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Objective: This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within-pair ΔBMI ≥ 3 kg/m 2 )., Methods: Together, 3227 like-sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<-2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms., Results: In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co-twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co-twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3-4.8)., Conclusions: Categorizing BMI as below, within, or above polygenic risk score-predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset ( ~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions., (© 2023. The Author(s).)

Background: Anthropometric measures show high heritability, and genetic correlations have been found between obesity-related traits. However, we lack a comprehensive analysis of the genetic background of human body morphology using detailed anthropometric measures., Methods: Height, weight, 7 skinfold thicknesses, 7 body circumferences and 4 body diameters (skeletal breaths) were measured in 214 pairs of twin children aged 3-18 years (87 monozygotic pairs) in the Autonomous Region of Madeira, Portugal. Factor analysis (Varimax rotation) was used to analyze the underlying structure of body physique. Genetic twin modeling was used to estimate genetic and environmental contributions to the variation and co-variation of the anthropometric traits., Results: Together, two factors explained 80% of the variation of all 22 anthropometric traits in boys and 73% in girls. Obesity measures (body mass index, skinfold thickness measures, as well as waist and hip circumferences) and limb circumferences loaded most strongly on the first factor, whereas height and body diameters loaded especially on the second factor. These factors as well as all anthropometric measures showed high heritability (80% or more for most of the traits), whereas the rest of the variation was explained by environmental factors not shared by co-twins. Obesity measures showed high genetic correlations (0.75-0.98). Height showed the highest genetic correlations with body diameter measures (0.58-0.76). Correlations between environmental factors not shared by co-twins were weaker than the genetic correlations but still substantial. The correlation patterns were roughly similar in boys and girls., Conclusions: Our results show high genetic correlations underlying the human body physique, suggesting that there are sets of genes widely affecting anthropometric traits. Better knowledge of these genetic variants can help to understand the development of obesity and other features of the human physique., (© 2023. The Author(s).)

Background: Living in single parent and blended families or as an only child-compared to living in two-parent biological families or with siblings, respectively-is associated with a higher body mass index (BMI) in cross-sectional studies. However, longitudinal research addressing the children's BMI in this context is scarce. Further, little is known about the association between family structure and metabolic health., Objectives: This study aimed at investigating the association between both aspects of family structure with BMI and a metabolic score (MetS)., Methods: Cross-sectional data from 7804 children participating in the European multi-center I.Family study (2013/2014) and longitudinal data from 5621 children who also participated previously in the IDEFICS study (2007-2010) were used. Family structure was assessed by a detailed interview. BMI z-score and the MetS were based on measured anthropometry, blood pressure, high-density lipoprotein, blood glucose, and triglycerides. Linear regressions were performed to model associations between family structure with BMI and MetS., Results: Children from single-parent families had higher BMI z-scores in the cross-sectional (β = 0.09, 95% confidence interval [CI]: 0.001 to 0.18) and longitudinal analyses compared to those from two-parent families. Cross-sectionally, the number of siblings was associated with lower BMI z-scores (β = -0.07, 95% CI: -0.10 to -0.03) and lower MetS (β = -0.14, 95% CI: -0.26 to -0.01). Longitudinally, only children between baseline and follow-up had higher BMI z-scores at follow-up (β = 0.07, 95% CI: 0.01 to 0.14) compared to stable siblings., Conclusion: Obesity prevention measures should focus on single-parent households and families with an only child., (© 2022 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: The heritability of traits such as body mass index (BMI), a measure of obesity, is generally estimated using family and twin studies, and increasingly by molecular genetic approaches. These studies generally assume that genetic effects are uniform across all trait values, yet there is emerging evidence that this may not always be the case., Method/subjects: This paper analyzes twin data using a recently developed measure of heritability called the heritability curve. Under the assumption that trait values in twin pairs are governed by a flexible Gaussian mixture distribution, heritability curves may vary across trait values. The data consist of repeated measures of BMI on 1506 monozygotic (MZ) and 2843 like-sexed dizygotic (DZ) adult twin pairs, gathered from multiple surveys in older Finnish Twin Cohorts., Results: The heritability curve and BMI value-specific MZ and DZ pairwise correlations were estimated, and these varied across the range of BMI. MZ correlations were highest at BMI values from 21 to 24, with a stronger decrease for women than for men at higher values. Models with additive and dominance effects fit best at low and high BMI values, while models with additive genetic and common environmental effects fit best in the normal range of BMI., Conclusions: We demonstrate that twin and molecular genetic studies need to consider how genetic effects vary across trait values. Such variation may reconcile findings of traits with high heritability and major differences in mean values between countries or over time., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

We analyzed the contribution of genetic factors on the association between puberty timing and body mass index (BMI) using longitudinal data and two approaches: (i) genetic twin design and (ii) polygenic scores (PGS) of obesity indices. Our data were derived from Finnish cohorts: 9080 twins had information on puberty timing and BMI and 2468 twins also had genetic data. Early puberty timing was moderately associated with higher BMI in childhood in both boys and girls; in adulthood these correlations were weaker and largely disappeared after adjusting for childhood BMI. The largest proportion of these correlations was attributable to genetic factors. The higher PGSs of BMI and waist circumference were associated with earlier timing of puberty in girls, whereas weaker associations were found in boys. Early puberty is not an independent risk factor for adult obesity but rather reflects the association between puberty timing and childhood BMI contributed by genetic predisposition., (© 2022. The Author(s).)

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

As the number of obese people is globally increasing, reports about the putative protective effect of obesity in life-threatening diseases, such as subarachnoid hemorrhage (SAH), are gaining more interest. This theory-the obesity paradox-is challenging to study, and the impact of obesity has remained unclear in survival of several critical illnesses, including SAH. Thus, we performed a systematic review to clarify the relation of obesity and SAH mortality. Our study protocol included systematic literature search in PubMed, Scopus, and Cochrane library databases, whereas risk-of-bias estimation and quality of each selected study were evaluated by the Critical Appraisal Skills Program and Cochrane Collaboration guidelines. A directional power analysis was performed to estimate sufficient sample size for significant results. From 176 reviewed studies, six fulfilled our eligibility criteria for qualitative analysis. One study found paradoxical effect (odds ratio, OR = 0.83 (0.74-0.92)) between morbid obesity (body mass index (BMI) > 40) and in-hospital SAH mortality, and another study found the effect between continuously increasing BMI and both short-term (OR = 0.90 (0.82-0.99)) and long-term SAH mortalities (OR = 0.92 (0.85-0.98)). However, according to our quality assessment, methodological shortcomings expose all reviewed studies to a high-risk-of-bias. Even though two studies suggest that obesity may protect SAH patients from death in the acute phase, all reviewed studies suffered from methodological shortcomings that have been typical in the research field of obesity paradox. Therefore, no definite conclusions could be drawn.

Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of TGM family members to acquired weight gain in a rare set of monozygotic (MZ) twins discordant for body weight, i.e., heavy-lean twin pairs. We report that F13A1 is the only TGM family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte F13A1 to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of F13A1 to adipocyte size in the MZ twins via a previously conducted TWA study that was further mined for genes that specifically associate to hypertrophic adipocytes. We report that differential expression of F13A1 (ΔHeavy-Lean) associated with 47 genes which were linked via gene enrichment analysis to immune response, leucocyte and neutrophil activation, as well as cytokine response and signaling. Our work brings further support to the role of F13A1 in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation.

Background: Obesity susceptibility genes are highly expressed in the brain suggesting that they might exert their influence on body weight through eating-related behaviors., Objectives: To examine whether the genetic susceptibility to obesity is mediated by eating behavior patterns., Methods: Participants were 3977 twins (33% monozygotic, 56% females), aged 31-37 y, from wave 5 of the FinnTwin16 study. They self-reported their height and weight, eating behaviors (15 items), diet quality, and self-measured their waist circumference (WC). For 1055 twins with genome-wide data, we constructed a polygenic risk score for BMI (PRSBMI) using almost 1 million single nucleotide polymorphisms. We used principal component analyses to identify eating behavior patterns, twin modeling to decompose correlations into genetic and environmental components, and structural equation modeling to test mediation models between the PRSBMI, eating behavior patterns, and obesity measures., Results: We identified 4 moderately heritable (h2 = 36-48%) eating behavior patterns labeled "snacking," "infrequent and unhealthy eating," "avoidant eating," and "emotional and external eating." The highest phenotypic correlation with obesity measures was found for the snacking behavior pattern (r = 0.35 for BMI and r = 0.32 for WC; P < 0.001 for both), largely due to genetic factors in common (bivariate h2 > 70%). The snacking behavior pattern partially mediated the association between the PRSBMI and obesity measures (βindirect = 0.06; 95% CI: 0.02, 0.09; P = 0.002 for BMI; and βindirect = 0.05; 95% CI: 0.02, 0.08; P = 0.003 for WC)., Conclusions: Eating behavior patterns share a common genetic liability with obesity measures and are moderately heritable. Genetic susceptibility to obesity can be partly mediated by an eating pattern characterized by frequent snacking. Obesity prevention efforts might therefore benefit from focusing on eating behavior change, particularly in genetically susceptible individuals., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Background and Aims: Plasma apolipoprotein C3 (ApoC3) is associated with higher plasma triglyceride and type 2 diabetes incidence. We evaluated whether body mass index (BMI) or glucose metabolism were associated with ApoC3 in healthy monozygotic (MZ) twins., Methods and Results: Forty-seven MZ twin-pairs (20 man, 27 women), aged 23-42 years, were divided in subgroups according to discordance or concordance for (a) BMI (within-pair difference (Δ) in BMI≥3.0 or<3.0 kg/m 2 ), or (b) 2-h glucose iAUC, during oral glucose tolerance test (ΔGlucose iAUC ≥97.5 or<97.5 mmol × 120 minutes). Within these discordant or concordant subgroups, we tested (Wilcoxon signed-rank test) co-twin differences in ApoC3, adiposity measures, insulin-resistance and beta-cell function indices, and plasma and lipoprotein lipids. In BMI-Discordant (p = 0.92) or BMI-Concordant (p = 0.99) subgroups, ApoC3 did not differ between leaner and heavier co-twins. In the Glucose-Discordant subgroup, ApoC3 was significantly higher in twins with higher Glucose iAUC than in their co-twins with the lower Glucose iAUC (10.03 ± 0.78 vs. 8.48 ± 0.52 mg/dl; M ± SE; p = 0.032). Co-twins with higher Glucose iAUC also had higher waist circumference, body fat percentage, liver fat content, worse insulin-sensitivity and beta-cell function and higher cholesterol and triglyceride in plasma VLDL, IDL, and LDL. In Glucose-Concordant twin-pairs, no significant differences were observed in the explored variables. In all twin-pairs, ΔApoC3 correlated with Δ in lipids and glucose metabolism variables, the closest relationship being between ΔApoC3 and ΔVLDL triglyceride (r = 0.74, p < 0.0001)., Conclusions: While ApoC3 was not related to acquired differences in BMI, it associated with early dysregulation of glucose metabolism independently of obesity and genetic background., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest associated with this manuscript., (Copyright © 2019. Published by Elsevier B.V.)

Background: There has been an increase in children growing up in non-traditional families, such as single-parent and blended families. Children from such families have a higher prevalence of obesity and poorer health outcomes, but research on the relationship with obesogenic behaviours is limited., Objectives: Therefore, the aim of this study was to investigate whether there are associations between family structures and obesogenic behaviours and related family rules in European children and adolescents., Methods: The sample included 7664 children (mean age ± SD: 10.9 ± 2.9) from 4923 families who were participants of the multi-centre I.Family study (2013/2014) conducted in 8 European countries. Family structure was assessed by a detailed interview on kinship and household. Obesogenic behaviours (screen time, sleep duration, consumption of sugar-sweetened beverages (SSBs)) and family rules (rules for computer and television, bedtime routine, availability of SSBs during meals) were determined by standardized questionnaires. Multilevel mixed-effects linear and logistic regression models were used to model the associations of family structure with obesogenic behaviours and family rules. Sex, age, parental education level, number of children and adults in the household and BMI z-score were covariates in the models. Two-parent biological families were set as the reference category., Results: Children from single-parent families were less likely to have family rules regarding screen time (OR: 0.62, 95% CI: 0.40-0.94, p = 0.026) with higher reported hours of screen time per week (β = 2.70 h/week, 95% CI: 1.39-4.00, p < 0.001). The frequency of weekly SSB consumption differed by family structure in a sex-specific manner: girls from single-parent (β = 3.19 frequency/week, 95% CI: 0.91-5.47, p = 0.006) and boys from blended/adoptive families (β = 3.01 frequency/week, 95% CI: 0.99-5.03, p = 0.004) consumed more SSBs. Sleep duration, bedtime routines and availability of SSBs during meals did not differ between children from these family structures. Parental education did not modify any of these associations., Conclusions: Parents in non-traditional family structures appear to experience more difficulties in restricting screen time and the intake of SSBs in their children than parents in traditional two-parent family structures. Our findings therefore suggest that additional support and effective strategies for parents in non-traditional families may help to reduce obesogenic behaviours in children from such family types.

We constructed a food-based diet quality score (DQS) and examined its association with obesity measures, eating styles and nutrient intakes. Participants were 3592 individuals (764 dizygotic [DZ] and 430 monozygotic [MZ] twin pairs) from the FinnTwin16 study. The DQS (0-12 points) was constructed from a short 14 item food frequency questionnaire. Anthropometric measures and eating styles were self-reported. Nutrient intakes were calculated from food diaries completed in a subsample of 249 individuals (45 same-sex DZ and 60 MZ twin pairs). Twins were analyzed both as individuals and as twin pairs. The DQS was inversely associated with body mass index (β = -0.12, per one-unit increase in DQS, p < 0.001), waist circumference (β = -0.34, p < 0.001), obesity (odds ratio [OR]: 0.95, p = 0.004) and abdominal obesity (OR: 0.88, p < 0.001), independent of sex, age, physical activity and education. A higher DQS was associated with health-conscious eating, having breakfast, less snacking, fewer evening meals, and a higher frequency and regularity of eating. The DQS was positively correlated with the intakes of protein, fiber and magnesium and negatively correlated with the intakes of total fat, saturated fat and sucrose. Within twin pairs, most of the associations between the DQS with eating styles and some nutrients remained, but the DQS was not associated with obesity measures within twin pairs. The DQS is an easy-to-use tool for ranking adults according to diet quality and shows an association with obesity measures, eating styles and key nutrients in the expected direction., Competing Interests: The authors declare no conflict of interest.

We aimed to study the eating behavioral traits that associate with body mass index (BMI) among BMI-discordant twin pairs. This cross-sectional study examined self-reported eating behaviors in 134 healthy young adult twin pairs (57 monozygotic [MZ] and 77 same-sex dizygotic [DZ]), of whom 29 MZ and 46 DZ pairs were BMI discordant (BMI difference ≥ 3 kg/m2). In both MZ and DZ BMI-discordant pairs, the heavier co-twins reported being less capable of regulating their food intake optimally than their leaner co-twins, mainly due to 'frequent overeating'. Furthermore, the heavier co-twins reported augmented 'disinhibited eating', 'binge-eating scores' and 'body dissatisfaction'. The twins agreed more frequently that the heavier co-twins (rather than the leaner co-twins) ate more food in general, and more fatty food, in particular. No significant behavioral differences emerged in BMI-concordant twin pairs. Overeating - measured by 'frequent overeating', 'disinhibited eating' and 'binge-eating score' - was the main behavioral trait associated with higher BMI, independent of genotype and shared environment.

Purpose: The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation., Experimental Design: The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Δ) in BMI > 3 kg m -2 , n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Δliver fat > 2%, n = 12) and liver fat concordant pairs (Δliver fat < 2%, n = 14), measured by magnetic resonance spectroscopy., Results: Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids., Conclusions and Clinical Relevance: The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Obesity is related to a myriad of cardiometabolic outcomes, each of which may have a specific metabolomic signature and a genetic basis. We identified plasma metabolites associating with different cardiometabolic risk factors (adiposity, cholesterol, insulin resistance, and inflammation) in monozygotic (MZ) twins. Additionally, we assessed if metabolite profiling can identify subgroups differing by cardiometabolic risk factors., Methods: We quantified 111 plasma metabolites (Acquity UPLC-triple quadrupole mass spectrometry), and measured blood lipids, HOMA index, CRP, and adiposity (BMI, %bodyfat by DEXA, fat distribution by MRI) in 40 MZ twin pairs (mean BMI 27.9 kg/m 2 , age 30.7). We determined associations among individuals (via linear regression) between metabolites and clinical phenotypes, and assessed, with within-twin pair analysis, if these associations were free from genetic confounding. We also performed cluster analysis to identify distinct subgroups based on subjects' metabolite profiles., Results: We identified 42 metabolite-phenotype associations (FDR < 0.05), 19 remained significant after controlling for shared factors within the twin pairs. Aspartate, propionylcarnitine, tyrosine hexanoylcarnitine, and deoxycytidine associated positively with two or more adiposity measures. HDL cholesterol (HDL-C) associated negatively and BMI positively with the most numbers of metabolites; 12 were unique for HDL-C and 3 for BMI. Metabolites associating with HDL-C had the strongest effect size. Metabolite profiling revealed two distinct subgroups of individuals, differing by 32 metabolites (p < 0.05), and by total and LDL cholesterol (LDL-C). Forty-two metabolites predicted subgroup membership in correlation with total cholesterol and 45 metabolites predicted subgroup membership in correlation with LDL-C., Conclusions: Different fat depots share metabolites associating with general adiposity. BMI and HDL-C associated with the most pronounced and specific metabolomic signature. Metabolomics profiling can be used to identify distinct subgroups of individuals that differ by cholesterol measures. Most of the observed metabolite-phenotype associations are free of confounding by genetics and environmental factors shared by the co-twins.

Introduction: Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects., Methods: We examined this hypothesis in 1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis., Results: Hazard ratios per 5-kg/m 2 increase in BMI for dementia were 0.71 (95% confidence interval = 0.66-0.77), 0.94 (0.89-0.99), and 1.16 (1.05-1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis., Conclusions: The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Obesity and ageing are associated with lower serum testosterone levels in men. How fat distribution or adipose tissue metabolism, independent of genetic factors and age, are related to sex steroid metabolism is less clear. We studied the associations between adiposity and serum sex hormone concentrations, and mRNA expression of genes regulating sex hormone metabolism in adipose tissue in young adult male monozygotic (MZ) twin pairs. The subjects [n=18 pairs; mean age, 32 years; individual body mass indexes (BMIs) 22-36kg/m 2 ] included 9 male MZ twin pairs discordant for BMI [intra-pair difference (Δ) in BMI ≥3kg/m 2 ]. Sex steroid concentrations were determined by liquid chromatography-tandem mass spectrometry, body composition by dual-energy X-ray absorptiometry and magnetic resonance imaging, and mRNA expressions from subcutaneous adipose tissue by Affymetrix. In BMI-discordant pairs (mean ΔBMI=5.9kg/m 2 ), serum dihydrotestosterone (DHT) was lower [mean 1.9 (SD 0.7) vs. 2.4 (1.0) nmol/l, P=0.040] and mRNA expressions of DHT-inactivating AKR1C2 (P=0.021) and cortisol-producing HSD11B1 (P=0.008) higher in the heavier compared to the leaner co-twins. Serum free 17β-estradiol (E2) was higher [2.3 (0.5) vs. 1.9 (0.5) pmol/l, P=0.028], and in all twin pairs, serum E2 and estrone concentrations were higher in the heavier than in the leaner co-twins [107 (28) vs. 90 (22) pmol/l, P=0.006; and 123 (43) vs. 105 (27) pmol/l, P=0.025]. Within all twin pairs, i.e. independent of genetic effects and age, 1) the amount of subcutaneous fat inversely correlated with serum total and free testosterone, DHT, and sex hormone-binding globulin (SHBG) concentrations (P<0.01 for all), 2) intra-abdominal fat with total testosterone and SHBG (P<0.05), and 3) liver fat with SHBG (P=0.006). Also, 4) general and intra-abdominal adiposity correlated positively with mRNA expressions of AKR1C2, HSD11B1, and aromatase in adipose tissue (P<0.05). In conclusion, acquired adiposity was associated with decreased serum DHT and increased estrogen concentrations, independent of genetic factors and age. The reduction of DHT could be linked to its increased degradation (by AKR1C2 and HSD11B1) and increased estrogen levels to increased adiposity-related expression of aromatase in adipose tissue., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m 2 )], but factors modifying these variance components are poorly understood. Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity. Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs). Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI. Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population., (© 2017 American Society for Nutrition.)

Aims/hypothesis: Low mitochondrial activity in adipose tissue is suggested to be an underlying factor in obesity and its metabolic complications. We aimed to find out whether mitochondrial measures are downregulated in obesity also in isolated adipocytes., Methods: We studied young adult monozygotic (MZ) twin pairs discordant (n = 14, intrapair difference ΔBMI ≥ 3 kg/m 2 ) and concordant (n = 5, ΔBMI < 3 kg/m 2 ) for BMI, identified from ten birth cohorts of 22- to 36-year-old Finnish twins. Abdominal body fat distribution (MRI), liver fat content (magnetic resonance spectroscopy), insulin sensitivity (OGTT), high-sensitivity C-reactive protein, serum lipids and adipokines were measured. Subcutaneous abdominal adipose tissue biopsies were obtained to analyse the transcriptomics patterns of the isolated adipocytes as well as of the whole adipose tissue. Mitochondrial DNA transcript levels in adipocytes were measured by quantitative real-time PCR. Western blots of oxidative phosphorylation (OXPHOS) protein levels in adipocytes were performed in obese and lean unrelated individuals., Results: The heavier (BMI 29.9 ± 1.0 kg/m 2 ) co-twins of the discordant twin pairs had more subcutaneous, intra-abdominal and liver fat and were more insulin resistant (p < 0.01 for all measures) than the lighter (24.1 ± 0.9 kg/m 2 ) co-twins. Altogether, 2538 genes in adipocytes and 2135 in adipose tissue were significantly differentially expressed (nominal p < 0.05) between the co-twins. Pathway analysis of these transcripts in both isolated adipocytes and adipose tissue revealed that the heavier co-twins displayed reduced expression of genes relating to mitochondrial pathways, a result that was replicated when analysing the pathways behind the most consistently downregulated genes in the heavier co-twins (in at least 12 out of 14 pairs). Consistently upregulated genes in adipocytes were related to inflammation. We confirmed that mitochondrial DNA transcript levels (12S RNA, 16S RNA, COX1, ND5, CYTB), expression of mitochondrial ribosomal protein transcripts and a major mitochondrial regulator PGC-1α (also known as PPARGC1A) were reduced in the heavier co-twins' adipocytes (p < 0.05). OXPHOS protein levels of complexes I and III in adipocytes were lower in obese than in lean individuals., Conclusions/interpretation: Subcutaneous abdominal adipocytes in obesity show global expressional downregulation of oxidative pathways, mitochondrial transcripts and OXPHOS protein levels and upregulation of inflammatory pathways., Data Availability: The datasets analysed and generated during the current study are available in the figshare repository, https://dx.doi.org/10.6084/m9.figshare.3806286.v1.

Background: Obesity has been recognized as a state of subclinical inflammation resulting in a loss of insulin receptors and decreased insulin sensitivity. We here studied in vivo the role of circulating matrix metalloproteinase-8 (MMP-8) among young healthy twin adults. Also, in vitro analysis of the cleavage of human insulin receptor (INSR) by MMP-8 was investigated as well its inhibition by doxycycline and other MMP-8 inhibitor, Ilomastat/GM6001, which are broad-spectrum MMP inhibitors., Materials and Methods: We analysed serum MMP-8 levels by a time-resolved immunofluorometric assay in obese (n = 34), overweight (n = 76) and normal weight (n = 130) twin individuals. The effect of MMP-8 on INSR and the effects of synthetic MMP-8 inhibitors, doxycycline and Ilomastat/GM6001, were studied by SDS-PAGE., Results: We found that in obese individuals relative to normal weight individuals, the serum MMP-8 levels and MMP-8/TIMP-1 ratio were significantly increased (P = 0·0031 and P = 0·031, respectively). Among normal weight and obese individuals, also smoking significantly increases serum MMP-8 and MMP-8/TIMP-1 ratio. In vitro, we found that INSR was degraded by MMP-8 and this was inhibited by doxycycline and Ilomastat/GM6001., Conclusions: Obesity associated with elevated circulating MMP-8 found among young adults may contribute to progression of insulin resistance by cleaving INSR. This INSR cleavage by MMP-8 can be inhibited by synthetic MMP-8 inhibitors such as doxycycline. In addition to obesity, also smoking independently explained increased MMP-8 levels. Our results suggest that MMP-8 is an essential mediator in systemic subclinical inflammatory response in obesity, and a potential drug target., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking., Objectives: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments., Design: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling., Results: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a(2) = 0.42) and girls (a(2) = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions., Conclusions: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity., (© 2016 American Society for Nutrition.)

Context: Sirtuins (SIRTs) regulate cellular metabolism and mitochondrial function according to the energy state of the cell reflected by NAD(+) levels., Objective: Our aim was to determine whether expressions of SIRTs and NAD(+) biosynthesis genes are affected by acquired obesity and how possible alterations are connected with metabolic dysfunction while controlling for genetic and familial factors., Design and Participants: We studied a cross-sectional sample of 40 healthy pairs of monozygotic twins, including 26 pairs who were discordant for body mass index (within-pair difference > 3 kg/m(2)), from the FinnTwin12 and FinnTwin16 cohorts., Main Outcome Measures: Subcutaneous adipose tissue (SAT) transcriptomics was analyzed by using Affymetrix U133 Plus 2.0 chips, total SAT (poly-ADP) ribose polymerase (PARP) activity by an ELISA kit, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging/spectroscopy, and insulin sensitivity by an oral glucose tolerance test., Results: SIRT1, SIRT3, SIRT5, NAMPT, NMNAT2, NMNAT3, and NRK1 expressions were significantly down-regulated and the activity of main cellular NAD(+) consumers, PARPs, trended to be higher in the SAT of heavier co-twins of body mass index-discordant pairs. Controlling for twin-shared factors, SIRT1, SIRT3, NAMPT, NMNAT3, and NRK1 were significantly negatively correlated with adiposity, SIRT1, SIRT5, NMNAT2, NMNAT3, and NRK1 were negatively correlated with inflammation, and SIRT1 and SIRT5 were positively correlated with insulin sensitivity. Expressions of genes involved in mitochondrial unfolded protein response were also significantly down-regulated in the heavier co-twins., Conclusions: Our data highlight a strong relationship of reduced NAD(+)/SIRT pathway expression with acquired obesity, inflammation, insulin resistance, and impaired mitochondrial protein homeostasis in SAT.

Objective: Some studies indicate an association between napping and increased risk of type 2 diabetes. We studied this prospectively in a sample representative of general population., Methods: A questionnaire was administered to the Finnish Twin Cohort in 1990 (response rate 77%, age 33-60 years). The study population included 12,244 subjects who replied to the question "Do you sleep during the daytime (take naps)?" with five response alternatives ranging from "no need" to "every or almost every day." Information on incident cases of diabetes was obtained by linkage to nationwide registers. Logistic regression models were used to obtain odds ratios (ORs) (95% confidence intervals) for incident type 2 diabetes risk in 1991-2004 by napping category. Adjustments were made for 11 socio-demographic and lifestyle covariates. For subjects aged 33-45 years at baseline, a questionnaire in 2011 provided information on prevalent diabetes., Results: Thirty-four per cent had no need for napping, and 15% did so on ≥3 days weekly. There were 356 incident type 2 diabetes cases during the follow-up. Using the 'no need' category as the reference, the risk of type 2 diabetes was significantly increased only among those napping most frequently [OR 1.86 (1.29-2.67), age- and sex-adjusted]. After adjusting for other covariates, the results were essentially the same, but when adjusted for body mass index, the association decreased (to about 1.3) and was statistically non-significant. Analysis of 2011 self-reported type 2 diabetes was in line with the register data., Conclusions: Frequent napping is associated with future risk of type 2 diabetes. This association is largely explained by obesity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The mechanisms through which genes influence body weight are not well understood, but appetite has been implicated as one mediating pathway. Here we use data from two independent population-based Finnish cohorts (4632 adults aged 25-74 years from the DILGOM study and 1231 twin individuals aged 21-26 years from the FinnTwin12 study) to investigate whether two appetitive traits mediate the associations between known obesity-related genetic variants and adiposity. The results from structural equation modelling indicate that the effects of a polygenic risk score (90 obesity-related loci) on measured body mass index and waist circumference are partly mediated through higher levels of uncontrolled eating (βindirect = 0.030-0.032, P < 0.001 in DILGOM) and emotional eating (βindirect = 0.020-0.022, P < 0.001 in DILGOM and βindirect = 0.013-0.015, P = 0.043-0.044 in FinnTwin12). Our findings suggest that genetic predispositions to obesity may partly exert their effects through appetitive traits reflecting lack of control over eating or eating in response to negative emotions. Obesity prevention and treatment studies should examine the impact of targeting these eating behaviours, especially among individuals having a high genetic predisposition to obesity.

Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8-36.2 years of age, who were discordant (ΔBMI >3 kg/m(2), mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI <3 kg/m(2), n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels., (© FASEB.)

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults.

Epicardial fat with its close proximity to coronary arteries has been suggested to be a significant predictor of cardiovascular disease. We studied the relations among acquired obesity, low-grade inflammation, and genetic factors in the accumulation of epicardial fat. A rare sample (n = 15) of healthy monozygotic (MZ) twin pairs discordant for obesity (intrapair difference in body mass index ≥3 kg/m(2)) and 9 concordant MZ pairs 23 to 33 years old were examined for cardiac structure, function, epicardial fat thickness (echocardiography), abdominal subcutaneous tissue, and visceral adipose tissue (VAT), liver fat (magnetic resonance imaging/spectroscopy), and serum high-sensitivity C-reactive protein. In the entire sample, MZ cotwins were remarkably similar in most echocardiographic measurements including epicardial fat (intraclass correlation 0.63, p = 0.0004). However, in the discordant pairs, the obese cotwins (16.5 kg, 23% heavier) had 26% more epicardial fat (p = 0.0029) than nonobese cotwins. They also had significantly larger atrial and left ventricular dimensions. Epicardial fat correlated with VAT (r = 0.49, p = 0.02) in individual twins and when using intrapair differences of measurements within pairs (r = 0.39, p = 0.06). In multiple regression analyses including abdominal subcutaneous tissue, VAT, and liver fat, high-sensitivity C-reactive protein was the only factor that remained significantly associated with epicardial fat in individual twins and within pairs. In conclusion, subjects who share the same genes seem to have similar cardiac dimensions. However, acquired obesity increases epicardial fat independent of genetic factors. The close relation between epicardial fat and low-grade inflammation is likely to contribute to the development of cardiovascular disease in obesity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

To investigate how parental education modifies genetic and environmental influences on variation in BMI during adolescence, self-reported BMI at 11-12, 14, and 17 years of age was collected from a population sample of 2,432 complete Finnish twin pairs born in 1983-1987. Based on parental report, twins were divided to those with high (both parents high school graduates), mixed level (one parent a graduate, the other not), and limited (neither parent a graduate) parental education. Genetic and environmental influences on variation in BMI in different education classes were modeled using twin analysis. Heritability of BMI among 11-12-year-olds with high parental education was 85-87% whereas it was 61-68% if parental education was limited or mixed level. Common environmental effect, i.e., effect of environmental factors shared by family members, was found (17-22%) if parental education was limited or mixed level but not if it was high. With increasing parental education, common environmental variance in BMI decreased at age 14 among boys (from 22 to 3%) and girls (from 17 to 10%); heritability increased among boys from 63 to 78%, but did not change among girls. The common environmental component disappeared and heritability of BMI was larger at the age of 17 in all parental education classes. To conclude, common environment did not affect variation of adolescent BMI in high-educated families but did so in families with limited parental education. This suggests that intervention and prevention campaigns could effectively target families identified by limited parental education.

Coagulation and fibrinolytic activities are under strong genetic control. We studied the effects of acquired obesity, independent of genetic factors on coagulation and fibrinolysis activities in obesity-discordant healthy monozygotic (MZ) twin pairs. Fourteen obesity-discordant (BMI within-pair difference >3 kg/m(2)) and 10 concordant (BMI difference <2 kg/m(2)) MZ twin pairs were identified from the nationwide FinnTwin16 study. Body composition (dual-energy x-ray absorptiometry), abdominal fat distribution (magnetic resonance imaging), liver fat (magnetic resonance spectroscopy), high sensitivity C-reactive protein, insulin sensitivity (euglycemic hyperinsulinemic clamp), and a panel of different markers of blood coagulation and fibrinolysis in the fasting state were measured. Strong resemblance was observed in most coagulation factors within all twin pairs, with the intraclass correlations ranging from 0.73 to 0.97, P < 0.03. However, the activities of fibrinogen and FIX, FXI, and FXII, and plasminogen activator inhibitor-1 (PAI-1) activities were increased in the obese co-twins (P < 0.05) and strongly correlated with the measures of adiposity, inflammation, and insulin resistance (r = 0.32-0.73, P < 0.05) among the twin individuals. Intrapair differences in fibrinogen and PAI-1 correlated with those in BMI, adiposity, and fasting insulin levels (r = 0.40-0.58, P < 0.05) indicating the independent effect of obesity. Derangements of blood coagulation and fibrinolysis are present already in early adulthood in obese subjects. Acquired obesity, independent of genetic factors, increases the activities of fibrinogen and activities of FIX, FXI, FXII, and PAI-1. This study confirms the mechanisms of simultaneous activities of intrinsic coagulation factors and impaired fibrinolysis predisposing obese subjects to thrombosis.

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

Animal studies have suggested that angiopoietin-like 4 (Angptl4) regulates adiposity through central and peripheral mechanisms. The aim of this study was to investigate whether serum concentration and adipose tissue expression of Angptl4 are associated with obesity-related parameters in humans. Altogether, 75 dizygotic (DZ) and 46 monozygotic (MZ) twin pairs were studied, from the FinnTwin12 and FinnTwin16 cohorts. Among the MZ pairs, 21 were discordant for body mass index (BMI) (intra-pair BMI-difference >2.5 kg/m², age 23-33 years). Serum Angptl4 (s-Angptl4) levels were measured by ELISA, and adipose tissue gene expression was analyzed by genome-wide transcript profiling. In MZ twin pairs discordant for BMI, s-Angptl4 and adipose tissue ANGPTL4 mRNA (at-ANGPTL4) levels were significantly decreased (P = 0.04 and P = 0.03, respectively) in obese twins as compared with their nonobese cotwins. In all twins, intra-pair differences in s-Angptl4 levels were inversely correlated with intra-pair differences in BMI (r = -0.27, P = 0.003). In individual MZ twins, at-ANGPTL4 expression was inversely correlated with BMI (r = -0.44, P = 0.001) and positively correlated with at-LIPE (r = 0.24, P = 0.01) and at-ABHD5 (r = 0.41, P = 0.005) expression. Our results demonstrated that variation in Angptl4 concentration was only modestly accounted for by genetic factors and suggest a role for Angptl4 in acquired obesity in humans.

Objective: To investigate whether bacterial lipopolysaccharide (LPS) activity in human serum is associated with the components of the metabolic syndrome (MetS) in type 1 diabetic patients with various degrees of kidney disease and patients with IgA glomerulonephritis (IgAGN)., Research Design and Methods: Serum LPS activity was determined with the Limulus Amoebocyte Lysate chromogenic end point assay in type 1 diabetic patients with a normal albumin excretion rate (n = 587), microalbuminuria (n = 144), macroalbuminuria (n = 173); patients with IgAGN (n = 98); and in nondiabetic control subjects (n = 345). The relationships of the LPS/HDL ratio and MetS-associated variables were evaluated with Pearson correlation., Results: The MetS was more prevalent in type 1 diabetic patients (48%) than in patients with IgAGN (15%). Diabetic patients with macroalbuminuria had a significantly higher serum LPS/HDL ratio than patients with IgAGN. In the normoalbuminuric type 1 diabetic group, patients in the highest LPS/HDL quartile were diagnosed as having the MetS three times more frequently than patients in the lowest quartile (69 vs. 22%; P < 0.001). High LPS activity was associated with higher serum triglyceride concentration, earlier onset of diabetes, increased diastolic blood pressure, and elevated urinary excretion of monocyte chemoattractant protein-1., Conclusions: High serum LPS activity is strongly associated with the components of the MetS. Diabetic patients with kidney disease seem to be more susceptible to metabolic endotoxemia than patients with IgAGN. Bacterial endotoxins may thus play an important role in the development of the metabolic and vascular abnormalities commonly seen in obesity and diabetes-related diseases.

Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect., Competing Interests: The authors have declared that no competing interests exist.

To get beyond the "low-hanging fruits" so far identified by genome-wide association (GWA) studies, new methods must be developed in order to discover the numerous remaining genes that estimates of heritability indicate should be contributing to complex human phenotypes, such as obesity. Here we describe a novel integrative method for complex disease gene identification utilizing both genome-wide transcript profiling of adipose tissue samples and consequent analysis of genome-wide association data generated in large SNP scans. We infer causality of genes with obesity by employing a unique set of monozygotic twin pairs discordant for BMI (n = 13 pairs, age 24-28 years, 15.4 kg mean weight difference) and contrast the transcript profiles with those from a larger sample of non-related adult individuals (N = 77). Using this approach, we were able to identify 27 genes with possibly causal roles in determining the degree of human adiposity. Testing for association of SNP variants in these 27 genes in the population samples of the large ENGAGE consortium (N = 21,000) revealed a significant deviation of P-values from the expected (P = 4x10(-4)). A total of 13 genes contained SNPs nominally associated with BMI. The top finding was blood coagulation factor F13A1 identified as a novel obesity gene also replicated in a second GWA set of approximately 2,000 individuals. This study presents a new approach to utilizing gene expression studies for informing choice of candidate genes for complex human phenotypes, such as obesity., Competing Interests: The authors have declared that no competing interests exist.

Aims: The study aimed to determine whether alcohol use during late adolescence contributes to the weight gain from adolescence to young adulthood or risk of obesity or waist circumference at young adulthood., Methods: A population-based, longitudinal study of 5563 Finnish twins born in 1975-1979 and surveyed at ages 16 (T1), 17 (T2), 18 (T3) and 23-27 (T4) years. Drinking habits, height and weight were self-reported at T1, T2, T3 and T4; waist circumference was self-measured at T4. As potential confounders, we used smoking, diet, physical activity, place of residence, socio-economic status and parents' body mass index (BMI)., Results: Compared to the reference group (drinking once to twice per month), the BMI increase from T3 to T4 was less among abstaining men (-0.62 kg/m(2), (95% CI -1.04, -0.20)) and among women in those drinking less than monthly (-0.38 kg/m(2), (-0.71, -0.04)). In women, at least weekly drinking was associated with larger waist circumference (Beta 1.55 cm, (0.48, 2.61)), but this became statistically non-significant after adjusting for potential confounders. In a multilevel model for change, drinking frequency was not associated with weight change in women; in men, a negative association was seen, but it was statistically non-significant after adjusting for potential confounders., Conclusions: These results from a population-based study with a large set of confounding variables suggest that alcohol use during adolescence has at most a minor effect on weight gain or development of abdominal obesity from adolescence to young adulthood.

The objective was to examine the association between several obesity-related nongenetic behaviors and body mass index (BMI) and waist circumference (WC) in young adult twins using reports from both twins on their similarities and differences. A total of 713 monozygotic (MZ) and 698 same-sex dizygotic (DZ) twin pairs aged 22-28 years filled in structured questionnaires to compare their eating, physical activity and dieting behavior with their co-twin's behavior, and to report their own eating and exercise habits. In both MZ and DZ pairs, the co-twins for whom both twin pair members concordantly answered that this twin eats more, snacks more, eats more fatty foods and sweet and fatty delicacies, chooses less healthy foods, eats faster and exercises less, had significantly higher BMIs (0.6-2.9 kg/m(2)) and WCs (1.5-7.5 cm). Multivariate regression analysis identified co-twin differences in the amount of food consumed as the strongest independent predictor of intrapair differences in BMI (beta = 0.63 and 1.21, for MZ and DZ, respectively, p < .001) and WC (beta = 1.52 and 3.53, for MZ and DZ, respectively, p < .001). Higher leisure-time physical activity and healthier dietary choices clustered in the same subjects. The measurement of habitual dietary intake and physical activity has previously relied on subjective self-reports that are prone to misreporting. By using comparative measures within twin pairs we found that the amount of food consumed is the major contributor to obesity independent of genetic predisposition.

Background: The development of obesity is still a poorly understood process that is dependent on both genetic and environmental factors., Objective: The objective was to examine how physical activity and the proportion of energy as protein in the diet modify the genetic variation of body mass index (BMI), waist circumference, and percentage body fat., Design: Twins from Denmark (756 complete pairs) and Finland (278 complete pairs) aged 18-67 and 21-24 y, respectively, participated. The proportion of energy as protein in the diet was estimated by using food-frequency questionnaires. The participants reported the frequency and intensity of their leisure time physical activity. Waist circumference and BMI were measured. Percentage body fat was assessed in Denmark by using a bioelectrical impedance method. The data were analyzed by using gene-environment interaction models for twin data with the Mx statistical package (Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA)., Results: High physical activity was associated with lower mean values, and a high proportion of protein in the diet was associated with higher mean BMI, waist circumference, and percentage body fat and a reduction in genetic and environmental variances. Genetic modification by physical activity was statistically significant for BMI (-0.18; 95% CI: -0.31, -0.05) and waist circumference (-0.14; 95% CI: -0.22, -0.05) in the merged data. A high proportion of protein in the diet reduced genetic and environmental variances in BMI and waist circumference in Danish men but not in women or in Finnish men., Conclusions: Our results suggest that, in physically active individuals, the genetic variation in weight is reduced, which possibly suggests that physical activity is able to modify the action of the genes responsible for predisposition to obesity, whereas the protein content of the diet has no appreciable effect.

Background/aims: This study aimed to determine the heritability of serum alanine aminotransferase (S-ALT) and fasting serum insulin (fS-insulin) concentration as well as determine the association of these measures with liver fat content in young adult monozygotic (MZ) and dizygotic (DZ) twins., Methods: Three hundred and thirteen individual twins were recruited from a population-based cohort (n = 4929). The study subjects represented a wide range of body mass indexes (BMI), were free of any diseases or regular medications and had an intake of less than two drinks of alcohol/day. To verify that S-ALT is a marker of liver fat, it was measured by proton magnetic resonance spectroscopy ((1)H MRS) in 66 subjects. Heritability estimations were performed using BMI- and gender-adjusted values., Results: Intra-pair correlations were significantly higher in the MZ twins than the DZ twins for both S-ALT (0.65 for MZ and 0.04 for DZ) and fS-insulin (0.58 and 0.34, respectively). Heritability of S-ALT was 55% and that of fS-insulin 61%. In the 66 subjects S-ALT (r = 0.70 for women and r = 0.50 for men, p < or = 0.01 for both) and fS-insulin (r = 0.58 and r = 0.59, respectively, p < or = 0.01 for both) concentrations correlated significantly with liver fat content., Conclusions: These twin data suggest that approximately 60% of the variation in S-ALT, a marker of liver fat content, is genetically determined.

Ghrelin is a hormone that is involved in the regulation of food intake. Neuronal, endocrine, and genetic factors have been shown to regulate plasma ghrelin levels; but the determinants of fasting ghrelin concentrations are not yet fully understood. The main aim was to explore the roles of adiposity and genetic differences in determining fasting plasma total ghrelin levels. We measured total ghrelin levels in a population of 23 monozygotic twin pairs discordant for obesity. In addition, 2 variants of ghrelin gene, namely, Arg51Gln and Leu72Met, were genotyped in 3 populations of monozygotic twin pairs: 23 obesity-discordant, 43 lean-concordant, and 46 obesity-concordant twin pairs. In discordant twins, lean co-twins had higher fasting plasma total ghrelin levels (950 pg/mL, SD = 328 pg/mL) than obese twins (720 pg/mL, SD = 143 pg/mL; P = .003). Arg51Gln-polymorphism of the ghrelin gene was equally distributed between the twin groups. However, there were significant differences in genotype frequencies at the Leu72Met polymorphism between the discordant and obese-concordant groups (P = .003) and between the discordant and lean-concordant groups (P = .011), but not between the 2 concordant groups. In the discordant group, there were fewer Met carriers (4%) than among the obese (17%) or the lean-concordant groups (15%). Plasma total ghrelin levels are affected by acquired obesity independent of genetic background. The Leu72 allele is particularly common among monozygotic twins discordant for obesity, suggesting that this ghrelin allele is more permissive in the regulation of energy balance. The ghrelin gene may thus play a role in the regulation of variability of body weight, such that Leu72 allele carriers are more prone to weight variability in response to environmental factors.

Objectives: We studied the association of adolescent smoking with overweight and abdominal obesity in adulthood., Methods: We used the FinnTwin16, a prospective, population-based questionnaire study of 5 consecutive and complete birth cohorts of Finnish twins born between 1975 and 1979 (N = 4296) and studied at four points between the ages of 16 and 27 years to analyze the effect of adolescent smoking on abdominal obesity and overweight in early adulthood., Results: Smoking at least 10 cigarettes daily when aged 16 to 18 years increased the risk of adult abdominal obesity (odds ratio [OR]=1.77; 95% confidence interval [CI] = 1.39, 2.26). After we adjusted for confounders, the OR was 1.44 (95% CI = 1.11, 1.88), and after further adjustment for current body mass index (BMI), the OR was 1.34 (95% CI = 0.95, 1.88). Adolescent smoking significantly increased the risk of becoming overweight among women even after adjustment for possible confounders, including baseline BMI (OR = 1.74; 95% CI = 1.06, 2.88)., Conclusions: Smoking is a risk factor for abdominal obesity among both genders and for overweight in women. The prevention of smoking during adolescence may play an important role in promoting healthy weight and in decreasing the morbidity related to abdominal obesity.

Aim and Method: Cause-specific mortality was studied in relation to body mass index (BMI) and weight stability (defined as less than 1 BMI unit change during a 6-year period) in 15,424 initially healthy twin subjects from the Finnish Twin Cohort, first examined in 1975, re-examined in 1981, and then followed over 22 years (1982-2003). Additionally, death discordant twin pairs were studied to assess whether body weight differences are associated with mortality independent of childhood factors and genetic background. Deaths and cause of death were ascertained from national registries. Associations with mortality were estimated by Cox proportional hazards model for all individuals and conditional logistic regression analysis for pairwise analyses., Results: Mortality increased with increasing BMI for all causes and coronary heart disease (CHD) in men, and there were no associations for all natural causes, cerebrovascular disease, and violent deaths. After adjustment for multiple co-variates and changes in co-variates between 1975 and 1981, BMI was associated with CHD mortality in all men (hazard ratio (HR) = 1.22, 95% CI 1.06-1.41) and in men with stable weight between 1975 and 1981 (HR = 1.26, 95% CI 1.03-1.55). Overall risk of death and cause-specific mortality was not associated with BMI in women., Conclusion: Among clinically healthy subjects at low risk of death, BMI appears to be associated with CHD risk in men., (Copyright 2009 S. Karger AG, Basel.)

The persistence of obesity from early childhood to late middle age is well known. We reviewed the results from existing genetic studies on tracking of BMI to discover how much genetic and environmental factors contribute to this tracking of obesity. In total, we found 5 genetic longitudinal studies on childhood obesity and 8 on obesity in adulthood. One was an adoption study, 3 were family studies, and 9 were twin studies. All were based on Caucasian populations, and one included genetic level information (the FTO gene). Strong genetic continuity in BMI was found from early childhood to onset of adulthood. Although new genetic factors started to affect BMI during the growth period, genetic correlations remained high. Evidence of the effect of common environment on the tracking of BMI during childhood was also found. The heritability estimates reported in twin studies ranged from 0.57 to 0.86 for the trend of BMI from early adulthood to late middle age. The three family studies gave lower estimates. Important unresolved questions are the genetics of BMI change in old age, the genetics of body composition change, the genetic architecture of tracking of obesity in ethnic groups other than Caucasians, and the interplay between genes and environment underlying the development and tracking of obesity., (Copyright 2009 S. Karger AG, Basel.)

Background: The relation between body weight and energy-dense foods remains unclear., Objective: We estimated the effects of genetic and environmental factors on cognitive and emotional aspects of dieting behavior, body mass index (BMI), and responses to fatty foods and on their relations., Design: A total of 1326 adult twin persons (aged 17-82 y; 17% M and 83% F) from the United Kingdom and Finland completed the revised version of the Three-Factor Eating Questionnaire (TFEQ-R18) and reported the liking and use-frequency of 4 sweet-and-fatty and salty-and-fatty food items (6 items in the United Kingdom and 5 items in Finland). Genetic modeling was done by using linear structural equations., Results: Heritability estimates were calculated separately for the countries and sexes; they were 26-63% for cognitive restraint, 45-69% for uncontrolled eating, and 9-45% for emotional eating, respectively. Of the variation in liking and use-frequency of fatty foods, 24-54% was attributed to interindividual genetic differences. No significant correlations were observed between BMI and fatty food use or liking. However, BMI was positively (mostly genetically) correlated (genetic r = 0.16-0.51) with all of the dieting behaviors, and they correlated with fatty food use and liking ratings. Uncontrolled eating was both genetically and environmentally associated with liking for salty-and-fatty foods (genetic and environmental r = 0.16), and emotional eating was genetically associated with liking for sweet-and-fatty foods (genetic r = 0.31)., Conclusions: The relation between BMI and diet appears to be mediated through dieting behaviors. Dietary counseling should focus on unhealthy dieting behaviors rather than only on direct advice on food use.

In older adults, mobility limitations often coexist with overweight or obesity, suggesting that similar factors may underlie both traits. This study examined the extent to which genetic and environmental influences explain the association between adiposity and mobility in older women. Body fat percentage (bioimpedance test), walking speed over 10 m, and distance walked in a 6-min test were evaluated in 92 monozygotic (MZ) and 104 dizygotic (DZ) pairs of twin sisters reared together, aged 63-76 years. Genetic and environmental influences on each trait were estimated using age-adjusted multivariate genetic modeling. The analyses showed that the means (and s.d.) for body fat percentage, walking speed, and walking endurance were 33.2+/-7.3%, 1.7+/-0.3 m/s and 529.7+/-75.4 m, respectively. The phenotypic correlation between adiposity and walking speed was -0.32 and between adiposity and endurance it was -0.33. Genetic influences explained 80% of the association between adiposity and speed, and 65% of adiposity and walking endurance. Cross-trait genetic influences accounted for 12% of the variability in adiposity, 56% in walking speed, and 34% in endurance. Trait-specific genetic influences were also detected for adiposity (54%) and walking endurance (13%), but not speed. In conclusion, among community-living older women, an inverse association was found between adiposity and mobility that was mostly due to the effect of shared genes. This result suggests that the identification of genetic variants for body fat metabolism may also provide understanding of the development of mobility limitations in older women.