Obesity Risk Variants Research Articles

Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment.

Increasing evidence points toward epigenetic variants as a risk factor for developing obesity. We analyzed DNA methylation of the POMC (pro-opiomelanocortin) gene, which is pivotal for satiety regulation. We identified sex-specific and nongenetically determined POMC hypermethylation associated with a 1.4-fold (confidence interval, 1.03 to 2.04) increased individual risk of developing obesity. To investigate the early embryonic establishment of POMC methylation states, we established a human embryonic stem cell (hESC) model. Here, hESCs (WA01) were transferred into a naïve state, which was associated with a reduction of DNA methylation. Naïve hESCs were differentiated via a formative state into POMC-expressing hypothalamic neurons, which was accompanied by re-establishment of DNA methylation patterning. We observed that reduced POMC gene expression was associated with increased POMC methylation in POMC-expressing neurons. On the basis of these findings, we treated POMC-hypermethylated obese individuals (n = 5) with an MC4R agonist and observed a body weight reduction of 4.66 ± 2.16% (means ± SD) over a mean treatment duration of 38.4 ± 26.0 weeks. In summary, we identified an epigenetic obesity risk variant at the POMC gene fulfilling the criteria for a metastable epiallele established in early embryonic development that may be addressable by MC4R agonist treatment to reduce body weight.

A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress.

Obesity and diabetes have strong heritable components, yet the genetic contributions to these diseases remain largely unexplained. In humans, a missense variant in Creb3 regulatory factor (CREBRF) [rs373863828 (p.Arg457Gln); CREBRFR457Q] is strongly associated with increased odds of obesity but decreased odds of diabetes. Although virtually nothing is known about CREBRF’s mechanism of action, emerging evidence implicates it in the adaptive transcriptional response to nutritional stress downstream of TORC1. The objectives of this study were to generate a murine model with knockin of the orthologous variant in mice (CREBRFR458Q) and to test the hypothesis that this CREBRF variant promotes obesity and protects against diabetes by regulating energy and glucose homeostasis downstream of TORC1. To test this hypothesis, we performed extensive phenotypic analysis of CREBRFR458Q knockin mice at baseline and in response to acute (fasting/refeeding), chronic (low- and high-fat diet feeding), and extreme (prolonged fasting) nutritional stress as well as with pharmacological TORC1 inhibition, and aging to 52 weeks. The results demonstrate that the murine CREBRFR458Q model of the human CREBRFR457Q variant does not influence energy/glucose homeostasis in response to these interventions, with the exception of possible greater loss of fat relative to lean mass with age. Alternative preclinical models and/or studies in humans will be required to decipher the mechanisms linking this variant to human health and disease.

Interaction of FTO rs9939609 and the native American-origin ABCA1 p.Arg230Cys with circulating leptin levels in Mexican adolescents diagnosed with eating disorders: Preliminary results

Eating disorders (ED) are characterized by disruption of eating behaviour and alteration of food intake. Leptin, is one of the main hormones that modulate food intake and are altered in individuals diagnosed with ED. Genetic risk variants for obesity, like those reported inFTO and ABCA1, have also been associated to ED disorders. The present study aimed to analysed leptin circulating levels and the interaction between obesity-risk variants in FTO and ABCA1, in adolescents diagnosed with ED. A total of 99 individuals diagnosed with ED were genotype using Taqman probes for FTO (rs9939609) and ABCA1 (p.Arg230Cys, rs9282541). Commercial enzyme-linked immunosorbent assays were utilized to determined circulating leptin. Differences in leptin concentration were analysed by t-Student or ANOVA test. Gene-gene interaction were analysed using general estimation equations. Circulating leptin levels differed between the three diagnostic groups, lead by individuals diagnosed with binge eating-disorder. In individuals with more than 3 of episodes of binge-eating per week having the highest leptin levels. Also, we found that carriers of both risk alleles had the highest leptin levels. Our observations found an interaction between FTO rs9969609 and the native American-origin ABCA1 p.Arg230Cys to modulate circulating leptin levels in Mexican adolescents diagnosed with eating-disorders.

IRX5 regulates adipocyte amyloid precursor protein and mitochondrial respiration in obesity.

ObjectiveA causal obesity risk variant in the FTO locus was recently shown to inhibit adipocyte thermogenesis via increased adipose expression of the homeobox transcription factors IRX3 and IRX5. However, causal effects of IRX5 on fat storage remain to be shown in vivo, and discovery of downstream mediators may open new therapeutic avenues.Methods17 WT and 13 Irx5 knockout (KO) mice were fed low-fat control (Ctr) or high-fat (HF) diet for 10 weeks. Body weight, energy intake and fat mass were measured. Irx5-dependent gene expression was explored by transcriptome analysis of epididymal white adipose tissue (eWAT), confirmatory obesity-dependent expression in human adipocytes in vivo, and in vitro knock-down, overexpression and transcriptional activation assays.ResultsIrx5 knock-out mice weighed less, had diminished fat mass, and were protected from diet-induced fat accumulation. Key adipose mitochondrial genes Pparγ coactivator 1-alpha (Pgc-1α) and uncoupling protein 1 (Ucp1) were upregulated, and a gene network centered on amyloid precursor protein (App) was downregulated in adipose tissue of knock-out mice and in isolated mouse adipocytes with stable Irx5 knock-down. An APP-centered network was also enriched in isolated adipocytes from obese compared to lean humans. IRX5 overexpression increased APP promoter activity and both IRX5 and APP inhibited transactivation of PGC-1α and UCP1. Knock-down of Irx5 or App increased mitochondrial respiration in adipocytes.ConclusionIrx5-KO mice were protected from obesity and this can partially be attributed to reduced adipose App and improved mitochondrial respiration. This novel Irx5-App pathway in adipose tissue is a possible therapeutic entry point against obesity.

Molecular Profiling of Human Induced Pluripotent Stem Cell-Derived Hypothalamic Neurones Provides Developmental Insights into Genetic Loci for Body Weight Regulation.

Recent data suggest that common genetic risks for metabolic disorders such as obesity may be human-specific and exert effects via the central nervous system. To overcome the limitation of human tissue access for study, we have generated induced human pluripotent stem cell (hiPSC)-derived neuronal cultures that recapture many features of hypothalamic neurones within the arcuate nucleus. In the present study, we have comprehensively characterised this model across development, benchmarked these neurones to invivo events, and demonstrate a link between obesity risk variants and hypothalamic development. The dynamic transcriptome across neuronal maturation was examined using microarray and RNA sequencing methods at nine time points. K-means clustering of the longitudinal data was conducted to identify co-regulation and microRNA control of biological processes. The transcriptomes were compared with those of 103 samples from 13 brain regions reported in the Genotype-Tissue Expression database (GTEx) using principal components analysis. Genes with proximity to body mass index (BMI)-associated genetic variants were mapped to the developmentally expressed genesets, and enrichment significance was assessed with Fisher's exact test. The human neuronal cultures have a transcriptional and physiological profile of neuropeptide Y/agouti-related peptide arcuate nucleus neurones. The neuronal transcriptomes were highly correlated with adult hypothalamus compared to any other brain region from the GTEx. Also, approximately 25% of the transcripts showed substantial changes in expression across neuronal development and potential co-regulation of biological processes that mirror neuronal development invivo. These developmentally expressed genes were significantly enriched for genes in proximity to BMI-associated variants. We confirmed the utility of this invitro human model for studying the development of key hypothalamic neurones involved in energy balance and show that genes at loci associated with body weight regulation may share a pattern of developmental regulation. These data support the need to investigate early development to elucidate the human-specific central nervous system pathophysiology underlying obesity susceptibility.

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?

BackgroundGenome-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.AimWe addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children.ResultsExpression 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.ConclusionOne 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.

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

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 depression status. Our data support the view that the association between obesity and major depressive disorder at the observational level may be explained, at least in part, by shared genetic factors.

Commentary: FTO obesity variant circuitry and adipocyte browning in humans.

Commentary: FTO obesity variant circuitry and adipocyte browning in humans.

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

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.

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

BackgroundBody 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.MethodsWe 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.ResultsWe 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.ConclusionsIn 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-015-0609-4) contains supplementary material, which is available to authorized users.

FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet.

While overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity risk variant in the FTO gene (rs1421085 single nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging (BLSA), one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high calorie foods during aging.

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

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.

Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations

Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993-2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987-1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991-1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10(-5)) and inversely associated with percentage of calories derived from carbohydrate (βmeta = -0.2796 (standard error, 0.0709); P = 8 × 10(-5)). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)(2)) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m(2), 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake.

Common variants near BDNF and SH2B1 show nominal evidence of association with snacking behavior in European populations

We investigated the effect of 24 obesity-predisposing single nucleotide polymorphisms (SNPs), separately and in combination, on snacking behavior in three European populations. The 24 SNPs were genotyped in 7,502 subjects (1,868 snackers and 5,634 non-snackers). We tested the hypothesis that obesity risk variants or a genetic risk score increases snacking using a logistic regression adjusted for sex, age, and body mass index. The obesity genetic risk score was not associated with snacking (odds ratio (OR) = 1.00 [0.98-1.02], P value = 0.48). The obesity risk variants of two SNPs (rs925946 and rs7498665) close to the BDNF and SH2B1 genes showed nominal evidence of association with increased snacking (OR = 1.09 [1.01-1.17], P value = 0.0348 and OR = 1.11 [1.04-1.19], P value = 0.00703, respectively) but did not survive Bonferroni corrections for multiple testing. The associations of rs925946 and rs7498665 obesity risk variants with increased BMI (β = 0.180 [0.022-0.339], P value = 0.0258 and β = 0.166 [0.019-0.313], P value = 0.0271, respectively) were slightly attenuated after adjusting for snacking (β = 0.151 [-0.006 to 0.309], P value = 0.0591 and β = 0.152 [0.006-0.297], P value = 0.0413). Our data suggest that genetic predisposition to obesity does not significantly contribute to snacking behavior. The nominal associations of rs925946 and rs7498665 obesity risk variants near the BDNF and SH2B1 genes with increased snacking deserve further investigation.

The Influence of Obesity-Related Single Nucleotide Polymorphisms on BMI Across the Life Course

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18–100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18–25 years), adulthood (ages 26–49 years), middle-age adulthood (ages 50–69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m2, respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.

Susceptibility variants for obesity and colorectal cancer risk: The multiethnic cohort and PAGE studies

Obesity is a leading contributor to colorectal cancer risk. We investigated whether the risk variants identified in genome-wide association studies of body mass index (BMI) and waist size are associated with colorectal cancer risk, independently of the effect of obesity phenotype due to a shared etiology. Twenty-four single nucleotide polymorphisms (SNPs) in 15 loci (BDNF, FAIM2, FTO, GNPDA2, KCTD15, LYPLAL1, MC4R, MSRA, MTCH2, NEGR1, NRXN3, SEC16B, SH2B1, TFAP2B and TMEM18) were genotyped in a case-control study of 2,033 colorectal cancer cases and 9,640 controls nested within the multiethnic cohort study, as part of the population architecture using genomics and epidemiology consortium. Risk alleles for two obesity SNPs were associated with colorectal cancer risk--KCTD15 rs29941 [odds ratio (OR) for C allele = 0.90, 95% confidence interval (CI) 0.83-0.98; p = 0.01] and MC4R rs17782313 (OR for C allele = 1.12, 95% CI 1.02-1.22; p = 0.02). These associations were independent of the effect of BMI. However, none of the results remained significant after adjustment for multiple comparisons. No heterogeneity was observed across race/ethnic groups. Our findings suggest that the obesity risk variants are not likely to affect the risk of colorectal cancer substantially.

No association of risk variants for diabetes and obesity with breast cancer: the Multiethnic Cohort and PAGE studies.

Body mass index is an established risk factor for postmenopausal breast cancer. Epidemiologic studies have also reported a positive association between type 2 diabetes (T2D) and breast cancer risk. To investigate a genetic basis linking these common phenotypes with breast cancer, we tested 31 common variants for T2D and obesity in a case-control study of 1,915 breast cancer cases and 2,884 controls nested within the Multiethnic Cohort (MEC) study. Following adjustment for multiple tests, we found no significant association between any variant and breast cancer risk. Summary scores comprising the numbers of risk alleles for T2D and/or obesity were also not found to be significantly associated with breast cancer risk. Our findings provide no evidence for association between established T2D and/or obesity risk variants and breast cancer risk among women of various ethnicities. These results suggest that the potential for a shared biology between T2D/obesity and breast cancer is not due to pleiotropic effects of these risk variants.