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Mechanisms of abdominal obesity GWAS variants have remained largely unknown. To elucidate these mechanisms, we leveraged subcutaneous adipose tissue (SAT) single nucleus RNA-sequencing and genomics data. After discovering that heritability of abdominal obesity is enriched in adipocytes, we focused on a SAT unique adipocyte marker gene, the transcription factor TBX15, and its abdominal obesity-associated deleterious missense variant, rs10494217. The allele frequency of rs10494217 revealed a north-to-south decreasing gradient, with consistent significant F ST values observed for 25 different populations when compared to Finns, a population with a history of genetic isolation. Given the role of Tbx15 in mouse thermogenesis, the frequency may have increased as an adaptation to cold in Finns. Our selection analysis provided significant evidence of selection for the abdominal obesity risk allele T of rs10494217 in Finns, with a north-to-south decreasing trend in other populations, and demonstrated that latitude significantly predicts the allele frequency. We also discovered that the risk allele status significantly affects SAT adipocyte expression of multiple adipocyte marker genes in trans in two cohorts. Two of these trans genes have been connected to thermogenesis, supporting the thermogenic effect of the TBX15 missense variant as a possible cause of its selection. Adipose expression of one trans gene, a lncRNA, AC002066.1, was strongly associated with adipocyte size, implicating it in metabolically unhealthy adipocyte hypertrophy. In summary, the abdominal obesity variant rs10494217 was selected in Finns, and individuals with the risk allele have trans effects on adipocyte expression of genes relating to thermogenesis and adipocyte hypertrophy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obesity is an important health concern that poses many public health challenges. Evidence-based treatment modalities, capable of cost-effectively reaching large patient groups are needed. In this paper, we present the design and methods of the updated national, 12-month, digital weight management program, the Healthy Weight Coaching (HWC). The major updates, as compared to the previous version, are related to the theoretical background of the obesity management and updated BMI cut-offs. The HWC is available, based on physicians' referrals, to adult Finnish citizens with BMI ≥30 kg/m 2 or ≥27 kg/m 2 with a comorbidity, who have a health-based need to lose weight. Rooted in the principles of behavioural therapy, the HWC focuses on teaching coping skills, guides to healthy self-reflection, and supports concrete lifestyle changes as part of healthy weight loss. The automated weekly training sessions, supplemented by 3-8 exercises, form the basis of the program. These sessions address topics such as diet, physical activity, stress management, and rest and recovery. Additionally, a personal coach is allocated to each patient to provide tailored support. At baseline, patients record their weight, height, and waist circumference, online, and complete questionnaires on lifestyle, diet, physical activity, sleep, psychological factors, and health. Thereafter weight recording is conducted at least every 4 weeks, while the questionnaires and measuring the weight circumference are repeated at 3, 6, 9, and 12 months. In addition, patients can make use of diaries and peer group chats for additional support. Data collected from the consenting patients will be used for research purposes with the weight change from baseline to 12 months as the main outcome in the real-life observational study. The study will provide invaluable insights into the application of digital modalities in the treatment of obesity.

Objective: To investigate cross-sectional associations between loneliness and health, health behaviours, and perceptions in Finnish individuals with overweight or obesity (BMI ≥25 kg/m 2 )., Methods: We used baseline data from patients participating, in 2016-2022, in a real-life digital 12-month weight management program known as Healthy Weight Coaching. Patients completed several questionnaires such as those related to loneliness, healthcare resource utilization, physical activity, and life satisfaction. BMI was computed based on self-reported weight and height. In addition to investigating individual health variables, we studied the association between loneliness and factor-analysis-derived health and wellbeing clusters., Results: Data were available from 2000 individuals (16.7% men, median age 48 years, median BMI 39.2 kg/m 2 ). Altogether, 11.6%, 42.4%, and 46.0% reported feeling lonely, somewhat lonely, and not lonely, respectively. Feeling lonely was associated with higher BMI, greater healthcare resource utilization, lower life satisfaction, burdensomeness of life, more negative perceptions related to obesity and to the upcoming coaching, lower daytime energy, and reduced 20-min brisk walk results, a measure of functional capacity. Of the five factor-analysis-derived clusters, loneliness was adversely associated with "Life satisfaction" [lonely, 0.337 (0.270-0.421), p < 0.001; somewhat lonely, 0.545 (0.475-0.625), p < 0.001]. Moreover, loneliness associated with "Negative perceptions of obesity/daytime fatigue" [lonely, 4.627 (3.391-6.314), p < 0.001; somewhat lonely 2.021 (1.694-2.412), p < 0.001], and "Obesity/low physical activity" [lonely, 1.474 (1.105-1.966), p = 0.008; somewhat lonely, 1.220 (1.019-1.460), p = 0.030]., Conclusions: Loneliness had several untoward associations with health, health behaviours, and perceptions. Further research should explore the intricate relationship between obesity, loneliness, and physical and psychosocial health., Trial Registration: The trial is registered at clinicaltrials.cov (Clinical Trials Identifier NCT04019249)., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Aim: To characterize healthcare resource (HCRU) and medication use and associated costs in individuals with obesity compared with individuals with normal weight or overweight in a population-based cohort of Finnish adults. The association between metabolic state and direct costs was also assessed., Methods: The study cohort included 5587 randomly selected individuals who participated in the national FinHealth 2017 health examination survey. Data on healthcare visits and hospital stays, including diagnoses (ICD-10), and purchases and costs of prescription medicines were collected from the nationwide registers by the Finnish Institute for Health and Welfare and Social Insurance Institution of Finland. The healthcare costs were calculated based on standard unit costs reported by the Finnish Institute for Health and Welfare., Results: The total annual direct costs were €2665 (SD €5673) and €1799 (SD €3874) per person with obesity and with normal weight or overweight, respectively. Obesity was associated with significantly increased total direct (age- and sex-adjusted cost rate ratio, RR, 1.356; p < 0.001), HCRU-related (1.273; p = 0.002), and medication (1.669; p < 0.001) costs. A vast majority (90%) of individuals with obesity were classified as metabolically unhealthy based on clinical measurements. The metabolically unhealthy state was associated with increased costs in individuals with obesity but not in individuals with normal weight or overweight., Conclusion: Obesity is associated with a significant and complex direct cost burden to society, arising primarily from increased comorbidity. Metabolically healthy obesity is uncommon and obesity prevention and timely treatment should be of high priority to tackle the increasing burden of obesity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The impact of obesity on quality of life (QoL) and working ability vary in different dimensions. This study investigated the association of obesity with QoL and working ability in Finnish adults. Comorbidities as associative factors were also characterised., Methods: This cross-sectional study included 4956 randomly selected adults. QoL (EUROHIS-QOL 8 total score and individual components), perceived physical and psychological working ability, and sick leave days were analysed in different body mass index (BMI) groups. Regression models were used to study the role of comorbidities as associative factors., Results: EUROHIS-QOL 8 total score was significantly lower in BMI group 25.0-29.9 kg/m 2 (4.01; 95% confidence interval 3.97-4.05), BMI 30.0-34.9 kg/m 2 (3.85; 3.79-3.91), BMI 35.0-39.9 kg/m 2 (3.75; 3.66-3.85), and BMI ≥ 40.0 kg/m 2 (3.73; 3.46-4.00) compared to individuals with normal (18.5-24.9 kg/m 2 ) BMI (4.08; 4.04-4.12). Individuals with obesity (BMI ≥ 30.0 kg/m 2 ) rated their QoL lower than individuals with normal BMI in seven of the eight EUROHIS-QOL 8 components. A lesser proportion of individuals (53-73%) with obesity rated their physical working ability as very or fairly good compared to individuals with normal BMI (90%, p values < 0.001). The psychological working ability was rated as very or fairly good by 71-75% of individuals with obesity compared to 85% of individuals with normal BMI (p = 0.008 and p = 0.001 in individuals with BMI 30.0-34.9 and BMI 35.0-39.9 kg/m 2 , respectively)., Conclusions: Obesity was negatively associated with both physical and psychological components of QoL, even after accounting for obesity-related comorbidities. Obesity treatment can benefit from a holistic approach that considers these multifaceted associations., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.)

The purpose of this review is to provide a detailed and updated description of the FinnTwin16 (FT16) study and its future directions. The Finnish Twin Cohort comprises three different cohorts: the Older Twin Cohort established in the 1970s and the FinnTwin12 and FT16 initiated in the 1990s. FT16 was initiated in 1991 to identify the genetic and environmental precursors of alcoholism, but later the scope of the project expanded to studying the determinants of various health-related behaviors and diseases in different stages of life. The main areas addressed are alcohol use and its consequences, smoking, physical activity, overall physical health, eating behaviors and eating disorders, weight development, obesity, life satisfaction and personality. To date, five waves of data collection have been completed and the sixth is now planned. Data from the FT16 cohort have contributed to several hundred studies and many substudies, with more detailed phenotyping and collection of omics data completed or underway. FT16 has also contributed to many national and international collaborations.

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.

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.

Background: Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear., Methods: We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3-10 kg m(-2), n=15) and concordant (ΔBMI 0-2 kg m(-)(2), n=5) young adult (22-35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A)., Results: The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91-0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6 ± 0.9 kg m(-2)) had significantly larger adipocytes (volume 547 ± 59 pl), than the lean co-twins (24.9 ± 0.9 kg m(-)(2); 356 ± 34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death., Conclusions: Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.

Purpose: Study how the dietary intake affects the fecal microbiota of a group of obese individuals after a 6-week very low-energy diet (VLED) and thereafter during a follow-up period of 5, 8, and 12 months. Additionally, we compared two different methods, fluorescent in situ hybridization (FISH) and real-time PCR (qPCR), for the quantification of fecal samples., Methods: Sixteen subjects participated in a 12-month dietary intervention which consisted of a VLED high in protein and low in carbohydrates followed by a personalized diet plan, combined with exercise and lifestyle counseling. Fecal samples were analyzed using qPCR, FISH, and denaturing gradient gel electrophoresis., Results: The VLED affected the fecal microbiota, in particular bifidobacteria that decreased approximately two logs compared with the baseline numbers. The change in numbers of the bacterial groups studied followed the dietary intake and not the weight variations during the 12-month intervention. Methanogens were detected in 56% of the participants at every sampling point, regardless of the dietary intake. Moreover, although absolute numbers of comparable bacterial groups were similar between FISH and qPCR measurements, relative proportions were higher according to FISH results., Conclusions: Changes in the fecal microbial numbers of obese individuals were primarily affected by the dietary intake rather than weight changes.

Objective: The effects of acquired obesity on lipid profile and lipoprotein composition in rare BMI-discordant monozygotic (MZ) twin pairs were studied., Design and Methods: Abdominal fat distribution, liver fat (magnetic resonance imaging and spectroscopy), fasting serum lipid profile (ultracentrifugation, gradient gel-electrophoresis, and colorimetric enzymatic methods), and lifestyle factors (questionnaires and diaries) were assessed in 15 BMI-discordant (within-pair difference [Δ] in BMI >3 kg/m2) and nin concordant (ΔBMI <3 kg/m2) MZ twin pairs, identified from two nationwide cohorts of Finnish twins., Results: Despite a strong similarity of MZ twins in lipid parameters (intra-class correlations 0.42-0.90, P < 0.05), concentrations of apolipoprotein B (ApoB), intermediate-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein 3a% (HDL3a%), and HDL3c% were higher (P < 0.05) and those of HDL cholesterol, HDL2-C, and HDL2b% were lower (P < 0.01) in the heavier co-twins of BMI-discordant pairs. The composition of lipoprotein particles was similar in the co-twins. When BMI-discordant pairs were further divided into liver fat-discordant and concordant (based on median for Δliver fat, 2.6%), the adverse lipid profile was only seen in those heavy co-twins who also had high liver fat. Conversely, BMI-discordant pairs concordant for liver fat did not differ significantly in lipid parameters. In multivariate analyses controlling for Δsubcutaneous, Δintra-abdominal fat, sex, Δsmoking and Δphysical activity, Δliver fat was the only independent variable explaining the variation in ΔApoB, Δtotal cholesterol, and ΔLDL-C concentration., Conclusions: Several pro-atherogenic changes in the amounts of lipids but not in the composition of lipoprotein particles were observed in acquired obesity. In particular, accumulation of liver fat was associated with lipid disturbances, independent of genetic effects., (Copyright © 2013 The Obesity Society.)

Background: High serum triglyceride (TG) levels is an established risk factor for coronary heart disease (CHD). Fat is stored in the form of TGs in human adipose tissue. We hypothesized that gene co-expression networks in human adipose tissue may be correlated with serum TG levels and help reveal novel genes involved in TG regulation., Methods: Gene co-expression networks were constructed from two Finnish and one Mexican study sample using the blockwiseModules R function in Weighted Gene Co-expression Network Analysis (WGCNA). Overlap between TG-associated networks from each of the three study samples were calculated using a Fisher's Exact test. Gene ontology was used to determine known pathways enriched in each TG-associated network., Results: We measured gene expression in adipose samples from two Finnish and one Mexican study sample. In each study sample, we observed a gene co-expression network that was significantly associated with serum TG levels. The TG modules observed in Finns and Mexicans significantly overlapped and shared 34 genes. Seven of the 34 genes (ARHGAP30, CCR1, CXCL16, FERMT3, HCST, RNASET2, SELPG) were identified as the key hub genes of all three TG modules. Furthermore, two of the 34 genes (ARHGAP9, LST1) reside in previous TG GWAS regions, suggesting them as the regional candidates underlying the GWAS signals., Conclusions: This study presents a novel adipose gene co-expression network with 34 genes significantly correlated with serum TG across populations.

Obesity is a genetically complex disorder that produces a myriad of health problems. Most of the recognized complications of obesity are not only strongly influenced by lifestyle factors, but also present with independent genetic predispositions that are notoriously difficult to disentangle in humans. Most studies on the causes and consequences of acquired obesity are encumbered by the incomplete ability to control for genetic influences. However, utilizing a unique experiment of nature, namely monozygotic twins (MZ) discordant for obesity as 'clonal controls' of obese and non-obese individuals has enabled the fine characterization of the effects and possible antecedents of acquired obesity while controlling for the genetic background, as well as pointed to novel obesity predisposing candidate genes. This review is a distillation of the findings from more than 10 years of research done in an exceptionally well-characterized collection of MZ and dizygotic (DZ) twins, based on the Finnish Twin Cohorts. Topics covered include the nature of development of obesity from the childhood onwards, the role of exercise in modifying the genetic susceptibility, the resulting inflammatory, prediabetic and preatherosclerotic changes in whole body and adipose tissue physiology, as well as the newest insights provided by the omics revolution.

Purpose: The aim of this study was to investigate genetic and environmental influences on different aspects of physical activity in young adult twins., Methods: We studied 1274 Finnish twins with a mean age of 22.4 yr, from the population-based FinnTwin12 study. Physical activity was assessed with the Baecke Questionnaire, yielding four indexes: the sport index, leisure time activity index, work index, and total score. Quantitative genetic analyses based on linear structural equations were used to estimate the contribution of genetic and environmental factors on these physical activity traits., Results: The overall heritability estimates were 64% (95% confidence interval (CI) = 0.56%-0.70%) for sports activity, 41% (95% CI = 0.31%-0.51%) for leisure time activity excluding sports, 56% (95% CI = 0.48%-0.63%) for physical activity at work, and 54% (95% CI = 0.45%-0.62%) for total physical activity. Unique environmental factors accounted for the rest of the trait variances. We did not find evidence for common environmental or dominant genetic influences. The heritability estimates did not differ between men and women, and no sex-specific genetic factors were found. Sports activity and leisure time activity excluding sports were associated (r = 0.27), and additive genetic factors explained 57% of their association., Conclusions: Our results suggest that genetic factors contribute significantly to physical activity levels in young adults and that sports activity is under stronger genetic influence than leisure time physical activity excluding sports. We also concluded that physical activity at work does not seem to be associated with sports activities or other leisure time physical activity at this age.

Objective: To investigate whether the paradoxical weight gain associated with dieting is better related to genetic propensity to weight gain than to the weight loss episodes themselves., Subjects: Subjects included 4129 individual twins from the population-based FinnTwin16 study (90% of twins born in Finland 1975-1979). Weight and height were obtained from longitudinal surveys at 16, 17, 18 and 25 years, and number of lifetime intentional weight loss (IWL) episodes of more than 5 kg at 25 years., Results: IWLs predicted accelerated weight gain and risk of overweight. The odds of becoming overweight (body mass index (BMI)≥ 25 kg m(-2)) by 25 years were significantly greater in subjects with one (OR 1.8, 95% CI 1.3-2.6, and OR 2.7, 1.7-4.3 in males and females, respectively), or two or more (OR 2.0, 1.3-3.3, and OR 5.2, 3.2-8.6, in males and females, respectively), IWLs compared with subjects with no IWL. In MZ pairs discordant for IWL, co-twins with at least one IWL were 0.4 kg m(-2) (P=0.041) heavier at 25 years than their non-dieting co-twins (no differences in baseline BMIs). In DZ pairs, co-twins with IWLs gained progressively more weight than non-dieting co-twins (BMI difference 1.7 kg m(-2) at 16 years and 2.2 kg m(-2) at 25 years, P<0.001)., Conclusion: Our results suggest that frequent IWLs reflect susceptibility to weight gain, rendering dieters prone to future weight gain. The results from the MZ pairs discordant for IWLs suggest that dieting itself may induce a small subsequent weight gain, independent of genetic factors.

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10(-10)) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.

Background: Studies on diet and high-density lipoprotein (HDL) subspecies distribution are limited., Objective: We examined the relationship between macronutrient composition and lipoprotein particle size and HDL subspecies independent of genetic effects by studying monozygotic (MZ) twins., Methods: 24 healthy MZ twin pairs aged 23-33 years were identified from two longitudinal population-based studies, FinnTwin16 and FinnTwin12. Total energy and nutrient intake were assessed with 3-day food records and physical activity was measured by the Baecke index. HDL subspecies distribution was determined by non-denaturing gradient gel electrophoresis. Associations between diet composition and HDL mean particle size were determined by multivariate nutrient density models adjusted for confounding variables., Results: Substituting one energy percentage from omega-3 polyunsaturated fatty acids (n-3 PUFAs) for a corresponding amount of energy from other type of fats was related to changes in the relative proportions of the HDL subspecies 2b, 3a and 3b toward a larger mean particle size in men (β ± SE: 1.00 ± 0.26 nm, p = 0.004) and women (β ± SE: 0.90 ± 0.21 nm, p = 0.001). This association remained significant in analyses controlling for genetic and shared environmental influences using within-pair differences of the measures in MZ twin pairs (β ± SE: 0.37 ± 0.14 nm, p = 0.019). Twins with the higher n-3 PUFA intake had significantly higher proportions of large HDL(2b) particles and lower proportions of smaller-sized HDL(3a) and HDL(3b) particles as compared to their co-twins with lower intakes (p < 0.05)., Conclusions: Our data suggest that n-3 PUFA intake is associated with a favorable change in the distribution of HDL subspecies towards larger particles independent of genetic and shared environmental factors., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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.

Exercise behavior, cardiorespiratory fitness, and obesity are strongly influenced by genetic factors. By studying young adult twins, we examined to what extent these interrelated traits have shared genetic and environmental etiologies. We studied 304 twin individuals selected from the population-based FinnTwin16 study. Physical activity was assessed with the Baecke questionnaire, yielding three indexes: sport index, leisure-time index, and work index. In this study, we focused on sport index, which describes sports participation. Body composition was determined using dual-energy X-ray absorptiometry and cardiorespiratory fitness using a bicycle ergometer exercise test with gas exchange analysis. The Baecke sport index was associated with high maximal oxygen uptake adjusted for lean body mass (Vo(2max)[adj]) (r = 0.40), with low body fat percentage (BF%) (r = -0.44) and low waist circumference (WC) (r = -0.29). Heritability estimates for the key traits were as follows: 56% for sport index, 71% for Vo(2max)[adj], 77% for body mass index, 66% for WC, and 68% for BF%. The association between sport index and Vo(2max) was mostly explained by genetic factors (70%), as were both the association between sport index and BF% (71%) and that between sport index and WC (59%). Our results suggest that genetic factors explain a considerable part of the associations between sports participation, cardiorespiratory fitness, and obesity.

Background and Aims: Obesity and the metabolic syndrome are established risk factors of venous thromboembolism. As most coagulation factors are produced exclusively by the liver and non-alcoholic fatty liver disease (NAFLD) is tightly related to metabolic disorders, we aimed at studying the association of liver fat with various coagulation factor activities., Methods: Plasma prothrombin (PT) and activated partial thromboplastin time, activities of vWF:RCo, FVII, FVIII, FIX, FXI, FXII, FXIII, fibrinogen and D-dimer concentrations were measured in 54 subjects with and 44 without NAFLD diagnosed by proton magnetic resonance spectroscopy. Subjects were recruited retrospectively for metabolic studies in our laboratory. The body composition and features of insulin resistance were measured in all subjects., Results: FVIII (107±30 vs. 84±22%, P<0.001), FIX (110±14 vs. 94±16%, P<0.001), FXI (109±16 vs. 96±19%, P=0.001) and FXII (113±21 vs. 99±32%, P=0.002) activities were consistently elevated in subjects with as compared with those without NAFLD. Liver fat percentage was positively related to FVIII (r=0.28, P=0.005), FIX (r=0.36, P=0.0003), FXI (r=0.29, P=0.004) and FXII (r=0.30, P=0.003) activities, again independent of age, gender and body mass index (BMI). PT%, vWF:RCo activity and fibrinogen were higher in subjects with as compared with those without NAFLD, but this difference disappeared after adjusting for age, gender and BMI., Conclusion: FVIII, FIX, FXI and FXII activities are increased in human NAFLD and correlate with the features of insulin resistance. The relationships between NAFLD and these coagulation factors are independent of age, gender and BMI, suggesting that the fatty liver can contribute to the risk of thrombosis., (© 2010 John Wiley & Sons A/S.)

Aims/hypothesis: We investigated whether BMI predicts type 2 diabetes in twins and to what extent that is explained by common genetic factors., Methods: This was a population-based twin cohort study. Monozygotic (n = 4,076) and dizygotic (n = 9,109) non-diabetic twin pairs born before 1958 answered a questionnaire in 1975, from which BMI was obtained. Information on incident cases of diabetes was obtained by linkage to nationwide registers until 2005., Results: Altogether, 1,332 twins (6.3% of men, 5.1% of women) developed type 2 diabetes. The HR for type 2 diabetes increased monotonically with a mean of 1.22 (95% CI 1.20-1.24) per BMI unit and of 1.97 (95% CI 1.87-2.08) per SD of BMI. The HRs for lean, overweight, obese and morbidly obese participants were 0.59, 2.96, 6.80 and 13.64 as compared with normal weight participants. Model heritability estimates for bivariate variance due to an additive genetic component and non-shared environmental component were 75% (men) and 71% (women) for BMI, and 73% and 64%, respectively for type 2 diabetes. The correlations between genetic variance components (r (g)) indicated that one fifth of the covariance of BMI and type 2 diabetes was due to shared genetic influences. Although the mean monozygotic concordance for type 2 diabetes was approximately twice the dizygotic one, age of onset of diabetes within twin pair members varied greatly, irrespective of zygosity., Conclusions/interpretation: A 28-year follow-up of adult Finnish twins showed that despite high trait heritability estimates, only a fraction of covariation in BMI and incident type 2 diabetes was of genetic origin.

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.

Background and Objective: Exercise is thought to reduce high-risk body fat, but intervention studies are frequently limited by short follow-ups and observational studies by genetic selection. Therefore, we studied the effects of a physically inactive vs active lifestyle on high-risk (visceral, liver and intramuscular) fat in twin pairs discordant for leisure-time physical activity habits for over 30 years., Design: A longitudinal population-based twin study., Subjects: Sixteen middle-aged (50-74 years) same-sex twin pairs (seven monozygotic (MZ), nine dizygotic (DZ)) with long-term discordance for physical activity habits were comprehensively identified from the Finnish Twin Cohort (TWINACTIVE study). Discordance was initially defined in 1975 and the same co-twin remained significantly more active during the 32-year-long follow-up., Main Outcome Measures: Magnetic resonance imaging-assessed visceral, liver and intramuscular fat., Results: In within-pair analyses carried out after the adult life-long discordance in physical activity habits, the physically inactive co-twins had 50% greater visceral fat area compared with the active co-twins (mean difference 55.5 cm2, 95% confidence interval (CI) 7.0-104.1, P=0.010). The liver fat score was 170% higher (13.2, 95% CI 3.5-22.8, P=0.030) and the intramuscular fat area 54% higher (4.9 cm2, 95% CI 1.9-7.9, P=0.002) among the inactive co-twins. All the trends were similar for MZ and DZ pairs. Peak oxygen uptake was inversely associated with visceral (r=-0.46, P=0.012) and intramuscular fat area (r=-0.48, P=0.028), with similar trends in intrapair difference correlations (r=-0.57, P=0.021 and r=-0.50, P=0.056, respectively). The intrapair difference correlation between visceral and intramuscular fat was also high (r=0.65, P=0.009)., Conclusion: Regular physical activity seems to be an important factor in preventing the accumulation of high-risk fat over time, even after controlling for genetic liability and childhood environment. Therefore, the prevention and treatment of obesity should emphasize the role of regular leisure-time physical activity.

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.

The association between abdominal obesity and atherogenic lipid profile emerges from complex interactions of genes and environment. We aimed to explore the heritability and effects of overweight on serum lipid profile (high-density lipoprotein-cholesterol (HDL-C), HDL mean particle size, percentages of HDL(2b, 2a, 3a, 3b, and 3c,) low-density lipoprotein-cholesterol (LDL-C), LDL peak particle size and triglycerides (TGs)) in healthy, young adults. HDL-C, LDL-C, and TG were measured in 52 monozygotic (MZ) and 89 dizygotic (DZ) twin pairs, aged 23-32 years, chosen to represent a wide range of BMIs (17.6-42.9 kg/m2). Of them, 24 MZ and 26 DZ pairs were chosen at random for measurements of HDL mean and LDL peak particle sizes and percentages of HDL subspecies. The heritabilities of the lipid parameters adjusted for BMI were HDL-C 73%, HDL mean particle size 56%, HDL subspecies 46-63%, LDL-C 79%, LDL peak particle size 49%, and TG 64%. Genetic and environmental correlations between BMI and HDL-C, LDL-C, and TG were modest (0.3-0.4). Abdominal overweight (waist circumference>or=94 cm for males and >or=80 cm for females) associated with decreased HDL-C, increased LDL-C, and TG concentrations, smaller HDL mean particle size, lower HDL2b, and higher HDL3c percentages in both genders. Within MZ twins, controlling for genetic influences, within-pair differences in HDL3c percentage were associated with those in waist (r=0.46, P=0.032) and BMI (r=0.51, P=0.013). In conclusion, serum lipid parameters, including LDL peak and HDL mean particle sizes and HDL subspecies distribution are under strong genetic control. Overweight associated with significant lipid profile changes, particularly, small HDL3c increased in overweight independent of genetic influences.

Aims: We investigated whether polymorphisms in candidate genes involved in lipid metabolism and type 2 diabetes are related to liver fat content., Methods: Liver fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS) in 302 Finns, in whom single nucleotide polymorphisms (SNPs) in acyl-CoA synthetase long-chain family member 4 (ACSL4), adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2), and the three peroxisome proliferator-activated receptors (PPARA, PPARD, and PPARG) were analyzed. To validate our findings, SNPs significantly associated with liver fat content were studied in two independent cohorts and related to surrogate markers of liver fat content., Results: In the Finnish subjects, polymorphisms in ACSL4 (rs7887981), ADIPOR2 (rs767870), and PPARG (rs3856806) were significantly associated with liver fat content measured with (1)H-MRS after adjusting for age, gender, and BMI. Anthropometric and circulating parameters were comparable between genotypes. In the first validation cohort of approximately 600 Swedish men, ACSL4 rs7887981 was related to fasting insulin and triglyceride concentrations, and ADIPOR2 rs767870 to serum gamma glutamyltransferase concentrations after adjusting for BMI. The SNP in PPARG (rs3856806) was not significantly associated with any relevant metabolic parameter in this cohort. In the second validation cohort of approximately 3000 subjects from Western Finland, ADIPOR2 rs767870, but not ACSL4 rs7887981 was related to fasting triglyceride concentrations., Conclusions: Genetic variation, particularly in the ADIPOR2 gene, contributes to variation in hepatic fat accumulation in humans.

Both genetic and environmental factors are involved in the etiology of obesity and the associated lipid disturbances. We determined whether acquired obesity is associated with changes in global serum lipid profiles independent of genetic factors in young adult monozygotic (MZ) twins. 14 healthy MZ pairs discordant for obesity (10 to 25 kg weight difference) and ten weight concordant control pairs aged 24-27 years were identified from a large population-based study. Insulin sensitivity was assessed by the euglycemic clamp technique, and body composition by DEXA (% body fat) and by MRI (subcutaneous and intra-abdominal fat). Global characterization of lipid molecular species in serum was performed by a lipidomics strategy using liquid chromatography coupled to mass spectrometry. Obesity, independent of genetic influences, was primarily related to increases in lysophosphatidylcholines, lipids found in proinflammatory and proatherogenic conditions and to decreases in ether phospholipids, which are known to have antioxidant properties. These lipid changes were associated with insulin resistance, a pathogonomic characteristic of acquired obesity in these young adult twins. Our results show that obesity, already in its early stages and independent of genetic influences, is associated with deleterious alterations in the lipid metabolism known to facilitate atherogenesis, inflammation and insulin resistance.

Objective: This study identified genetic and environmental influences on the tracking of body size from birth to 16 to 18.5 years of age., Research Methods and Procedures: Longitudinal information was collected from a nationally representative sample of Finnish twin adolescents (birth cohorts 1975 to 1979) and their parents through questionnaires mailed when the twins were ages 16 and 18.5 years old. The sample included 702 monozygotic, 724 same-sex dizygotic, and 762 opposite-sex dizygotic sets of twins. The measures used were length, weight, ponderal index (kilograms per cubic meters), and gestational age at birth, and height, weight, and body mass index (kilograms per square meters) at 16 to 18.5 years of age. The changes in genetic and environmental influences on body size from birth to early adulthood were analyzed by quantitative genetic modeling., Results: The twins who had a higher weight or ponderal index at birth were taller and heavier in early adulthood, whereas those who were longer at birth were taller, but not heavier, later in life. Adult height was affected more by the birth size than body mass index. In the genetic modeling analyses, the genetic factors accounting for the variation of body size became more apparent with age, and both genetic and environmental influences on stature had a sizable carry-over effect from birth to late adolescence, whereas for relative weight, the influences were more age-specific., Discussion: The genetic and environmental architecture of body size changes from birth to adulthood. Even in monozygotic twins who share their genetic background, the initially larger twin tended to remain larger, demonstrating the long-lasting effects of fetal environment on final body size.

Birth weight has correlated positively with adult body mass index (BMI), but rarely have birth length, duration of gestation, or parents' body size been taken into account. The authors examined tracking of birth length and weight, adjusted for gestational age, to late adolescence, with special reference to parents' height and BMI. Longitudinal information from a nationally representative sample of Finnish twin adolescents (birth cohorts 1975-1979) and their parents was collected via questionnaires mailed when the twins were aged 16 years (n = 4,376; 2,062 males, 2,314 females) and 18 years (n = 3,917; 1,742 males, 2,175 females). The twins showed significant tracking of body size from birth to late adolescence, which was greatly influenced by their parents' body size. Height in adolescence was predicted by length and weight at birth and by parents' height, whereas BMI was predicted by birth weight and parents' BMI. An especially high risk for overweight was found for subjects of average length but a high weight at birth. These findings suggest that the intrauterine period has enduring effects on later body size but leave unresolved whether these effects are genetic or environmental.

Objective: 1) To estimate the heritability of body mass index (BMI) in twins aged 16y and 17y, with a special emphasis on gender-specific genetic effects and 2) to compare heights, weights, BMIs, and prevalences of 'overweight' (BMI > or = 25 kg/m2) in these twins and in singletons aged 16.5y., Design: Cross-sectional and longitudinal epidemiological questionnaire study of twins at ages 16y and 17 y, and cross-sectional study of singletons at age 16.5y., Measurements: BMI (kg/m2) was calculated from self-reported heights (m) and weights (kg)., Subjects: 4884 twins (2299 boys, 2585 girls) at baseline (age 16 y), 4401 twins (2002 boys, 2399 girls) at age 17 y, and 2509 singletons (1147 boys, 1362 girls) at age 16.5 y. Both twin and singleton samples are nationally representative., Results: At the ages of 16y and 17y, genetic effects accounted for over 80% of the interindividual variation of BMI. The correlations for male-female pairs were smaller than for either male-male or female-female dizygotic pairs. The singletons, especially the boys, had a higher BMI than the twins. Nine percent of singleton boys, but only 4-6% of twin boys and twin and singleton girls were 'overweight' (BMI > or = 25 kg/m2)., Conclusions: Among adolescents, genetic factors play a significant role in the causes of variation in BMI. The genetic modelling suggested that the sets of genes explaining the variation of BMI may differ in males and females. At this age, the twin boys, but not girls, seem to be leaner than singletons. Further follow-up will indicate whether these small differences disappear, and if not, what implications it might have to the generalizability of twin studies.