000 Genomes Project (phase 3). We used hypergeometric model to assess whether the effect allele at a given SNP is significantly enriched or depleted in each of the 26 populations surveyed in the 1000 Genomes Project with respect to the overall pooled population. Our results indicate that 195 out of 225 SNPs (86.7%) possess effect alleles significantly enriched or depleted in at least one of the 26 populations. Populations within the same continental group exhibit similar allele enrichment/depletion patterns whereas inter-continental populations show distinct patterns. Among the 225 SNPs, 15 SNPs cluster in the first intron region of the FTO gene, which is a major gene associated with body-mass index (BMI) and fat mass. African populations exhibit much smaller blocks of LD (linkage disequilibrium) among these15 SNPs while European and Asian populations have larger blocks. To estimate the cumulative effect of all variants associated with obesity, we developed the personal composite genetic risk score for obesity. Our results indicate that the East Asian populations have the lowest averages of the composite risk scores, whereas three European populations have the highest averages. In addition, the population-level average of composite genetic risk scores is significantly correlated (R 2 = 0.35, P = 0.0060) with obesity prevalence. We have detected substantial population differentiation in allele frequencies of obesity-associated SNPs. The results will help elucidate the genetic basis which may contribute to population

Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants

PubMed Central

Flores, Raquel; González, Juan R.; Argente, Jesús; Pérez-Jurado, Luis A.

2017-01-01

Obesity is a multifactorial disorder with high heritability (50–75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity

Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants.

PubMed

Serra-Juhé, Clara; Martos-Moreno, Gabriel Á; Bou de Pieri, Francesc; Flores, Raquel; González, Juan R; Rodríguez-Santiago, Benjamín; Argente, Jesús; Pérez-Jurado, Luis A

2017-05-01

Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.

Interaction of FTO and physical activity level on adiposity in African-American and European-American adults: the ARIC study.

PubMed

Demerath, Ellen W; Lutsey, Pam L; Monda, Keri L; Linda Kao, Wen Hong; Bressler, Jan; Pankow, James S; North, Kari E; Folsom, Aaron R

2011-09-01

Physical inactivity accentuates the association of variants in the FTO locus with obesity-related traits but evidence is largely lacking in non-European populations. Here we tested the hypothesis that physical activity (PA) modifies the association of the FTO single-nucleotide polymorphism (SNP) rs9939609 with adiposity traits in 2,656 African Americans (AA) (1,626 women and 1,030 men) and 9,867 European Americans (EA) (5,286 women and 4,581 men) aged 45-66 years in the Atherosclerosis Risk in Communities (ARIC) study. Individuals in the lowest quintile of the sport activity index of the Baecke questionnaire were categorized as low PA. Baseline BMI, waist circumference (WC), and skinfold measures were dependent variables in regression models testing the additive effect of the SNP, low PA, and their interaction, adjusting for age, alcohol use, cigarette use, educational attainment, and percent European ancestry in AA adults, stratified by sex and race/ethnicity. rs9939609 was associated with adiposity in all groups other than AA women. The SNP × PA interaction was significant in AA men (P ≤ 0.002 for all traits) and EA men (P ≤ 0.04 for all traits). For each additional copy of the A (risk) allele, WC in AA men was higher in those with low PA (β(lowPA): 5.1 cm, 95% confidence interval (CI): 2.6-7.5) than high PA (β(highPA): 0.7 cm, 95% CI: -0.4 to 1.9); P (interaction) = 0.002). The interaction effect was not observed in EA or AA women. FTO SNP × PA interactions on adiposity were observed for AA as well as EA men. Differences by sex require further examination.

Association between genetic variants of the clock gene and obesity and sleep duration.

PubMed

Valladares, Macarena; Obregón, Ana María; Chaput, Jean-Philippe

2015-12-01

Obesity is a multifactorial disease caused by the interaction of genetic and environmental factors related to lifestyle aspects. It has been shown that reduced sleep is associated with increased body mass index (BMI). Circadian Locomotor Output Cycles Kaput (CLOCK) gene variants have also been associated with obesity. The objective of this mini-review was to discuss the available literature related to CLOCK gene variants associated with adiposity and sleep duration in humans. In total, 16 articles complied with the terms of the search that reported CLOCK variants associated with sleep duration, energy intake, and BMI. Overall, six CLOCK single nucleotide polymorphisms (SNPs) have been associated with sleep duration, and three variants have been associated with energy intake variables. Overall, the most studied area has been the association of CLOCK gene with obesity; close to eight common variants have been associated with obesity. The most studied CLOCK SNP in different populations is rs1801260, and most of these populations correspond to European populations. Collectively, identifying at risk CLOCK genotypes is a new area of research that may help identify individuals who are more susceptible to overeating and gaining weight when exposed to short sleep durations.

Association of ALOX15 gene polymorphisms with obesity-related phenotypes in Chinese nuclear families with male offspring.

PubMed

Ke, Yao-hua; Xiao, Wen-jin; He, Jin-wei; Zhang, Hao; Yu, Jin-bo; Hu, Wei-wei; Gu, Jie-mei; Gao, Gao; Yue, Hua; Wang, Chun; Hu, Yun-qiu; Li, Miao; Liu, Yu-juan; Fu, Wen-zhen; Zhang, Zhen-lin

2012-02-01

Genetic variation in ALOX12, which encoded human 12-lipoxygenase, was found to be associated with fat mass in young Chinese men. The objective of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) and haplotypes in the ALOX15 gene and obesity-related phenotypes in Chinese nuclear families with male offspring. We recruited 1,296 subjects from 427 nuclear families with male offspring and genotyped five SNPs (rs9894225, rs748694, rs2619112, rs2619118, and rs916055) in the ALOX15 gene locus. The total fat mass (TFM), trunk fat mass (tFM), leg fat mass (LFM) and arm fat mass (AFM) were measured using dual-energy X-ray absorptiometry (DXA). The percentage of fat mass (PFM) was the ratio of TFM and body weight. The association between SNPs and haplotypes of ALOX15 and obesity-related phenotypic variation was measured using quantitative transmission disequilibrium test (QTDT). Using QTDT to measure family-based genetic association, we found that rs916055 had a statistically significant association with PFM (P=0.038), whereas rs916055 had a marginal but statistically insignificant association with tFM (P=0.093). The multiple-parameter 1000 permutations test agreed with the family-based association results: both showed that rs916055 had a statistically significant association with PFM (P=0.033). rs916055 in ALOX15 gene was significantly associated with the percentage of fat mass in Chinese nuclear families with male offspring in the family-based association study using QTDT approach.

Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study.

PubMed

Soubry, Adelheid; Guo, Lisa; Huang, Zhiqing; Hoyo, Cathrine; Romanus, Stephanie; Price, Thomas; Murphy, Susan K

2016-01-01

Epigenetic reprogramming in mammalian gametes resets methylation marks that regulate monoallelic expression of imprinted genes. In males, this involves erasure of the maternal methylation marks and establishment of paternal-specific methylation to appropriately guide normal development. The degree to which exogenous factors influence the fidelity of methylation reprogramming is unknown. We previously found an association between paternal obesity and altered DNA methylation in umbilical cord blood, suggesting that the father's endocrine, nutritional, or lifestyle status could potentiate intergenerational heritable epigenetic abnormalities. In these analyses, we examine the relationship between male overweight/obesity and DNA methylation status of imprinted gene regulatory regions in the gametes. Linear regression models were used to compare sperm DNA methylation percentages, quantified by bisulfite pyrosequencing, at 12 differentially methylated regions (DMRs) from 23 overweight/obese and 44 normal weight men. Our study population included 69 volunteers from The Influence of the Environment on Gametic Epigenetic Reprogramming (TIEGER) study, based in NC, USA. After adjusting for age and fertility patient status, semen from overweight or obese men had significantly lower methylation percentages at the MEG3 (β = -1.99; SE = 0.84; p = 0.02), NDN (β = -1.10; SE = 0.47; p = 0.02), SNRPN (β = -0.65; SE = 0.27; p = 0.02), and SGCE/PEG10 (β = -2.5; SE = 1.01; p = 0.01) DMRs. Our data further suggest a slight increase in DNA methylation at the MEG3-IG DMR (β = +1.22; SE = 0.59; p = 0.04) and H19 DMR (β = +1.37; SE = 0.62; p = 0.03) in sperm of overweight/obese men. Our data support that male overweight/obesity status is traceable in the sperm epigenome. Further research is needed to understand the effect of such changes and the point of origin of DNA methylation differences between lean and

Significant obesity-associated gene expression changes occur in the stomach but not intestines in obese mice.

PubMed

Chen, Jing; Chen, Lihong; Sanseau, Philippe; Freudenberg, Johannes M; Rajpal, Deepak K

2016-05-01

The gastrointestinal (GI) tract can have significant impact on the regulation of the whole-body metabolism and may contribute to the development of obesity and diabetes. To systemically elucidate the role of the GI tract in obesity, we performed a transcriptomic analysis in different parts of the GI tract of two obese mouse models: ob/ob and high-fat diet (HFD) fed mice. Compared to their lean controls, significant changes in the gene expression were observed in both obese mouse groups in the stomach (ob/ob: 959; HFD: 542). In addition, these changes were quantitatively much higher than in the intestine. Despite the difference in genetic background, the two mouse models shared 296 similar gene expression changes in the stomach. Among those genes, some had known associations to obesity, diabetes, and insulin resistance. In addition, the gene expression profiles strongly suggested an increased gastric acid secretion in both obese mouse models, probably through an activation of the gastrin pathway. In conclusion, our data reveal a previously unknown dominant connection between the stomach and obesity in murine models extensively used in research. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

A novel gene THSD7A is associated with obesity.

PubMed

Nizamuddin, S; Govindaraj, P; Saxena, S; Kashyap, M; Mishra, A; Singh, S; Rotti, H; Raval, R; Nayak, J; Bhat, B K; Prasanna, B V; Dhumal, V R; Bhale, S; Joshi, K S; Dedge, A P; Bharadwaj, R; Gangadharan, G G; Nair, S; Gopinath, P M; Patwardhan, B; Kondaiah, P; Satyamoorthy, K; Valiathan, M S; Thangaraj, K

2015-11-01

Body mass index (BMI) is a non-invasive measurement of obesity. It is commonly used for assessing adiposity and obesity-related risk prediction. Genetic differences between ethnic groups are important factors, which contribute to the variation in phenotypic effects. India inhabited by the first out-of-Africa human population and the contemporary Indian populations are admixture of two ancestral populations; ancestral north Indians (ANI) and ancestral south Indians (ASI). Although ANI are related to Europeans, ASI are not related to any group outside Indian-subcontinent. Hence, we expect novel genetic loci associated with BMI. In association analysis, we found eight genic SNPs in extreme of distribution (P⩽3.75 × 10(-5)), of which WWOX has already been reported to be associated with obesity-related traits hence excluded from further study. Interestingly, we observed rs1526538, an intronic SNP of THSD7A; a novel gene significantly associated with obesity (P=2.88 × 10(-5), 8.922 × 10(-6) and 2.504 × 10(-9) in discovery, replication and combined stages, respectively). THSD7A is neural N-glycoprotein, which promotes angiogenesis and it is well known that angiogenesis modulates obesity, adipose metabolism and insulin sensitivity, hence our result find a correlation. This information can be used for drug target, early diagnosis of obesity and treatment.

Exercise training improves obesity-related lymphatic dysfunction.

PubMed

Hespe, Geoffrey E; Kataru, Raghu P; Savetsky, Ira L; García Nores, Gabriela D; Torrisi, Jeremy S; Nitti, Matthew D; Gardenier, Jason C; Zhou, Jie; Yu, Jessie Z; Jones, Lee W; Mehrara, Babak J

2016-08-01

Obesity results in perilymphatic inflammation and lymphatic dysfunction. Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells. Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells. Although previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (all P < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti-inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene

[Generation and phenotype analysis of zebrafish mutations of obesity-related genes lepr and mc4r].

PubMed

Fei, Fei; Sun, Shao-Yang; Yao, Yu-Xiao; Wang, Xu

2017-02-25

Obesity has become a severe public health problem across the world, and seriously affects the health and life quality of human beings. Here we generated lepr and mc4r mutant zebrafish via the CRISPR/Cas9 technique, and performed morphological and functional characterizations of those mutants. We observed that there was no significant phenotypic difference between homozygous mutants and wild-type controls before 2.5 months post-fertilization (mpf). However, the adult lepr -/- and mc4r -/- individuals displayed increased food intake, heavier weight, and higher body fat percentage, the characteristics of obesity phenotypes. Blood glucose test showed that overfeeding induced significantly impaired glucose tolerance in adult lepr -/- and mc4r -/- zebrafish. Furthermore, we analyzed 76 energy metabolism-related transcripts in lepr -/- and mc4r -/- zebrafish livers by using real-time RT-PCR, and compared the results with the published microarray data of Lep ob/ob mouse livers, and found that the changes in the expression of insulin/IGF signaling (IIS) pathway genes in lepr -/- zebrafish and Lep ob/ob mouse were positively correlated, suggesting that the IIS pathway maintains functional conservation between zebrafish and mammals during the evolution of the obesity-regulating molecule network.

Exploring single nucleotide polymorphisms previously related to obesity and metabolic traits in pediatric-onset type 2 diabetes.

PubMed

Miranda-Lora, América Liliana; Cruz, Miguel; Aguirre-Hernández, Jesús; Molina-Díaz, Mario; Gutiérrez, Jorge; Flores-Huerta, Samuel; Klünder-Klünder, Miguel

2017-07-01

To evaluate the association of 64 obesity-related polymorphisms with pediatric-onset type 2 diabetes and other glucose- and insulin-related traits in Mexican children. Case-control and case-sibling designs were followed. We studied 99 patients with pediatric-onset type 2 diabetes, their siblings (n = 101) without diabetes, 83 unrelated pediatric controls and 137 adult controls. Genotypes were determined for 64 single nucleotide polymorphisms, and a possible association was examined between those genotypes and type 2 diabetes and other quantitative traits, after adjusting for age, sex and body mass index. In the case-pediatric control and case-adult control analyses, five polymorphisms were associated with increased likelihood of pediatric-onset type 2 diabetes; only one of these polymorphisms (CADM2/rs1307880) also showed a consistent effect in the case-sibling analysis. The associations in the combined analysis were as follows: ADORA1/rs903361 (OR 1.9, 95% CI 1.2; 3.0); CADM2/rs13078807 (OR 2.2, 95% CI 1.2; 4.0); GNPDA2/rs10938397 (OR 2.2, 95% CI 1.4; 3.7); VEGFA/rs6905288 (OR 1.4, 95% CI 1.1; 2.1) and FTO/rs9939609 (OR 1.8, 95% CI 1.0; 3.2). We also identified 16 polymorphisms nominally associated with quantitative traits in participants without diabetes. ADORA/rs903361, CADM2/rs13078807, GNPDA2/rs10938397, VEGFA/rs6905288 and FTO/rs9939609 are associated with an increased risk of pediatric-onset type 2 diabetes in the Mexican population.

Leptin gene and leptin receptor gene polymorphisms are associated with sweet preference and obesity.

PubMed

Mizuta, Einosuke; Kokubo, Yoshihiro; Yamanaka, Itaru; Miyamoto, Yoshihiro; Okayama, Akira; Yoshimasa, Yasunao; Tomoike, Hitonobu; Morisaki, Hiroko; Morisaki, Takayuki

2008-06-01

Leptin is an adipocyte-secreted hormone that regulates food intake and body weight, and that was recently reported to suppress sweet sensitivity in an animal model. We investigated the associations among sweet preference, obesity, and polymorphisms of the leptin gene (LEP) or leptin receptor gene (LEPR). A total of 3,653 residents randomly selected from among the citizens of Suita City, Osaka, Japan were enlisted as subjects, in whom we investigated sweet preference, clinical characteristics, including obesity and serum leptin level, and the polymorphisms of LEP and LEPR (G-2548A and A19G for LEP; R109K, R223Q, and rs3790439 for LEPR). We determined the associations among the parameters using logistic regression analysis, in order to consider potential confounding factors for sweet preference and/or obesity. The LEP A19G and LEPR R109K polymorphisms were associated with sweet preference, whereas the serum leptin level was not. Further, the LEPR 109KK genotype was found to be associated with obesity along with sweet preference. In conclusion, our results are the first to show associations of LEP and LEPR polymorphisms with sweet preference, and may provide useful information for diagnosis and treatment of lifestyle-related diseases.

Polymorphisms in endothelin system genes, arsenic levels and obesity risk.

PubMed

Martínez-Barquero, Vanesa; de Marco, Griselda; Martínez-Hervas, Sergio; Rentero, Pilar; Galan-Chilet, Inmaculada; Blesa, Sebastian; Morchon, David; Morcillo, Sonsoles; Rojo, Gemma; Ascaso, Juan Francisco; Real, José Tomás; Martín-Escudero, Juan Carlos; Chaves, Felipe Javier

2015-01-01

Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity. We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex. We found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53). Our results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to obesity and can interact with plasma arsenic levels.

Welded-Ag-nanowires/FTO conducting film with high transmittance and its application in transparent supercapacitors

NASA Astrophysics Data System (ADS)

Qiao, Zhensong; Yang, Xiaopeng; Liu, Feng; Duan, Guangbin; Cao, Bingqiang

2017-03-01

Silver nanowires (AgNW) with a small diameter were synthesized by a facile and novel polyol reduction method. Ag nanowires ink was then spun on the surface of F-doped SnO2 (FTO) to form the AgNW/FTO conducting film. Welding treatment of the AgNW/FTO conducting film not only increased the optical transmittance from 71.9 % to 79.3 % at 550 nm and decreased the sheet resistance from 11.4 ohm sq-1 to 9.8 ohm sq-1, but also improved the adhesivity of AgNW network on FTO substrate. Furthermore, MnO2 nanosheets were directly deposited on welded-AgNW/FTO (wAF) substrate to prepare a transparent MnO2/weled-AgNW/FTO (MwAF) composite electrode. The MwAF electrode displayed excellent electrochemical performance, including high specific capacitance (375 F g-1 at 5 mV s-1) and superior cycle stability (173.3 % of the initial capacitance after 20000 GCD cycles).

Effect of Cytokine Signaling 3 Gene Polymorphisms in Childhood Obesity.

PubMed

Boyraz, Mehmet; Yeşilkaya, Ediz; Ezgü, Fatih; Bideci, Aysun; Doğan, Haldun; Ulucan, Korkut; Cinaz, Peyami

2016-12-01

Although polymorphisms in suppressor of cytokine signaling 3 (SOCS3) was reported to be related to obesity, Metabolic syndrome (MS), and type 2 diabetes mellitus in various adult studies, there is a lack of data in children. In this study, we examined eight reported polymorphisms of SOCS3 in obese Turkish children and adolescent with and without MS and compared the results with that of controls. One hundred and forty eight obese and 63 age- and sex-matched control subjects were enrolled in the study. Obesity classification was carried out according to body mass index. World Health Organization and National Cholesterol Education Program criteria were used for the diagnosis of MS. Genotyping procedure was carried out by polymerase chain reaction and Sanger sequencing protocol. The frequency of rs2280148 polymorphism was significantly higher in obese subjects with MS than in the control group, whereas the frequency of rs8064821 polymorphism was significantly higher in obese subjects with MS than in obese children without MS. The significant associations of certain SOCS3 polymorphisms with obesity parameters in both MS and MS -related insulin resistance, hypertension, and fatty liver suggest that polymorphisms in this gene may play a role in the pathogenesis of MS and also that they can be potentially used as a marker for attenuated or aggressive disease.

Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment.

PubMed

Teoh, Seong Lin; Das, Srijit

2016-11-01

Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.

Genetics of fat intake in the determination of body mass.

PubMed

Chmurzynska, Agata; Mlodzik, Monika A

2017-06-01

Body mass and fat intake are multifactorial traits that have genetic and environmental components. The gene with the greatest effect on body mass is FTO (fat mass and obesity-associated), but several studies have shown that the effect of FTO (and of other genes) on body mass can be modified by the intake of nutrients. The so-called gene-environment interactions may also be important for the effectiveness of weight-loss strategies. Food choices, and thus fat intake, depend to some extent on individual preferences. The most important biological component of food preference is taste, and the role of fat sensitivity in fat intake has recently been pointed out. Relatively few studies have analysed the genetic components of fat intake or fatty acid sensitivity in terms of their relation to obesity. It has been proposed that decreased oral fatty acid sensitivity leads to increased fat intake and thus increased body mass. One of the genes that affect fatty acid sensitivity is CD36 (cluster of differentiation 36). However, little is known so far about the genetic component of fat sensing. We performed a literature review to identify the state of knowledge regarding the genetics of fat intake and its relation to body-mass determination, and to identify the priorities for further investigations.

Genetic Obesity and the Risk of Atrial Fibrillation – Causal Estimates from Mendelian Randomization

PubMed Central

Chatterjee, Neal A.; Arking, Dan E.; Ellinor, Patrick T.; Heeringa, Jan; Lin, Honghuang; Lubitz, Steven A.; Soliman, Elsayed Z.; Verweij, Niek; Alonso, Alvaro; Benjamin, Emelia J.; Gudnason, Vilmundur; Stricker, Bruno H. C.; Van Der Harst, Pim; Chasman, Daniel I.; Albert, Christine M.

2017-01-01

Background Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF using genetic predictors of BMI. Methods We identified 51 646 individuals of European ancestry without AF at baseline from seven prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged 7.4 to 19.2 years, over which period there were a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were utilized: FTO genotype (rs1558902) and a BMI gene score comprised of 39 single nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance weighted meta-analysis. Results In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% CI: 0.32 – 0.54] kg/m2 per A-allele, p<0.001); BMI gene score: 1.05 [95% CI: 0.90-1.20] kg/m2 per 1 unit increase, p<0.001) and incident AF (FTO – HR: 1.07 [1.02-1.11] per A-allele, p=0.004; BMI gene score – HR: 1.11 [1.05-1.18] per 1-unit increase, p<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were HR 1.15 [1.04-1.26] per kg/m2, p=0.005 (FTO) and 1.11 [1.05-1.17] per kg/m2, p<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted HR 1.05 [1

A global evolutionary and metabolic analysis of human obesity gene risk variants.

PubMed

Castillo, Joseph J; Hazlett, Zachary S; Orlando, Robert A; Garver, William S

2017-09-05

It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa). Our results also provide novel information for association of these obesity genes or encoded proteins with diverse metabolic pathways and other human diseases. The overall results indicate a significant differential evolutionary pattern for the selection of obesity gene ancestral and derived risk variants proposed to optimize energy metabolism in varying global environments and complex association with metabolic pathways and other human diseases. These results are consistent with obesity genes that encode proteins possessing a fundamental role in maintaining energy metabolism and survival during the course of human evolution. Copyright © 2017. Published by Elsevier B.V.

Liver alpha-amylase gene expression as an early obesity biomarker.

PubMed

Mojbafan, Marzieh; Afsartala, Zohreh; Amoli, Mahsa M; Mahmoudi, Mahdi; Yaghmaei, Parichehreh; Larijani, Bagher; Ebrahim-Habibi, Azadeh

2017-04-01

Obesity is a major health problem worldwide, for which preventive and therapeutic means are still needed. Alpha-amylase is a digestive enzyme whose inhibition has been targeted as a potential anti-obesity strategy. However, alpha-amylase gene expression has not been particularly attended to, and in contrast with pancreatic and salivary amylases, fewer studies have focused on liver alpha-amylase. The present study aimed at investigating the expression of alpha-amylase gene in obese and normal mice at RNA and protein level as well as acarbose effect on this gene expression in hepatocyte cell culture. Control and case groups were fed by normal mouse pellet and high-fat diet respectively, during 8 weeks. After this period, serum biochemical parameters including glucose, cholesterol, triglycerides, AST, ALT and alpha-amylase were assayed. Liver alpha-amylase gene was analyzed by real time PCR, and liver enzyme was assayed with Bernfeld and ELISA methods Hepatocyte cell culture derived from both group were also treated by acarbose and alpha-amylase activity and gene expression was analyzed by above mentioned methods. All biochemical factors showed an increase in obese mice, but the increase in ALT and AST were not statistically significant. Alpha-amylase levels were also increased in obese mice, both at RNA and protein level, while a decrease was seen in obese mice derived hepatocytes after acarbose treatment. Elevated liver alpha-amylase levels may be indicative of initial stages of obesity and the use of acarbose could be considered as a treatment of obesity which could be potentially effective at multiple levels. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Obesity Disrupts Rhythmic Clock Gene Expression in Maternal Adipose Tissue during Rat Pregnancy.

PubMed

Crew, Rachael C; Mark, Peter J; Waddell, Brendan J

2018-06-01

Obesity during pregnancy causes numerous maternal and fetal health complications, but the underlying mechanisms remain unclear. Adipose tissue dysfunction in obesity has previously been linked to disruption of the intrinsic adipose clock gene network that is crucial for normal metabolic function. This adipose clock also undergoes major change as part of the maternal metabolic adaptation to pregnancy, but whether this is affected by maternal obesity is unknown. Consequently, in this study we tested the hypothesis that obesity disturbs rhythmic gene expression in maternal adipose tissue across pregnancy. A rat model of maternal obesity was established by cafeteria (CAF) feeding, and adipose expression of clock genes and associated nuclear receptors ( Ppars and Pgc1α) was measured across days 15-16 and 21-22 of gestation (term = 23 days). CAF feeding suppressed the mesor and/or amplitude of adipose tissue clock genes (most notably Bmal1, Per2, and Rev-erbα) relative to chow-fed controls (CON) across both days of gestation. On day 15, the CAF diet also induced adipose Pparα, Pparδ, and Pgc1α rhythmicity but repressed that of Pparγ, while expression of Pparα, Pparδ, and Pgc1α was reduced at select time points. CAF mothers were hyperleptinemic at both stages of gestation, and at day 21 this effect was time-of-day dependent. Fetal plasma leptin exhibited clear rhythmicity, albeit with low amplitude, but interestingly these levels were unaffected by CAF feeding. Our data show that maternal obesity disrupts rhythmic expression of clock and metabolic genes in maternal adipose tissue and leads to maternal but not fetal hyperleptinemia.

Genetic Variations in Sweet Taste Receptor Gene Are Related to Chocolate Powder and Dietary Fiber Intake in Obese Children and Adolescents

PubMed Central

Pioltine, Marina B.; de Melo, Maria Edna; Santos, Aritânia S.; Machado, Alisson D.; Fernandes, Ariana E.; Fujiwara, Clarissa T.; Cercato, Cintia; Mancini, Marcio C.

2018-01-01

Childhood obesity is a major public health problem. It has a direct impact on the quality of life of children and adolescents, as well as on their future risk of developing chronic diseases. Dietary patterns rich in fats and sugars and lacking dietary fibers, vitamins, and minerals, as well as lack of physical exercise have been associated with the rise of obesity prevalence. However, factors that contribute to the preference for foods rich in these nutrients are not well established. Taste is recognized as an important predictor of food choices, and polymorphisms in taste-related genes may explain the variability of taste preference and food intake. The aim of this research is to evaluate the influence of polymorphisms of the sweet taste receptor gene TAS1R2 on diet and metabolic profile in obese children and adolescents. A cross-sectional study with 513 obese children and adolescents and 135 normal-weight children was carried out. A molecular study was performed for the single nucleotide polymorphisms (SNPs) rs9701796 and rs35874116 of TAS1R2, and dietary intake, anthropometric parameters (weight, height, waist circumference, waist-to-height ratio (WHtR)), and metabolic profile (including fasting glucose, insulin, triglyceride, high-density lipoprotein (HDL)–cholesterol, and leptin levels) were analyzed. The variant rs9701796 was associated with increased waist-height ratio, as well as with a higher chocolate powder intake in obese children. The variant rs35874116 was associated with a lower dietary fiber intake. In conclusion, there was no relationship between genotypes and risk of obesity. Obese adolescents carrying the serine allele of SNP rs9701796 in TAS1R2 showed higher waist-to-height ratio and chocolate powder intake, whereas those carrying the valine allele of SNP rs35874116 in TAS1R2 were characterized by lower dietary fiber intake. PMID:29382185

Genetic Variations in Sweet Taste Receptor Gene Are Related to Chocolate Powder and Dietary Fiber Intake in Obese Children and Adolescents.

PubMed

Pioltine, Marina B; de Melo, Maria Edna; Santos, Aritânia S; Machado, Alisson D; Fernandes, Ariana E; Fujiwara, Clarissa T; Cercato, Cintia; Mancini, Marcio C

2018-01-29

Childhood obesity is a major public health problem. It has a direct impact on the quality of life of children and adolescents, as well as on their future risk of developing chronic diseases. Dietary patterns rich in fats and sugars and lacking dietary fibers, vitamins, and minerals, as well as lack of physical exercise have been associated with the rise of obesity prevalence. However, factors that contribute to the preference for foods rich in these nutrients are not well established. Taste is recognized as an important predictor of food choices, and polymorphisms in taste-related genes may explain the variability of taste preference and food intake. The aim of this research is to evaluate the influence of polymorphisms of the sweet taste receptor gene TAS1R2 on diet and metabolic profile in obese children and adolescents. A cross-sectional study with 513 obese children and adolescents and 135 normal-weight children was carried out. A molecular study was performed for the single nucleotide polymorphisms (SNPs) rs9701796 and rs35874116 of TAS1R2 , and dietary intake, anthropometric parameters (weight, height, waist circumference, waist-to-height ratio (WHtR)), and metabolic profile (including fasting glucose, insulin, triglyceride, high-density lipoprotein (HDL)-cholesterol, and leptin levels) were analyzed. The variant rs9701796 was associated with increased waist-height ratio, as well as with a higher chocolate powder intake in obese children. The variant rs35874116 was associated with a lower dietary fiber intake. In conclusion, there was no relationship between genotypes and risk of obesity. Obese adolescents carrying the serine allele of SNP rs9701796 in TAS1R2 showed higher waist-to-height ratio and chocolate powder intake, whereas those carrying the valine allele of SNP rs35874116 in TAS1R2 were characterized by lower dietary fiber intake.

Addictive genes and the relationship to obesity and inflammation.

PubMed

Heber, David; Carpenter, Catherine L

2011-10-01

There is increasing evidence that the same brain reward circuits involved in perpetuating drug abuse are involved in the hedonic urges and food cravings observed clinically in overweight and obese subjects. A polymorphism of the D2 dopamine receptor which renders it less sensitive to dopamine stimulation has been proposed to promote self-stimulatory behavior such as consuming alcohol, abusing drugs, or binging on foods. It is important to determine how this polymorphism may interact with other well-known candidate genes for obesity including polymorphisms of the leptin receptor gene and the opiomelanocortin gene. Leptin is a proinflammatory cytokine as well as a long-term signal maintaining body fat. Upper-body obesity stimulates systemic inflammation through the action of multiple cytokines including leptin throughout many organs including the brain. The association of numerous diseases including diabetes mellitus, heart disease, as well as depression with chronic low-grade inflammation due to abdominal obesity has raised the possibility that obesity-associated inflammation affecting the brain may promote addictive behaviors leading to a self-perpetuating cycle that may affect not only foods but addictions to drugs, alcohol, and gambling. This new area of interdisciplinary research holds the promise of developing new approaches to treating drug abuse and obesity.

Contribution of 32 GWAS-Identified Common Variants to Severe Obesity in European Adults Referred for Bariatric Surgery

PubMed Central

Yousseif, Ahmed; Pucci, Andrea; Santini, Ferruccio; Karra, Efthimia; Querci, Giorgia; Pelosini, Caterina; McCarthy, Mark I.; Lindgren, Cecilia M.; Batterham, Rachel L.

2013-01-01

The prevalence of severe obesity, defined as body mass index (BMI) ≥35.0 kg/m2, is rising rapidly. Given the disproportionately high health burden and healthcare costs associated with this condition, understanding the underlying aetiology, including predisposing genetic factors, is a biomedical research priority. Previous studies have suggested that severe obesity represents an extreme tail of the population BMI variation, reflecting shared genetic factors operating across the spectrum. Here, we sought to determine whether a panel of 32 known common obesity-susceptibility variants contribute to severe obesity in patients (n = 1,003, mean BMI 48.4±8.1 kg/m2) attending bariatric surgery clinics in two European centres. We examined the effects of these 32 common variants on obesity risk and BMI, both as individual markers and in combination as a genetic risk score, in a comparison with normal-weight controls (n = 1,809, BMI 18.0–24.9 kg/m2); an approach which, to our knowledge, has not been previously undertaken in the setting of a bariatric clinic. We found strong associations with severe obesity for SNP rs9939609 within the FTO gene (P = 9.3×10−8) and SNP rs2815752 near the NEGR1 gene (P = 3.6×10−4), and directionally consistent nominal associations (P<0.05) for 12 other SNPs. The genetic risk score associated with severe obesity (P = 8.3×10−11) but, within the bariatric cohort, this score did not associate with BMI itself (P = 0.264). Our results show significant effects of individual BMI-associated common variants within a relatively small sample size of bariatric patients. Furthermore, the burden of such low-penetrant risk alleles contributes to severe obesity in this population. Our findings support that severe obesity observed in bariatric patients represents an extreme tail of the population BMI variation. Moreover, future genetic studies focused on bariatric patients may provide valuable insights into the pathogenesis of

Role of mRNA Methylation in Prostate Cancer

DTIC Science & Technology

2015-02-01

position of adenosine (m6A) is a post-transcriptional modification of mRNA. However, little is known regarding the biological meanings of this epigenetic ...its level is altered in various cancer cell lines. FTO, the fat mass and obesity associated gene, was recently shown as an m6A demethylase. FTO gene...mRNA. However, little is known regarding the biological meanings of this epigenetic regulation of mRNA. Recent technological advances have made it

Adiponectin gene polymorphisms: Association with childhood obesity

PubMed Central

Fraga, Vanêssa Gomes; Gomes, Karina Braga

2014-01-01

The current childhood obesity epidemic represents a particular challenge for public health. Understanding of the etiological mechanisms of obesity remains integral in treating this complex disorder. In recent years, studies have elucidated the influence of hormones secreted by adipose tissue named adipokines. Adiponectin is a adipokine that exhibits important anti-inflammatory, insulin-sensitizing and anti-atherogenic properties and it is strongly associated to obesity development. It is well known that adiponectin levels decrease with obesity. Furthermore, studies show that some single nucleotide polymorphisms in the gene encoding adiponectin, ADIPOQ, may influence the expression of this protein. The objective of this paper is to provide an up-to-date review of ADIPOQ polymorphisms in the context of childhood obesity. PMID:27625863

Obesity-related known and candidate SNP markers can significantly change affinity of TATA-binding protein for human gene promoters

PubMed Central

2015-01-01

Background Obesity affects quality of life and life expectancy and is associated with cardiovascular disorders, cancer, diabetes, reproductive disorders in women, prostate diseases in men, and congenital anomalies in children. The use of single nucleotide polymorphism (SNP) markers of diseases and drug responses (i.e., significant differences of personal genomes of patients from the reference human genome) can help physicians to improve treatment. Clinical research can validate SNP markers via genotyping of patients and demonstration that SNP alleles are significantly more frequent in patients than in healthy people. The search for biomedical SNP markers of interest can be accelerated by computer-based analysis of hundreds of millions of SNPs in the 1000 Genomes project because of selection of the most meaningful candidate SNP markers and elimination of neutral SNPs. Results We cross-validated the output of two computer-based methods: DNA sequence analysis using Web service SNP_TATA_Comparator and keyword search for articles on comorbidities of obesity. Near the sites binding to TATA-binding protein (TBP) in human gene promoters, we found 22 obesity-related candidate SNP markers, including rs10895068 (male breast cancer in obesity); rs35036378 (reduced risk of obesity after ovariectomy); rs201739205 (reduced risk of obesity-related cancers due to weight loss by diet/exercise in obese postmenopausal women); rs183433761 (obesity resistance during a high-fat diet); rs367732974 and rs549591993 (both: cardiovascular complications in obese patients with type 2 diabetes mellitus); rs200487063 and rs34104384 (both: obesity-caused hypertension); rs35518301, rs72661131, and rs562962093 (all: obesity); and rs397509430, rs33980857, rs34598529, rs33931746, rs33981098, rs34500389, rs63750953, rs281864525, rs35518301, and rs34166473 (all: chronic inflammation in comorbidities of obesity). Using an electrophoretic mobility shift assay under nonequilibrium conditions, we

The role of established East Asian obesity-related loci on pediatric leptin levels highlights a neuronal influence on body weight regulation in Chinese children and adolescents: the BCAMS study

PubMed Central

Fu, Junling; Li, Ge; Li, Lujiao; Yin, Jinhua; Cheng, Hong; Han, Lanwen; Zhang, Qian; Li, Naishi; Xiao, Xinhua; Grant, Struan F.A.; Li, Mingyao; Gao, Shan; Mi, Jie; Li, Ming

2017-01-01

Genome-wide association studies have identified multiple variants associated with adult obesity, mostly in European-ancestry populations. We aimed to systematically assess the contribution of key loci, which had been previously shown to be associated in East Asian adults, to childhood obesity, related adipokine profiles and metabolic traits in a Chinese pediatric population. Twelve single-nucleotide polymorphisms (SNPs) plus metabolic profiles and levels of five adipokines (leptin, adiponectin, resistin, fibroblast growth factor 21 and retinol binding protein 4) were evaluated in 3,506 Chinese children and adolescents aged 6-18. After correction for multiple comparisons, six of these SNPs were robustly associated with childhood obesity: FTO-rs1558902 (P=5.6×10−5), MC4R-rs2331841 (P=4.4×10−4), GNPDA2-rs16858082 (P = 3.4×10−4), PCSK1-rs261967 (P = 0.001), SEC16B-rs516636 (P = 0.004) and MAP2K5-rs4776970 (P = 0.004), with odds ratios ranging from 1.211 to 1.421; while ITIH4-rs2535633 and BDNF-rs2030323 yielded nominal association with the same trait (P < 0.05). Moreover, the risk alleles of six SNPs displayed significant (P < 0.004) or nominal (P < 0.05) association with leptin levels, namely at in/near PCSK1, MC4R, FTO, MAP2K5, GNPDA2 and BDNF plus their cumulative genetic score yielded stronger association with increased leptin levels (P = 6.2×10−11). Our results reveal that key obesity-associated loci previously reported in Europeans, but also associated with East Asian adults, are also associated with obesity and/or metabolic quantitative traits in Chinese children. These associations coincide with six brain-expressed loci that correlate with leptin levels, thus may point to an important neuronal influence on body weight regulation in the pediatric setting. PMID:29212175

Schottky diode behaviour with excellent photoresponse in NiO/FTO heterostructure

NASA Astrophysics Data System (ADS)

Saha, B.; Sarkar, K.; Bera, A.; Deb, K.; Thapa, R.

2017-10-01

Delocalization of charge carriers through formation of native defects in NiO, to achieve a good metal oxide hole transport layer was attemted in this work and thus a heterojunction of p-type NiO and n-type FTO have been prepared through sol-gel process on FTO coated glass substrate. The synthesis process was stimulated by imparting large number of OH- sites during nucleation of Ni(OH)2 on FTO, so that during oxidation through annealing Ni vacancies are introduced. The structural properties as observed from X-ray diffraction measurement indicate formation of well crystalline NiO nanoparticles. Uniform distribution of NiO nanoparticles has been observed in the images obtained from scanning electron microscope. The occurrence of p-type conductivity in the NiO film was stimulated through the formation of delocalized defect carriers originated from crystal defects like vacancies or interstitials in the lattice. Ni vacancy creates shallow levels with respect to the valance band maxima and they readily produce holes. Thus a native p-type conductivity of NiO originates from Ni vacancies. NiO was thus obtained as an auspicious hole transport medium, which creates an expedient heterojunction at the interface with FTO. Excellent rectifying behavior was observed in the electrical J-V plot obtained from the prepared heterojunction. The results are explained from the band energy diagram of the NiO/FTO heterojunction. Remarkable photoresponse has been observed in the reverse characteristics of the heterojunction caused by photon generated electron hole pairs.

Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma.

PubMed

Mendoza-Pérez, Julia; Gu, Jian; Herrera, Luis A; Tannir, Nizar M; Zhang, Shanyu; Matin, Surena; Karam, Jose A; Wood, Christopher G; Wu, Xifeng

2017-09-15

Greater than 40% of renal cell carcinoma (RCC) cases in the United States are attributed to excessive body weight. Moreover, obesity also may be linked to RCC prognosis. However, the molecular mechanisms underlying these associations are unclear. In the current study, the authors evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and disease recurrence. Paired tumors (TU) and normal adjacent (N-Adj) tissues from 240 newly diagnosed and previously untreated white patients with RCC were examined. For the discovery phase, 63 RCC pairs were analyzed. An additional 177 RCC pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent data set from The Cancer Genome Atlas also was analyzed for functional validation. The association between methylation and disease recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis. Methylation in neuropeptide Y (NPY), leptin (LEP), and leptin receptor (LEPR) was significantly higher in TU compared with N-Adj tissues (P<.0001) in both the discovery and validation groups. High methylation in LEPR was associated with an increased risk of disease recurrence (hazard ratio, 3.15; 95% confidence interval, 1.23-8.07 [P = .02]). Patients with high methylation in LEPR had a shorter recurrence-free survival compared with patients in the low-methylation group (log-rank P = 2.25 × 10 -3 ). In addition, high LEPR methylation in TU was associated with more advanced features (P≤.05). Consistent with the findings of the current study, lower LEPR expression in TU compared with N-Adj tissues (P = 1.00 × 10 -3 ) was found in data from The Cancer Genome Atlas. Somatic alterations of promoter methylation in the NPY, LEP, and LEPR genes are involved in RCC tumorigenesis. Furthermore, LEPR methylation appears to be associated with RCC recurrence. Future research to

Genetic variants influencing effectiveness of exercise training programmes in obesity - an overview of human studies.

PubMed

Leońska-Duniec, A; Ahmetov, I I; Zmijewski, P

2016-09-01

Frequent and regular physical activity has significant benefits for health, including improvement of body composition and help in weight control. Consequently, promoting training programmes, particularly in those who are genetically predisposed, is a significant step towards controlling the presently increasing epidemic of obesity. Although the physiological responses of the human body to exercise are quite well described, the genetic background of these reactions still remains mostly unknown. This review not only summarizes the current evidence, through a literature review and the results of our studies on the influence of gene variants on the characteristics and range of the body's adaptive response to training, but also explores research organization problems, future trends, and possibilities. We describe the most reliable candidate genetic markers that are involved in energy balance pathways and body composition changes in response to training programmes, such as FTO, MC4R, ACE, PPARG, LEP, LEPR, ADRB2, and ADRB3. This knowledge can have an enormous impact not only on individualization of exercise programmes to make them more efficient and safer, but also on improved recovery, traumatology, medical care, diet, supplementation and many other areas. Nevertheless, the current studies still represent only the first steps towards a better understanding of the genetic factors that influence obesity-related traits, as well as gene variant x physical activity interactions, so further research is necessary.

Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader–Willi and Alström syndromes

PubMed Central

Butler, Merlin G; Wang, Kun; Marshall, Jan D; Naggert, Jürgen K; Rethmeyer, Jasmine A; Gunewardena, Sumedha S; Manzardo, Ann M

2015-01-01

Obesity is accompanied by hyperphagia in several classical genetic obesity-related syndromes that are rare, including Prader–Willi syndrome (PWS) and Alström syndrome (ALMS). We compared coding and noncoding gene expression in adult males with PWS, ALMS, and nonsyndromic obesity relative to nonobese males using readily available lymphoblastoid cells to identify disease-specific molecular patterns and disturbed mechanisms in obesity. We found 231 genes upregulated in ALMS compared with nonobese males, but no genes were found to be upregulated in obese or PWS males and 124 genes were downregulated in ALMS. The metallothionein gene (MT1X) was significantly downregulated in ALMS, in common with obese males. Only the complex SNRPN locus was disturbed (downregulated) in PWS along with several downregulated small nucleolar RNAs (snoRNAs) in the 15q11-q13 region (SNORD116, SNORD109B, SNORD109A, SNORD107). Eleven upregulated and ten downregulated snoRNAs targeting multiple genes impacting rRNA processing, developmental pathways, and associated diseases were found in ALMS. Fifty-two miRNAs associated with multiple, overlapping gene expression disturbances were upregulated in ALMS, and four were shared with obese males but not PWS males. For example, seven passenger strand microRNAs (miRNAs) (miR-93*, miR-373*, miR-29b-2*, miR-30c-1*, miR27a*, miR27b*, and miR-149*) were disturbed in association with six separate downregulated target genes (CD68, FAM102A, MXI1, MYO1D, TP53INP1, and ZRANB1). Cell cycle (eg, PPP3CA), transcription (eg, POLE2), and development may be impacted by upregulated genes in ALMS, while downregulated genes were found to be involved with metabolic processes (eg, FABP3), immune responses (eg, IL32), and cell signaling (eg, IL1B). The high number of gene and noncoding RNA disturbances in ALMS contrast with observations in PWS and males with nonsyndromic obesity and may reflect the progressing multiorgan pathology of the ALMS disease process. PMID

Identifying candidate genes for Type 2 Diabetes Mellitus and obesity through gene expression profiling in multiple tissues or cells.

PubMed

Chen, Junhui; Meng, Yuhuan; Zhou, Jinghui; Zhuo, Min; Ling, Fei; Zhang, Yu; Du, Hongli; Wang, Xiaoning

2013-01-01

Type 2 Diabetes Mellitus (T2DM) and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL) within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying high percentages of differential expression were filtered out. Specifically, DENND1B, LYN, MRPL30, POC1B, PRKCB, RP4-655J12.3, HIBADH, and TMBIM4 were identified from the T2DM-control study, and BCAT1, BMP2K, CSRNP2, MYNN, NCKAP5L, SAP30BP, SLC35B4, SP1, BAP1, GRB14, HSP90AB1, ITGA5, and TOMM5 were identified from the obesity-control study. The majority of these genes are known to be involved in T2DM and obesity. Therefore, analysis of gene expression in various tissues using GEO datasets may be an effective and feasible method to determine novel or causal genes associated with T2DM and obesity.

Genetic variants influencing effectiveness of exercise training programmes in obesity – an overview of human studies

PubMed Central

Ahmetov, II; Zmijewski, P

2016-01-01

Frequent and regular physical activity has significant benefits for health, including improvement of body composition and help in weight control. Consequently, promoting training programmes, particularly in those who are genetically predisposed, is a significant step towards controlling the presently increasing epidemic of obesity. Although the physiological responses of the human body to exercise are quite well described, the genetic background of these reactions still remains mostly unknown. This review not only summarizes the current evidence, through a literature review and the results of our studies on the influence of gene variants on the characteristics and range of the body's adaptive response to training, but also explores research organization problems, future trends, and possibilities. We describe the most reliable candidate genetic markers that are involved in energy balance pathways and body composition changes in response to training programmes, such as FTO, MC4R, ACE, PPARG, LEP, LEPR, ADRB2, and ADRB3. This knowledge can have an enormous impact not only on individualization of exercise programmes to make them more efficient and safer, but also on improved recovery, traumatology, medical care, diet, supplementation and many other areas. Nevertheless, the current studies still represent only the first steps towards a better understanding of the genetic factors that influence obesity-related traits, as well as gene variant x physical activity interactions, so further research is necessary. PMID:27601774

Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity.

PubMed

Hendricks, Audrey E; Bochukova, Elena G; Marenne, Gaëlle; Keogh, Julia M; Atanassova, Neli; Bounds, Rebecca; Wheeler, Eleanor; Mistry, Vanisha; Henning, Elana; Körner, Antje; Muddyman, Dawn; McCarthy, Shane; Hinney, Anke; Hebebrand, Johannes; Scott, Robert A; Langenberg, Claudia; Wareham, Nick J; Surendran, Praveen; Howson, Joanna M; Butterworth, Adam S; Danesh, John; Nordestgaard, Børge G; Nielsen, Sune F; Afzal, Shoaib; Papadia, Sofia; Ashford, Sofie; Garg, Sumedha; Millhauser, Glenn L; Palomino, Rafael I; Kwasniewska, Alexandra; Tachmazidou, Ioanna; O'Rahilly, Stephen; Zeggini, Eleftheria; Barroso, Inês; Farooqi, I Sadaf

2017-06-29

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10 -3 ), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Expression of the central obesity and Type 2 Diabetes mellitus genes is associated with insulin resistance in young obese children.

PubMed

Skoczen, S; Wojcik, M; Fijorek, K; Siedlar, M; Starzyk, J B

2015-04-01

The assessment of the health consequences associated with obesity in young children is challenging. The aims of this study were: (1) to compare insulin resistance indices derived from OGTT in obese patients and healthy control (2) to analyze central obesity and Type 2 Diabetes genes expression in obese children, with special attention to the youngest group (< 10 years old). The study included 49 children with obesity (median age 13.5 years old), and 25 healthy peers. Biochemical blood tests and expression of 11 central obesity and 33 Type 2 Diabetes genes was assessed. A significant difference in insulin resistance between obese and non-obese adolescents was observed in all studied indices (mean values of the insulin levels: 24.9 vs. 9.71 mIU/L in T0, 128 vs. 54.7 mIU/L in T60 and 98.7 vs. 41.1 mIU/L in T120 respectively; AUC: 217 vs. 77.2 ng/ml*h, mean values of B% (state beta cell function), S% (insulin sensitivity), and IR were 255 (±97) vs. 135 (±37.8), 46.6 (±37.3) vs. 84.2 (±29.6) and 3 (±1.55) vs. 1.36 (±0,56); HIS, WBIS and ISIBel median 3.89, 44.7, 0.73 vs. 8.57, 110, 2.25. All comparisons differed significantly p<0.001). Moreover, insulin sensitivity was significantly better in the older obese group (>10 years old): median AUC 239 vs. 104 ng/ml*h, and HIS, WBIS and ISIBel 3.57, 38, 0.67 vs. 6.23, 75.6, 1.87 respectively in the obese older compared to the obese younger subgroup, p<0.05. The expression of 64% of the central obesity genes and 70% of Type 2 Diabetes genes was higher in the obese compared to control groups. The differences were more pronounced in the younger obese group. Insulin resistance may develop in early stage of childhood obesity and in very young children may be associated with higher expression of the central obesity and Type 2 Diabetes genes. © Georg Thieme Verlag KG Stuttgart · New York.

Preparation and characterization of sprayed FTO thin films

NASA Astrophysics Data System (ADS)

Abd-Lefdil, M.; Diaz, R.; Bihri, H.; Aouaj, M. Ait; Rueda, F.

2007-06-01

Fluorine doped tin oxide (FTO) thin films have been prepared by spray pyrolysis technique with no further annealing. Films with 2.5% of fluorine grown at 400 °C present a single phase and exhibit a tetragonal structure with lattice parameters a = 4.687 Å and c = 3.160 Å. Scanning electron micrographs showed homogeneous surfaces with average grain size around 190 nm. The films are transparent in the visible zone and exhibit a high reflectance in the near infrared region. The best electrical resistivity was 6.3 × 10-4 Ω cm for FTO with 2.5% of fluorine. The ratio of transmittance in the visible to the sheet resistance are in the 0.57 × 10-2 1.96 × 10-2 {Ω }-1 range.

Companion Animals Symposium: nutrigenomics: using gene expression and molecular biology data to understand pet obesity.

PubMed

de Godoy, M R C; Swanson, K S

2013-06-01

Approximately 55% of dogs and 53% of cats in the United States are considered overweight or obese. The domestication of dogs and cats and, more recently, their anthropomorphism, have drastically changed their environment and social behavior. A greater manifestation of chronic diseases is observed with pet obesity (e.g., insulin resistance, type-2 diabetes, musculoskeletal disorders). The advances in "omics" technology may provide new tools to investigate the complexity of obesity and its comorbidities. The field of nutrigenomics focuses specifically on the mechanisms by which nutrients and dietary bioactive molecules affect gene expression. The main objective of this review is to discuss factors involved in the etiology of pet obesity and demonstrate how the field of nutrigenomics has been used to better understand and characterize this disease. Currently, most of the genomics literature available on companion animal obesity has focused on adipose tissue, with fewer studies focused on other tissues (e.g., skeletal muscle, liver). Initial studies focused on the sequence and functionality of a few specific genes, such as leptin and adiponectin, and identified their association with obesity. Subsequent studies focused on gene expression levels across tissues and how they were impacted by BW status or if animals were intact, spayed, or neutered. Dietary interventions to induce obesity, promote BW loss, or alter dietary nutrient profile have also been investigated. Diets including prebiotics, green tea extract, or increased concentrations of protein have been shown to modify the expression of several genes related to glucose and lipid metabolism in adipose [e.g., uncoupling protein-2, carnitine palmitoyltransferase-1, PPARα, lipoprotein lipase (LPL), and glucose transporter 4] and skeletal muscle (e.g., PPARα and LPL) tissues. In general, the outcomes derived from these studies demonstrated that dogs and cats share similar adipokines and hormones to other species, and

Differential DNA Methylation in Relation to Age and Health Risks of Obesity.

PubMed

Mansego, María Luisa; Milagro, Fermín I; Zulet, María Ángeles; Moreno-Aliaga, María J; Martínez, José Alfredo

2015-07-24

The aim of this study was to evaluate whether genome-wide levels of DNA methylation are associated with age and the health risks of obesity (HRO); defined according to BMI categories as "Low HRO" (overweight and class 1 obesity) versus "High HRO" (class 2 and class 3 obesity). Anthropometric measurements were assessed in a subsample of 48 volunteers from the Metabolic Syndrome Reduction in Navarra (RESMENA) study and 24 women from another independent study, Effects of Lipoic Acid and Eicosapentaenoic Acid in Human Obesity (OBEPALIP study). In the pooled population; the methylation levels of 55 CpG sites were significantly associated with age after Benjamini-Hochberg correction. In addition, DNA methylation of three CpG sites located in ELOVL2; HOXC4 and PI4KB were further negatively associated with their mRNA levels. Although no differentially methylated CpG sites were identified in relation to HRO after multiple testing correction; several nominally significant CpG sites were identified in genes related to insulin signaling; energy and lipid metabolism. Moreover, statistically significant associations between BMI or mRNA levels and two HRO-related CpG sites located in GPR133 and ITGB5 are reported. As a conclusion, these findings from two Spanish cohorts add knowledge about the important role of DNA methylation in the age-related regulation of gene expression. In addition; a relevant influence of age on DNA methylation in white blood cells was found, as well as, on a trend level, novel associations between DNA methylation and obesity.

Obesity susceptibility loci and dietary intake in the Look AHEAD Trial.

PubMed

McCaffery, Jeanne M; Papandonatos, George D; Peter, Inga; Huggins, Gordon S; Raynor, Hollie A; Delahanty, Linda M; Cheskin, Lawrence J; Balasubramanyam, Ashok; Wagenknecht, Lynne E; Wing, Rena R

2012-06-01

Genome-wide association studies (GWAS) have identified consistent associations with obesity. However, the mechanisms remain unclear. The objective was to determine the association between obesity susceptibility loci and dietary intake. The association of GWAS-identified obesity risk alleles (FTO, MC4R, SH2B1, BDNF, INSIG2, TNNI3K, NISCH-STAB1, MTIF3, MAP2K5, QPCTL/GIPR, and PPARG) with dietary intake, measured through food-frequency questionnaires, was investigated in 2075 participants from the Look AHEAD (Action for Health in Diabetes) clinical trial. We adjusted for age, sex, population stratification, and study site. Obesity risk alleles at FTO rs1421085 significantly predicted more eating episodes per day (P = 0.001)-an effect that persisted after adjustment for body weight (P = 0.004). Risk variants within BDNF were significantly associated with more servings from the dairy product and the meat, eggs, nuts, and beans food groups (P ≤ 0.004). The risk allele at SH2B1 rs4788099 was significantly associated with more servings of dairy products (P = 0.001), whereas the risk allele at TNNI3K rs1514176 was significantly associated with a lower percentage of energy from protein (P = 0.002). These findings suggest that obesity risk loci may affect the pattern and content of food consumption among overweight or obese individuals with type 2 diabetes. The Look AHEAD Genetic Ancillary Study was registered at clinicaltrials.gov as NCT01270763 and the Look AHEAD study as NCT00017953.

Gene-gene interaction between PPAR gamma 2 and ADR beta 3 increases obesity risk in children and adolescents.

PubMed

Ochoa, M C; Marti, A; Azcona, C; Chueca, M; Oyarzábal, M; Pelach, R; Patiño, A; Moreno-Aliaga, M J; Martínez-González, M A; Martínez, J A

2004-11-01

Multiple genes are likely to be involved in obesity and these genes may interact with environmental factors to influence obesity risk. Our aim was to explore the synergistic contribution of the two polymorphisms: Pro12Ala of the PPAR gamma 2 gene and Trp64Arg of the ADR beta 3 gene to obesity risk in a Spanish children and adolescent population. We designed a sex- and age-matched case-control study. Participants were 185 obese and 185 control children (aged 5-18 y) from the Navarra region, recruited through Departments of Pediatrics (Hospital Virgen del Camino, Navarra University Clinic and several Primary Health Centers). The obesity criterion (case definition) was BMI above the 97th percentile according to Spanish BMI reference data for age and gender. Anthropometric parameters were measured by standard protocols. The genotype was assessed by PCR-RFLP after digestion with BstUI for PPAR gamma 2 mutation and BstNI for ADR beta 3 variants. Face-to-face interviews were conducted to assess the physical activity. Using a validated physical activity questionnaire, we computed an activity metabolic equivalent index (METs h/week), which represents the physical exercise during the week for each participant. Statistical analysis was performed by conditional logistic regression, taking into account the matching between cases and controls. Carriers of the polymorphism Pro12Ala of the PPAR gamma 2 gene had a significantly higher obesity risk than noncarriers (odds ratio (OR)=2.18, 95% CI=1.09-4.36) when we adjusted for sex, age and physical activity. Moreover, the risk of obesity was higher (OR=2.59, 95% CI=1.17-5.34) when family history of obesity was also taken into account in the model. The OR for obesity linked to both polymorphisms (PPAR gamma 2 and ADR beta 3) was 5.30 (95% CI=1.08-25.97) when we adjusted for sex, age and physical activity. After adjustment for family history of obesity, the OR for carriers of both polymorphisms was 19.5 (95% CI=2.43-146.8). A

Red pitaya juice supplementation ameliorates energy balance homeostasis by modulating obesity-related genes in high-carbohydrate, high-fat diet-induced metabolic syndrome rats.

PubMed

Ramli, Nurul Shazini; Ismail, Patimah; Rahmat, Asmah

2016-07-26

Red pitaya (Hylocereus polyrhizus) or known as buah naga merah in Malay belongs to the cactus family, Cactaceae. Red pitaya has been shown to give protection against liver damage and may reduce the stiffness of the heart. Besides, the beneficial effects of red pitaya against obesity have been reported; however, the mechanism of this protection is not clear. Therefore, in the present study, we have investigated the red pitaya-targeted genes in obesity using high-carbohydrate, high-fat diet-induced metabolic syndrome rat model. A total of four groups were tested: corn-starch (CS), corn-starch + red pitaya juice (CRP), high-carbohydrate, high-fat (HCHF) and high-carbohydrate, high-fat + red pitaya juice (HRP). The intervention with 5 % red pitaya juice was continued for 8 weeks after 8 weeks initiation of the diet. Retroperitoneal, epididymal and omental fat pads were collected and weighed. Plasma concentration of IL-6 and TNF-α were measured using commercial kits. Gene expression analysis was conducted using RNA extracted from liver samples. A total of eighty-four genes related to obesity were analyzed using PCR array. The rats fed HCHF-diet for 16 weeks increased body weight, developed excess abdominal fat deposition and down-regulated the expression level of IL-1α, IL-1r1, and Cntfr as compared to the control group. Supplementation of red pitaya juice for 8 weeks increased omental and epididymal fat but no change in retroperitoneal fat was observed. Red pitaya juice reversed the changes in energy balance homeostasis in liver tissues by regulation of the expression levels of Pomc and Insr. The increased protein expression levels of IL-6 and TNF-α in HCHF group and red pitaya treated rats confirmed the results of gene expression. Collectively, this study revealed the usefulness of this diet-induced rat model and the beneficial effects of red pitaya on energy balance homeostasis by modulating the anorectic, orexigenic and energy expenditure related

A novel hierarchical Pt- and FTO-free counter electrode for dye-sensitized solar cell

PubMed Central

2014-01-01

A novel hierarchical Pt- and FTO-free counter electrode (CE) for the dye-sensitized solar cell (DSSC) was prepared by spin coating the mixture of TiO2 nanoparticles and poly(3,4-ethylenedioxy-thiophene):poly(styrenesulfonate) (PEDOT:PSS) solution onto the glass substrate. Compared with traditional Pt/FTO CE, the cost of the new CE is dramatically reduced by the application of bilayer TiO2-PEDOT:PSS/PEDOT:PSS film and the glass substrate. The sheet resistance of this composite film is 35 Ω sq−1 and is low enough to be used as an electrode. The surface morphologies of TiO2-PEDOT:PSS layer and modified PEDOT:PSS layer were characterized by scanning electron microscope, which shows that the former had larger surface areas than the latter. Electrochemical impedance spectra and Tafel polarization curves prove that the catalytic activity of TiO2-PEDOT:PSS/PEDOT:PSS/glass CE is higher than that of PEDOT:PSS/FTO CE and is similar to Pt/FTO CE's. This new fabricated device with TiO2-PEDOT:PSS/PEDOT:PSS/glass CE achieves a high power conversion efficiency (PCE) of 4.67%, reaching 91.39% of DSSC with Pt/FTO CE (5.11%). PMID:24808802

Distinct skeletal muscle fiber characteristics and gene expression in diet-sensitive versus diet-resistant obesity.

PubMed

Gerrits, Martin F; Ghosh, Sujoy; Kavaslar, Nihan; Hill, Benjamin; Tour, Anastasia; Seifert, Erin L; Beauchamp, Brittany; Gorman, Shelby; Stuart, Joan; Dent, Robert; McPherson, Ruth; Harper, Mary-Ellen

2010-08-01

Inter-individual variability in weight gain and loss under energy surfeit and deficit conditions, respectively, are well recognized but poorly understood phenomena. We documented weight loss variability in an intensively supervised clinical weight loss program and assessed skeletal muscle gene expression and phenotypic characteristics related to variable response to a 900 kcal regimen. Matched pairs of healthy, diet-compliant, obese diet-sensitive (ODS) and diet-resistant (ODR) subjects were defined as those in the highest and lowest quintiles for weight loss rate. Physical activity energy expenditure was minimal and comparable. Following program completion and weight stabilization, skeletal muscle biopsies were obtained. Gene expression analysis of rectus femoris and vastus lateralis indicated upregulation of genes and gene sets involved in oxidative phosphorylation and glucose and fatty acid metabolism in ODS compared with ODR. In vastus lateralis, there was a higher proportion of oxidative (type I) fibers in ODS compared with ODR women and lean controls, fiber hypertrophy in ODS compared with ODR women and lean controls, and lower succinate dehydrogenase in oxidative and oxidative-glycolytic fibers in all obese compared with lean subjects. Intramuscular lipid content was generally higher in obese versus lean, and specifically higher in ODS vs. lean women. Altogether, our findings demonstrate differences in muscle gene expression and fiber composition related to clinical weight loss success.

Distinct skeletal muscle fiber characteristics and gene expression in diet-sensitive versus diet-resistant obesity

PubMed Central

Gerrits, Martin F.; Ghosh, Sujoy; Kavaslar, Nihan; Hill, Benjamin; Tour, Anastasia; Seifert, Erin L.; Beauchamp, Brittany; Gorman, Shelby; Stuart, Joan; Dent, Robert; McPherson, Ruth; Harper, Mary-Ellen

2010-01-01

Inter-individual variability in weight gain and loss under energy surfeit and deficit conditions, respectively, are well recognized but poorly understood phenomena. We documented weight loss variability in an intensively supervised clinical weight loss program and assessed skeletal muscle gene expression and phenotypic characteristics related to variable response to a 900 kcal regimen. Matched pairs of healthy, diet-compliant, obese diet-sensitive (ODS) and diet-resistant (ODR) subjects were defined as those in the highest and lowest quintiles for weight loss rate. Physical activity energy expenditure was minimal and comparable. Following program completion and weight stabilization, skeletal muscle biopsies were obtained. Gene expression analysis of rectus femoris and vastus lateralis indicated upregulation of genes and gene sets involved in oxidative phosphorylation and glucose and fatty acid metabolism in ODS compared with ODR. In vastus lateralis, there was a higher proportion of oxidative (type I) fibers in ODS compared with ODR women and lean controls, fiber hypertrophy in ODS compared with ODR women and lean controls, and lower succinate dehydrogenase in oxidative and oxidative-glycolytic fibers in all obese compared with lean subjects. Intramuscular lipid content was generally higher in obese versus lean, and specifically higher in ODS vs. lean women. Altogether, our findings demonstrate differences in muscle gene expression and fiber composition related to clinical weight loss success. PMID:20332421

Effects of a High-Protein/Low-Carbohydrate Diet versus a Standard Hypocaloric Diet on Weight and Cardiovascular Risk Factors: Role of a Genetic Variation in the rs9939609 FTO Gene Variant.

PubMed

de Luis, Daniel Antonio; Aller, Rocío; Izaola, Olatz; Primo, David; Urdiales, Silvia; Romero, Enrique

2015-01-01

The common polymorphism rs9939609 of the fat mass- and obesity-associated gene (FTO) has been linked to obesity. Our aim was to investigate its role in weight loss after the administration of a high-protein/low-carbohydrate diet compared to a standard hypocaloric diet (1,000 kcal/day). During 9 months, 195 patients were randomly allocated to a high-protein hypocaloric diet (HP diet) and a standard hypocaloric diet (S diet). With the HP diet, BMI (-1.9 ± 1.2 vs. -2.10 ± 1.8; p < 0.05), weight (-6.5 ± 2.1 vs. -10.1 ± 4.1 kg; p < 0.05), fat mass (-3.9 ± 3.2 vs. -6.0 ± 3.4 kg; p < 0.05) and waist circumference (-5.7 ± 5.0 vs. -9.9 ± 5.5 cm; p < 0.05) decreased in both genotype groups (TT vs. AT + AA). With the S diet, BMI (-0.9 ± 1.1 vs. -1.8 ± 1.2; p < 0.05), weight (-3.2 ± 3.0 vs. -9.1 ± 3.6 kg; p < 0.05), fat mass (-3.0 ± 3.1 vs. -5.2 ± 3.1 kg; p < 0.05) and waist circumference (-3.1 ± 4.0 vs. -8.1 ± 4.9 cm; p < 0.05) decreased in both genotype groups. With the HP diet and in both genotype groups, glucose, insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol, triglycerides and low-density lipoprotein (LDL) decreased. With the S diet, total cholesterol and LDL decreased. Weight loss was better in A allele carriers than noncarriers, and metabolic improvement was better with the HP diet. © 2015 S. Karger AG, Basel.

Selected single-nucleotide polymorphisms in FOXE1, SERPINA5, FTO, EVPL, TICAM1 and SCARB1 are associated with papillary and follicular thyroid cancer risk: replication study in a German population

PubMed Central

Sigurdson, Alice J.; Brenner, Alina V.; Roach, James A.; Goudeva, Lilia; Müller, Jörg A.; Nerlich, Kai; Reiners, Christoph; Schwab, Robert; Pfeiffer, Liliane; Waldenberger, Melanie; Braganza, Melissa; Xu, Li; Sturgis, Erich M.; Yeager, Meredith; Chanock, Stephen J.; Pfeiffer, Ruth M.; Abend, Michael; Port, Matthias

2016-01-01

Several single-nucleotide polymorphisms (SNPs) have been associated with papillary and follicular thyroid cancer (PTC and FTC, respectively) risk, but few have replicated. After analyzing 17525 tag SNPs in 1129 candidate genes, we found associations with PTC risk in SERPINA5, FTO, HEMGN (near FOXE1) and other genes. Here, we report results from a replication effort in a large independent PTC/FTC case–control study conducted in Germany. We evaluated the best tagging SNPs from our previous PTC study and additionally included SNPs in or near FOXE1 and NKX2-1 genes, known susceptibility loci for thyroid cancer. We genotyped 422 PTC and 130 FTC cases and 752 controls recruited from three German clinical centers. We used polytomous logistic regression to simultaneously estimate PTC and FTC associations for 79 SNPs based on log-additive models. We assessed effect modification by body mass index (BMI), gender and age for all SNPs, and selected SNP by SNP interactions. We confirmed associations with PTC and SNPs in FOXE1/HEMGN, SERPINA5 (rs2069974), FTO (rs8047395), EVPL (rs2071194), TICAM1 (rs8120) and SCARB1 (rs11057820) genes. We found associations with SNPs in FOXE1, SERPINA5, FTO, TICAM1 and HSPA6 and FTC. We found two significant interactions between FTO (rs8047395) and BMI (P = 0.0321) and between TICAM1 (rs8120) and FOXE1 (rs10984377) (P = 0.0006). Besides the known associations with FOXE1 SNPs, we confirmed additional PTC SNP associations reported previously. We also found several new associations with FTC risk and noteworthy interactions. We conclude that multiple variants and host factors might interact in complex ways to increase risk of PTC and FTC. PMID:27207655

Selected single-nucleotide polymorphisms in FOXE1, SERPINA5, FTO, EVPL, TICAM1 and SCARB1 are associated with papillary and follicular thyroid cancer risk: replication study in a German population.

PubMed

Sigurdson, Alice J; Brenner, Alina V; Roach, James A; Goudeva, Lilia; Müller, Jörg A; Nerlich, Kai; Reiners, Christoph; Schwab, Robert; Pfeiffer, Liliane; Waldenberger, Melanie; Braganza, Melissa; Xu, Li; Sturgis, Erich M; Yeager, Meredith; Chanock, Stephen J; Pfeiffer, Ruth M; Abend, Michael; Port, Matthias

2016-07-01

Several single-nucleotide polymorphisms (SNPs) have been associated with papillary and follicular thyroid cancer (PTC and FTC, respectively) risk, but few have replicated. After analyzing 17525 tag SNPs in 1129 candidate genes, we found associations with PTC risk in SERPINA5, FTO, HEMGN (near FOXE1) and other genes. Here, we report results from a replication effort in a large independent PTC/FTC case-control study conducted in Germany. We evaluated the best tagging SNPs from our previous PTC study and additionally included SNPs in or near FOXE1 and NKX2-1 genes, known susceptibility loci for thyroid cancer. We genotyped 422 PTC and 130 FTC cases and 752 controls recruited from three German clinical centers. We used polytomous logistic regression to simultaneously estimate PTC and FTC associations for 79 SNPs based on log-additive models. We assessed effect modification by body mass index (BMI), gender and age for all SNPs, and selected SNP by SNP interactions. We confirmed associations with PTC and SNPs in FOXE1/HEMGN, SERPINA5 (rs2069974), FTO (rs8047395), EVPL (rs2071194), TICAM1 (rs8120) and SCARB1 (rs11057820) genes. We found associations with SNPs in FOXE1, SERPINA5, FTO, TICAM1 and HSPA6 and FTC. We found two significant interactions between FTO (rs8047395) and BMI (P = 0.0321) and between TICAM1 (rs8120) and FOXE1 (rs10984377) (P = 0.0006). Besides the known associations with FOXE1 SNPs, we confirmed additional PTC SNP associations reported previously. We also found several new associations with FTC risk and noteworthy interactions. We conclude that multiple variants and host factors might interact in complex ways to increase risk of PTC and FTC. Published by Oxford University Press 2016.

Fermented green tea extract alleviates obesity and related complications and alters gut microbiota composition in diet-induced obese mice.

PubMed

Seo, Dae-Bang; Jeong, Hyun Woo; Cho, Donghyun; Lee, Bum Jin; Lee, Ji Hae; Choi, Jae Young; Bae, Il-Hong; Lee, Sung-Joon

2015-05-01

Obesity is caused by an imbalance between caloric intake and energy expenditure and accumulation of excess lipids in adipose tissues. Recent studies have demonstrated that green tea and its processed products (e.g., oolong and black tea) are introduced to exert beneficial effects on lipid metabolism. Here, we propose that fermented green tea (FGT) extract, as a novel processed green tea, exhibits antiobesity effects. FGT reduced body weight gain and fat mass without modifying food intake. mRNA expression levels of lipogenic and inflammatory genes were downregulated in white adipose tissue of FGT-administered mice. FGT treatment alleviated glucose intolerance and fatty liver symptoms, common complications of obesity. Notably, FGT restored the changes in gut microbiota composition (e.g., the Firmicutes/Bacteroidetes and Bacteroides/Prevotella ratios), which is reported to be closely related with the development of obesity and insulin resistance, induced by high-fat diets. Collectively, FGT improves obesity and its associated symptoms and modulates composition of gut microbiota; thus, it could be used as a novel dietary component to control obesity and related symptoms.

Polymorphisms of the resistin gene and their association with obesity and resistin levels in Malaysian Malays.

PubMed

Apalasamy, Yamunah Devi; Rampal, Sanjay; Salim, Agus; Moy, Foong Ming; Su, Tin Tin; Majid, Hazreen Abdul; Bulgiba, Awang; Mohamed, Zahurin

2015-06-01

Single nucleotide polymorphisms (SNP) in the resistin gene (RETN) are linked to obesity and resistin levels in various populations. However, results have been inconsistent. This study aimed to investigate association between polymorphisms in the resistin gene with obesity in a homogenous Malaysian Malay population. This study is also aimed to determine association between resistin levels with certain SNPs and haplotypes of RETN. A total of 631 Malaysian Malay subjects were included in this study and genotyping was carried out using Sequenom MassARRAY. There was no significant difference found in both allelic and genotype frequencies of each of the RETN SNPs between the obese and non-obese groups after Bonferroni correction. RETN rs34861192 and rs3219175 SNPs were significantly associated with log-resistin levels. The GG genotype carriers are found to have higher levels of log-resistin compared to A allele carriers. The RETN haplotypes (CAG, CGA and GA) were significantly associated with resistin levels. However, the haplotypes of the RETN gene were not associated with obesity. Resistin levels were not correlated to metabolic parameters such as body weight, waist circumference, body mass index, and lipid parameters. RETN SNPs and haplotypes are of apparent functional importance in the regulation of resistin levels but are not correlated with obesity and related markers.

Association studies on ghrelin and ghrelin receptor gene polymorphisms with obesity.

PubMed

Gueorguiev, Maria; Lecoeur, Cécile; Meyre, David; Benzinou, Michael; Mein, Charles A; Hinney, Anke; Vatin, Vincent; Weill, Jacques; Heude, Barbara; Hebebrand, Johannes; Grossman, Ashley B; Korbonits, Márta; Froguel, Philippe

2009-04-01

Ghrelin exerts a stimulatory effect on appetite and regulates energy homeostasis. Ghrelin gene variants have been shown to be associated with metabolic traits, although there is evidence suggesting linkage and association with obesity and the ghrelin receptor (GHSR). We hypothesized that these genes are good candidates for susceptibility to obesity. Direct sequencing identified 12 ghrelin single-nucleotide polymorphisms (SNPs) and 8 GHSR SNPs. The 10 common SNPs were genotyped in 1,275 obese subjects and in 1,059 subjects from a general population cohort of European origin. In the obesity case-control study, the GHSR SNP rs572169 was found to be associated with obesity (P = 0.007 in additive model, P = 0.001 in dominant model, odds ratio (OR) 1.73, 95% confidence interval (1.23-2.44)). The ghrelin variant, g.A265T (rs4684677), showed an association with obesity (P = 0.009, BMI adjusted for age and sex) in obese families. The ghrelin variant, g.A-604G (rs27647), showed an association with insulin levels at 2-h post-oral glucose tolerance test (OGTT) (P = 0.009) in obese families. We found an association between the eating behavior "overeating" and the GHSR SNP rs2232169 (P = 0.02) in obese subjects. However, none of these associations remained significant when corrected for multiple comparisons. Replication of the nominal associations with obesity could not be confirmed in a German genome-wide association (GWA) study for rs4684677 and rs572169 polymorphisms. Our data suggest that common polymorphisms in ghrelin and its receptor genes are not major contributors to the development of polygenic obesity, although common variants may alter body weight and eating behavior and contribute to insulin resistance, in particular in the context of early-onset obesity.

Association of VNTR polymorphisms in DRD4, 5-HTT and DAT1 genes with obesity.

PubMed

Uzun, Mustafa; Saglar, Emel; Kucukyildirim, Sibel; Erdem, Beril; Unlu, Hande; Mergen, Hatice

2015-05-01

To investigate the association between VNTR polymorphisms of DRD4, DAT1 and 5-HTT genes and obesity. Peripheral blood samples of 234 obese (BMI ≥ 30) and 148 healthy individuals (BMI ≤ 25) were objected to PCR to detect the VNTR of the 2nd intron of 5-HTT, 3rd exon of DRD4 and 3'UTR of DAT1 genes. The association between obesity and genotype distributions of 5-HTT, DAT1 and DRD4 genes and between obesity and distributions of allele frequencies were tested by Chi Square (χ(2)) test and were not found statistically significant. BMI values for genotype of obese and morbidly obese (BMI > 40) individuals were analyzed by Kruskal-Wallis and not found statistically significant differences between BMI values for the most frequent genotypes of 5-HTT, DAT1 and DRD4 genes. As a conclusion, there was no association between 5-HTT, DAT1 and DRD4 genes VNTR polymorphisms and obesity.

Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction.

PubMed

Butler, Merlin G; McGuire, Austen; Manzardo, Ann M

2015-04-01

Obesity is a growing public health concern now reaching epidemic status worldwide for children and adults due to multiple problems impacting on energy intake and expenditure with influences on human reproduction and infertility. A positive family history and genetic factors are known to play a role in obesity by influencing eating behavior, weight and level of physical activity and also contributing to human reproduction and infertility. Recent advances in genetic technology have led to discoveries of new susceptibility genes for obesity and causation of infertility. The goal of our study was to provide an update of clinically relevant candidate and known genes for obesity and infertility using high resolution chromosome ideograms with gene symbols and tabular form. We used computer-based internet websites including PubMed to search for combinations of key words such as obesity, body mass index, infertility, reproduction, azoospermia, endometriosis, diminished ovarian reserve, estrogen along with genetics, gene mutations or variants to identify evidence for development of a master list of recognized obesity genes in humans and those involved with infertility and reproduction. Gene symbols for known and candidate genes for obesity were plotted on high resolution chromosome ideograms at the 850 band level. Both infertility and obesity genes were listed separately in alphabetical order in tabular form and those highlighted when involved with both conditions. By searching the medical literature and computer generated websites for key words, we found documented evidence for 370 genes playing a role in obesity and 153 genes for human reproduction or infertility. The obesity genes primarily affected common pathways in lipid metabolism, deposition or transport, eating behavior and food selection, physical activity or energy expenditure. Twenty-one of the obesity genes were also associated with human infertility and reproduction. Gene symbols were plotted on high resolution

Phospholipid biosynthesis genes and susceptibility to obesity: analysis of expression and polymorphisms.

PubMed

Sharma, Neeraj K; Langberg, Kurt A; Mondal, Ashis K; Das, Swapan K

2013-01-01

Recent studies have identified links between phospholipid composition and altered cellular functions in animal models of obesity, but the involvement of phospholipid biosynthesis genes in human obesity are not well understood. We analyzed the transcript of four phospholipid biosynthesis genes in adipose and muscle from 170 subjects. We examined publicly available genome-wide association data from the GIANT and MAGIC cohorts to investigate the association of SNPs in these genes with obesity and glucose homeostasis traits, respectively. Trait-associated SNPs were genotyped to evaluate their roles in regulating expression in adipose. In adipose tissue, expression of PEMT, PCYT1A, and PTDSS2 were positively correlated and PCYT2 was negatively correlated with percent fat mass and body mass index (BMI). Among the polymorphisms in these genes, SNP rs4646404 in PEMT showed the strongest association (p = 3.07E-06) with waist-to-hip ratio (WHR) adjusted for BMI. The WHR-associated intronic SNP rs4646343 in the PEMT gene showed the strongest association with its expression in adipose. Allele "C" of this SNP was associated with higher WHR (p = 2.47E-05) and with higher expression (p = 4.10E-04). Our study shows that the expression of PEMT gene is high in obese insulin-resistant subjects. Intronic cis-regulatory polymorphisms may increase the genetic risk of obesity by modulating PEMT expression.

Variants in the human intestinal fatty acid binding protein 2 gene in obese subjects.

PubMed

Sipiläinen, R; Uusitupa, M; Heikkinen, S; Rissanen, A; Laakso, M

1997-08-01

Fatty acid binding protein 2 gene (FABP2) has been proposed to be an important candidate gene for insulin resistance; therefore, it also could be a promising candidate gene for obesity. We screened the whole coding region of the FABP2 gene in 40 obese nondiabetic Finnish subjects. Furthermore, we investigated the effects of the codon 54 polymorphism of this gene (Ala-->Thr) on insulin levels and basal metabolic rate in 170 obese subjects. The frequencies of the variants found in exon 4 (GTA-->GTG) and 3'-noncoding region (GCGCA-->GCACA), as well as the allele frequencies for the variable lengths of the ATT repeat sequence in intron 2 did not differ between the obese subjects and nonobese controls. The frequency of threonine-encoding allele in codon 54 of the FABP2 gene did not differ between obese and control subjects (28 vs. 29%, respectively). In the obese group there were no differences in gender distribution, age, weight, body mass index, lean body mass, percentage of body fat, waist circumference, and waist-to-hip ratio among the individuals homozygous for Ala54, heterozygous for Thr54, and homozygous for Thr54-encoding alleles. Similarly, fasting serum insulin, glucose, lipids and lipoprotein concentrations, basal metabolic rate (adjusted for lean body mass and age), respiratory quotient, and rates of glucose and lipid oxidation did not differ among the groups. We conclude that obesity is not associated with specific variants in the FABP2 gene. Furthermore, the codon 54 Ala to Thr polymorphism of this gene does not influence insulin levels or basal metabolic rate in obese Finns.

Multi-variant study of obesity risk genes in African Americans: The Jackson Heart Study.

PubMed

Liu, Shijian; Wilson, James G; Jiang, Fan; Griswold, Michael; Correa, Adolfo; Mei, Hao

2016-11-30

Genome-wide association study (GWAS) has been successful in identifying obesity risk genes by single-variant association analysis. For this study, we designed steps of analysis strategy and aimed to identify multi-variant effects on obesity risk among candidate genes. Our analyses were focused on 2137 African American participants with body mass index measured in the Jackson Heart Study and 657 common single nucleotide polymorphisms (SNPs) genotyped at 8 GWAS-identified obesity risk genes. Single-variant association test showed that no SNPs reached significance after multiple testing adjustment. The following gene-gene interaction analysis, which was focused on SNPs with unadjusted p-value<0.10, identified 6 significant multi-variant associations. Logistic regression showed that SNPs in these associations did not have significant linear interactions; examination of genetic risk score evidenced that 4 multi-variant associations had significant additive effects of risk SNPs; and haplotype association test presented that all multi-variant associations contained one or several combinations of particular alleles or haplotypes, associated with increased obesity risk. Our study evidenced that obesity risk genes generated multi-variant effects, which can be additive or non-linear interactions, and multi-variant study is an important supplement to existing GWAS for understanding genetic effects of obesity risk genes. Copyright © 2016 Elsevier B.V. All rights reserved.

Obesity is associated with depot-specific alterations in adipocyte DNA methylation and gene expression.

PubMed

Sonne, Si Brask; Yadav, Rachita; Yin, Guangliang; Dalgaard, Marlene Danner; Myrmel, Lene Secher; Gupta, Ramneek; Wang, Jun; Madsen, Lise; Kajimura, Shingo; Kristiansen, Karsten

2017-04-03

The present study aimed to identify genes exhibiting concomitant obesity-dependent changes in DNA methylation and gene expression in adipose tissues in the mouse using diet-induced obese (DIO) C57BL/6J and genetically obese ob/ob mice as models. Mature adipocytes were isolated from epididymal and inguinal adipose tissues of ob/ob and DIO C57BL/6J mice. DNA methylation was analyzed by MeDIP-sequencing and gene expression by microarray analysis. The majority of differentially methylated regions (DMRs) were hypomethylated in obese mice. Global methylation of long interspersed elements indicated that hypomethylation did not reflect methyl donor deficiency. In both DIO and ob/ob mice, we observed more obesity-associated methylation changes in epididymal than in inguinal adipocytes. Assignment of DMRs to promoter, exon, intron and intergenic regions demonstrated that DIO-induced changes in DNA methylation in C57BL/6J mice occurred primarily in exons, whereas inguinal adipocytes of ob/ob mice exhibited a higher enrichment of DMRs in promoter regions than in other regions of the genome, suggesting an influence of leptin on DNA methylation in inguinal adipocytes. We observed altered methylation and expression of 9 genes in epididymal adipocytes, including the known obesity-associated genes, Ehd2 and Kctd15, and a novel candidate gene, Irf8, possibly involved in immune type 1/type2 balance. The use of 2 obesity models enabled us to dissociate changes associated with high fat feeding from those associated with obesity per se. This information will be of value in future studies on the mechanisms governing the development of obesity and changes in adipocyte function associated with obesity.

Experimental hyperthyroidism decreases gene expression and serum levels of adipokines in obesity.

PubMed

Luvizotto, Renata de Azevedo Melo; do Nascimento, André Ferreira; de Síbio, Maria Teresa; Olímpio, Regiane Marques Castro; Conde, Sandro José; Lima-Leopoldo, Ana Paula; Leopoldo, André Soares; Cicogna, Antonio Carlos; Nogueira, Célia Regina

2012-01-01

To analyze the influence of hyperthyroidism on the gene expression and serum concentration of leptin, resistin, and adiponectin in obese animals. Male Wistar rats were randomly divided into two groups: control (C)-fed with commercial chow ad libitum-and obese (OB)-fed with a hypercaloric diet. After group characterization, the OB rats continued receiving a hypercaloric diet and were randomized into two groups: obese animals (OB) and obese with 25 μg triiodothyronine (T(3))/100 BW (OT). The T(3) dose was administered every day for the last 2 weeks of the study. After 30 weeks the animals were euthanized. Samples of blood and adipose tissue were collected for biochemical and hormonal analyses as well as gene expression of leptin, resistin, and adiponectin. T(3) treatment was effective, increasing fT(3) levels and decreasing fT(4) and TSH serum concentration. Administration of T(3) promotes weight loss, decreases all fat deposits, and diminishes serum levels of leptin, resistin, and adiponectin by reducing their gene expression. Our results suggest that T(3) modulate serum and gene expression levels of leptin, resistin, and adiponectin in experimental model of obesity, providing new insights regarding the relationship between T(3) and adipokines in obesity.

Experimental Hyperthyroidism Decreases Gene Expression and Serum Levels of Adipokines in Obesity

PubMed Central

Luvizotto, Renata de Azevedo Melo; do Nascimento, André Ferreira; de Síbio, Maria Teresa; Olímpio, Regiane Marques Castro; Conde, Sandro José; Lima-Leopoldo, Ana Paula; Leopoldo, André Soares; Cicogna, Antonio Carlos; Nogueira, Célia Regina

2012-01-01

Aims. To analyze the influence of hyperthyroidism on the gene expression and serum concentration of leptin, resistin, and adiponectin in obese animals. Main Methods. Male Wistar rats were randomly divided into two groups: control (C)—fed with commercial chow ad libitum—and obese (OB)—fed with a hypercaloric diet. After group characterization, the OB rats continued receiving a hypercaloric diet and were randomized into two groups: obese animals (OB) and obese with 25 μg triiodothyronine (T3)/100 BW (OT). The T3 dose was administered every day for the last 2 weeks of the study. After 30 weeks the animals were euthanized. Samples of blood and adipose tissue were collected for biochemical and hormonal analyses as well as gene expression of leptin, resistin, and adiponectin. Results. T3 treatment was effective, increasing fT3 levels and decreasing fT4 and TSH serum concentration. Administration of T3 promotes weight loss, decreases all fat deposits, and diminishes serum levels of leptin, resistin, and adiponectin by reducing their gene expression. Conclusions. Our results suggest that T3 modulate serum and gene expression levels of leptin, resistin, and adiponectin in experimental model of obesity, providing new insights regarding the relationship between T3 and adipokines in obesity. PMID:22645452

Behavioral science and the study of gene-nutrition and gene-physical activity interactions in obesity research.

PubMed

Faith, Myles S

2008-12-01