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Objective: To determine the association between long-term leisure-time physical activity/inactivity and eating behaviours in twin pairs discordant for physical activity for 30 years., Design: Co-twin control design with cross-sectional data collection using questionnaire on eating habits and 5 d food diary. Differences in eating behaviours between physically active and inactive co-twins were analysed with pairwise tests., Setting: Finland., Subjects: Sixteen same-sex twin pairs (seven monozygotic and nine dizygotic, mean age 60 years) discordant for physical activity, selected from the Finnish Twin Cohort on the basis of physical activity discordance for 30 years, blinded to their possible differences in eating behaviours., Results: The eating habits questionnaire revealed that physically active co-twins more frequently reported that it is easy to eat according to need, whereas overeating and/or restrictive eating was more common among the inactive co-twins (P = 0·035). Avoiding calories was more common among the active than inactive co-twins (P = 0·034). Based on food diaries the physically active co-twins had daily energy intake on average 15·5 kJ/kg higher than their inactive co-twins (P = 0·030). The active co-twins also had a higher intake of vitamin C (P = 0·004), total water (P = 0·044), legumes and nuts (P = 0·015) and sweets (P = 0·036), as well as a lower energy-adjusted intake of meat (P = 0·013)., Conclusions: The physically active persons seem to eat more but not necessarily healthier food. However, habitual physical activity may help in eating according to need and in reaching and maintaining a healthy body composition. Therefore, it is necessary to incorporate both dietary and physical activity advice into health counselling.

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.

Context: Emerging as an important metabolic regulator, fibroblast growth factor 21 (FGF21) has gained considerable interest in diabetes and obesity research. The circulating FGF21 concentration is fairly low in normal individuals, but elevated hormone levels may associate with obesity. The determining factors of FGF21 levels in humans are not clear., Objective: Our objective was to study the influence of genetic and acquired components to serum FGF21 variability in healthy young adult twins., Design and Participants: Fasting serum FGF21, lipids, body fat, and oral glucose tolerance test were investigated in 46 monozygotic (MZ) and 75 dizygotic twin pairs aged 22.8-33.1 yr. Subcutaneous, intraabdominal, and liver fat content were measured by magnetic resonance imaging/spectroscopy in a subsample of 24 MZ pairs., Results: Genetic factors contributed moderately (heritability 40%) to circulating serum FGF21 levels. Subjects with high FGF21 concentrations (≥ 250 pg/ml, n = 30) had higher fasting triglycerides, insulin, homeostasis model assessment index, and area under the curve glucose and lower high-density lipoprotein cholesterol but similar measures of overall adiposity (body mass index, body fat percent) than subjects with lower FGF21 (<100 pg/ml, n = 148). Importantly, in the MZ subsample, higher liver fat but not sc or intraabdominal fat content was found in subjects with high FGF21. Furthermore, in analyses controlling for genetic/familial effects in twin pairs, within-pair differences in liver fat (MZ) and triglycerides (dizygotic pairs) were the major acquired factors that correlated with differences in FGF21 concentrations., Conclusions: Genetic factors influence serum FGF21 levels. Of the acquired components, high liver fat and triglycerides rather than overall adiposity associate with high FGF21 levels.

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.)

The purpose of this study was to investigate the relationship of fat mass (FM) and lean mass (LM) with bone mineral density (BMD) independent of genetic effects. We also assessed the extent to which genetic and environmental influences explain the associations between these phenotypes. Body composition and BMD were measured using dual-energy X-ray absorptiometry in 57 monozygotic and 92 same-sex dizygotic twin pairs, aged 23 to 31 years, chosen to represent a wide range of intrapair differences in body mass index (BMI; 0 to 15.2 kg/m(2)). Heritability estimates were adjusted for height and gender. In multiple linear regression analysis, intrapair differences in both FM and LM were independently associated with intrapair differences in BMD at most skeletal sites after adjustment for gender and differences in height. Within monozygotic and dizygotic pairs, LM was a significantly stronger predictor of whole-body BMD than FM (p < .01). Additive genetic factors explained 87% [95% confidence interval (CI) 80%-91%), 81% (95% CI 70%-88%), and 61% (95% CI 41%-75%) of the variation in whole-body BMD, LM, and FM, respectively. Additive genetic factors also accounted for 69% to 88% of the covariance between LM and BMD and for 42% to 72% of the covariance between FM and BMD depending on the skeletal site. The genetic correlation between LM and whole-body BMD (r(g) = 0.46, 95% CI 0.32-0.58) was greater than that of FM and whole-body BMD (r(g) = 0.25, 95% CI 0.05-0.42). In conclusion, our data indicate that peak BMD is influenced by acquired body weight as well as genetic factors. In young adulthood, LM and BMD may have more genes in common than do FM and BMD., (© 2011 American Society for Bone and Mineral Research.)

Abdominally obese individuals with the metabolic syndrome often have excess fat deposition both intra-abdominally (IA) and in the liver, but the relative contribution of these two deposits to variation in components of the metabolic syndrome remains unclear. We determined the mutually independent quantitative contributions of IA and liver fat to components of the syndrome, fasting serum (fS) insulin, and liver enzymes and measures of hepatic insulin sensitivity in 356 subjects (mean age 42 years, mean BMI 29.7 kg/m²) in whom liver fat and abdominal fat volumes were measured. IA and liver fat contents were correlated (r = 0.65, P < 0.0001). In multivariate linear regression analyses including either liver or IA fat, liver fat or IA fat explained variation in fS-triglyceride (TG) and high-density lipoprotein (HDL) cholesterol, plasma glucose, insulin and liver enzyme concentrations, and hepatic insulin sensitivity independent of age, gender, subcutaneous (SC) fat, and/or lean body mass (LBM). Including both liver and IA fat, liver and IA fat both explained variation in TG, HDL cholesterol, insulin and hepatic insulin sensitivity independent of each other and of age, gender, SC fat, and LBM. Liver fat independently predicted glucose and liver enzymes. SC fat and age explained variation in blood pressure. In conclusion, both IA and liver fat independently of each other explain variation in serum TG, HDL cholesterol, insulin concentrations and hepatic insulin sensitivity, thus supporting that both fat depots are important predictors of these components of the metabolic syndrome.

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

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.

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.

Bread is an elementary part of the western diet, and especially rye bread is regarded as an important source of fibre. We investigated the heritability of eating bread in terms of choice of white and rye bread and use-frequency of bread in female and male twins in Denmark and Finland. The study cohorts included 575 Danish (age range 18-67 years) and 2009 Finnish (age range 22-27 years) adult twin pairs. Self-reported frequency of eating bread was obtained by food frequency questionnaires. Univariate models based on linear structural equations for twin data were used to estimate the relative magnitude of the additive genetic, shared environmental and individual environmental effects on bread eating frequency and choice of bread. The analysis of bread intake frequency demonstrated moderate heritability ranging from 37-40% in the Finnish cohort and 23-26% in the Danish cohort. The genetic influence on intake of white bread was moderate (24-31%), while the genetic influence on intake of rye bread was higher in men (41-45%) than in women (24-33%). Environmental influences shared by the twins were not significant. Consumption of bread as well as choice of bread is influenced by genetic predisposition. Environmental factors shared by the co-twins (e.g., childhood environment) seem to have no significant effects on bread consumption and preference in adulthood.

Objective: To study whether eating or physical-activity (PA) habits differ between obese and non-obese monozygotic (MZ) co-twins independent of genetic effects., Methods: Rare MZ pairs discordant for obesity (n=14, body mass index difference 5.2+/-1.8 kg m(-2)) and weight-concordant control pairs (n=10, 1.0+/-0.7 kg m(-2)), identified through a population-based registry of 24-28-year-old twins (n=658 MZ pairs), completed 3-day food and PA diaries and eating behavior questionnaires. Each twin was asked to compare his/her own eating and PA patterns with the co-twin's behavior by structured questionnaires. Accuracy of energy intake was validated by doubly labeled water., Results: Non-obese co-twins consistently reported that their obese twin siblings ate more food overall, consumed less healthy foods and exercised less than the non-obese co-twins do. However, no differences in energy intake (9.6+/-1.0 MJ per day vs 9.8+/-1.1 MJ per day, respectively) in the food diaries or in the mean PA level (1.74+/-0.02 vs 1.79+/-0.04, respectively) in the PA diaries were found between obese and non-obese co-twins. A considerable underreporting of energy intake (3.2+/-1.1 MJ per day, P=0.036) and overreporting of PA (1.8+/-0.8 MJ per day, P=0.049) was observed in the obese, but not in the non-obese co-twins., Conclusions: On the basis of rare MZ twin pairs discordant for obesity, the co-twin assessments confirmed substantial differences in eating and PA behavior between obese and non-obese persons. These may be overlooked in population studies using food and PA diaries because of considerable misreporting by the obese.

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.

Objective: In Parkinson's disease, striatal dopamine transporter (DAT) binding and cardiac sympathetic function are disturbed. In addition, heart rate (HR)-corrected cardiac repolarisation time (QTc interval), which is partly under autonomic control, is prolonged. Whether there is physiological coupling between striatal DAT binding and QTc time (QTc-DAT relation) is not known. The purpose of this study is to evaluate QTc-DAT relation in healthy young adults., Methods: Thirty-five participants (18 women, age 26.4+/-1.8 years; mean+/-SD) were studied with iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single photon emission tomography. Signal-averaged ECG was recorded at rest from each participant. QTc interval was computed with Bazett's correction and with the approach by Karjalainen, getting QTc and QTk intervals, respectively., Results: Mean striatal DAT binding, as (striatum-cerebellum)/cerebellum, was 2.63+/-0.31. Mean HR, QT, QTc and QTk intervals were 66+/-9 bpm, 340+/-25 ms, 354+/-18 ms and 351+/-16 ms, respectively. HR-QT correlation was -0.63, P value of less than 0.001. HR was not related to striatal DAT binding. QTc-DAT and QTk-DAT relations were significant, r = -0.50, P = 0.004 and r = -0.59, P = 0.0002, respectively. In linear regression model, striatal DAT binding explained 35% of the variance of QTk interval (95% confidence interval: -46.9 to -13.0, P = 0.0002)., Conclusion: This study suggests significant physiological QTc-DAT relation in young healthy adults. QTc interval measurements might carry diagnostically important information in clinical conditions, which have an effect on both striatal DAT binding and cardiac sympathetic function.

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.

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.

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.

The physically active lifestyle is associated with low future morbidity and mortality, but the causality between physical activity and health is not always clear. As some inherited biological characteristics and childhood experiences may cause selection bias in observational studies, we sought to take them into account by identifying 16 twin pairs (7 MZ, 9 DZ, mean age 60 years) discordant for leisure time physical activity habits for thirty years. We conducted detailed health-related examinations among these twin pairs. Our main aims were to study the effects of physical activity and genes on fitness and body composition, with special reference to body fat compartments, metabolic syndrome components and related diseases and risk factor levels, status of arteries, structure and function of the heart, bone properties, and muscle and fat tissue-related mechanisms linked to physical activity and chronic disease development. Our physical activity assessments showed that inactive co-twins were on average 8.8 MET hours/day less active than their active co-twins through out their midlife (2.2+/-2.3 vs. 11.0+/-4.1 MET h/day, p< .001). Follow-up fitness tests showed that physically inactive co-twins were less fit than their active co-twins (estimated VO(2peak) 26.4+/-4.9 vs. 32.5+/-5.5 ml/kg/min, p< .001). Similar differences were found in both MZ and DZ pairs. On the basis of earlier epidemiological observations on nonrelated individuals, these physical activity and fitness differences are large enough to cause differences in many mechanisms and risk factors related to the development of chronic diseases and to permit future analyses.

Recent functional magnetic resonance imaging (fMRI) studies have revealed links between genetic polymorphisms and cognitive and behavioural processes. Serotonin is a classical neurotransmitter of central nervous system, and it is connected to the control of appetite and satiety. In this study, the relationship between the functional variation in the serotonin transporter gene and the activity in the left posterior cingulate cortex (PCC), a brain area activated by visual food stimuli was explored. Thirty subjects underwent serial fMRI studies and provided DNA for genetic analyses. Subjects homozygous for the long allele exhibited greater left PCC activity in the comparison food > non-food compared with individuals heterozygous or homozygous for the short allele. The association between genotype and activation was linear, the subjects with two copies of the long allele variant having the strongest activation. These results demonstrate the possible genetically driven variation in the response of the left PCC to visual presentation of food in humans.

Defects in expression of genes of oxidative phosphorylation in mitochondria have been suggested to be a key pathophysiological feature in familial insulin resistance. We examined whether such defects can arise from lifestyle-related factors alone. Fourteen obesity-discordant (BMI difference 5.2 +/- 1.8 kg/m(2)) and 10 concordant (1.0 +/- 0.7 kg/m(2)) monozygotic (MZ) twin pairs aged 24-27 yr were identified among 658 MZ pairs in the population-based FinnTwin16 study. Whole body insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique. Transcript profiles of mitochondrial genes were compared using microarray data of fat biopsies from discordant twins. Body composition of twins was determined using DEXA and maximal oxygen uptake (Vo(2max)) and working capacity (W(max)) using a bicycle ergometer exercise test with gas exchange analysis. The obese cotwins had lower insulin sensitivity than their nonobese counterparts (M value 6.1 +/- 2.0 vs. 9.2 +/- 3.2 mg x kg LBM(-1) x min(-1), P < 0.01). Transcript levels of genes involved in the oxidative phosphorylation pathway (GO:0006119) in adipose tissue were lower (P < 0.05) in the obese compared with the nonobese cotwins. The obese cotwins were also less fit, as measured by Vo(2max) (50.6 +/- 6.5 vs. 54.2 +/- 6.4 ml x kg LBM(-1) x min(-1), for obese vs. nonobese, P < 0.05), W(max) (3.9 +/- 0.5 vs. 4.4 +/- 0.7 W/kg LBM, P < 0.01) and also less active, by the Baecke leisure time physical activity index (2.8 +/- 0.5 vs. 3.3 +/- 0.6, P < 0.01). This implies that acquired poor physical fitness is associated with defective expression of the oxidative pathway components in adipose tissue mitochondria.

Growth is a complex process, and only little is known on the genetic regulation of it. We analyzed the effect of genetic and environmental factors on growth in a longitudinal Swedish cohort of 231 monozygotic and 144 dizygotic twin pairs born 1973-1979 with length or height measured annually from birth to age 18. The data were analyzed by two different multivariate variance component models for twin data using the Mx statistical package. At birth and 1 year of age, a substantial part of the variation in length was because of common environment (50 and 57%, respectively) and the effect of genetic factors was minor. After 2 years of age, 91-97% of the variation of height could be explained by genetic differences whereas the rest was because of environmental variation not shared by twins. The genetic correlation between heights at ages 2 and 18 was 0.73 (95% confidence intervals 0.68-0.77) showing that 53% of the genes affecting height at these ages are the same or closely linked; with increasing age the correlation with genetic effects at age 18 become subsequently stronger. Especially in mid-childhood, growth was largely regulated by the same genetic factors. During puberty new genetic factors started to affect height, but also genetic variation affecting height at previous ages remained. These results suggest that genetic regulation of growth is rather uniform, which is encouraging for further efforts to identify genes affecting growth.

Serotonin (5-HT) has been implicated as one factor controlling body weight and feeding behaviour. We studied the association between obesity and 5-HT by investigating the brain serotonin transporter (SERT) binding in 16 monozygotic twin pairs with varying body mass index (BMI) differences. The radioligand [(123)I]nor-beta-CIT was used for single photon emission computed tomography (SPECT) imaging of SERT binding. SERT genotype was also identified for each subject. We hypothesized reduced SERT binding in twins with higher BMI as compared to their leaner co-twins, and increased SERT binding in subjects with LL homozygotes compared to LS heterozygotes and SS homozygotes. In pairwise analyses, twins with higher BMI had higher SERT binding than their leaner co-twins in the hypothalamus/thalamus (specific binding ratios 1.21+/-0.23 vs. 1.12+/-0.16, p=0.04). The difference was striking in women (1.17+/-0.24 vs. 1.04+/-0.16, p=0.01), but not in men (1.26+/-0.22 vs. 1.22+/-0.08, p=0.61). In individuals, no correlation between SERT binding and BMI was evident, and no differences were found in SERT binding between the three SERT genotypes. Our finding suggests an association between acquired obesity and the 5-HT system, particularly in women. However, this association was seen only in twin data, where genetic effects and many shared environmental factors are eliminated.

Background: The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background., Methods and Findings: We used a special study design of "clonal controls," rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean +/- standard deviation (SD) age 25.8 +/- 1.4 y and a body mass index (BMI) difference 5.2 +/- 1.8 kg/m(2). Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults., Conclusions: Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.

Objective: Physical activity (PA) begins to decline in adolescence with a concomitant increase in weight. We hypothesized that a vicious circle may arise between decreasing PA and weight gain from adolescence to early adulthood., Methods and Procedures: PA and self-perceived physical fitness assessed in adolescents (16-18 years of age) were used to predict the development of obesity (BMI > or =30 kg/m(2)) and abdominal obesity (waist >/=88 cm in females and > or =102 cm in males) at age 25 in 4,240 twin individuals (90% of twins born in Finland, 1975-1979). Ten 25-year-old monozygotic (MZ) twin pairs who were discordant for obesity (with a 16 kg weight difference) were then carefully evaluated for current PA (using a triaxial accelerometer), total energy expenditure (TEE, assessed by means of the doubly labeled water (DLW) method), and basal metabolic rate (BMR, assessed by indirect calorimetry)., Results: Physical inactivity in adolescence strongly predicted the risk for obesity (odds ratio (OR) 3.9, 95% confidence interval (CI) 1.4-10.9) and abdominal obesity (4.8, 1.9-12.0) at age 25, even after adjusting for baseline and current BMI. Poor physical fitness in adolescence also increased the risk for overall obesity (5.1, 2.0-12.7) and abdominal obesity (3.2, 1.5-6.7) in adulthood. Physical inactivity was both causative and secondary to the development of obesity discordance in the MZ pairs. TEE did not differ between the MZ co-twins. PA was lower whereas BMR was higher in the obese co-twins., Discussion: Physical inactivity in adolescence strongly and independently predicts total (and especially) abdominal obesity in young adulthood, favoring the development of a self-perpetuating vicious circle of obesity and physical inactivity. Physical activity should therefore be seriously recommended for obesity prevention in the young.

The contribution of genetic factors to individual differences in food use was estimated in a large population-based twin cohort of young adults (22- to 27-year-old). Male and female twins (n=2009 complete twin pairs) evaluated use-frequencies of 24 food items using 5 categories (1=never-5=several times a day) in a postal questionnaire. Foods were categorized by factor analysis. Estimates of the relative proportions of additive genetic, shared environmental, and unshared environmental effects on the use-frequency of food items and factor scores were obtained by quantitative genetic modeling of twin data based on linear structural equations. Four factors of food use were identified: "healthy" foods, high-fat foods, sweet foods, and meats. The variance of the use-frequency of food items and food categories was explained by additive genetic and unshared environmental influences, whereas shared environmental factors did not contribute to food use. The average proportions of genetic effects on the total variance of the use-frequency of food items and food categories were 40% and 45%, respectively. Sex differences were observed in the magnitude of genetic influences for use-frequency of four food items (chocolate, other sweets, fried foods, and meat), and in genetic factors underlying the use of three (fresh vegetables, fruits, and cheeses) items. In conclusion, family environment does not appear to influence the food use of young adults and thus nutritional education should be targeted at this age group to support development of healthy eating patterns. In addition, the results illuminate the importance of the sex-specific genetic effects on food use.

Background: The liver, once fatty, overproduces components of the metabolic syndrome, such as glucose and lipids. The amount of liver fat in subjects with and without the metabolic syndrome has not been determined. It is unknown which clinically available markers best reflect liver fat content., Measurements: Components of the metabolic syndrome as defined by the International Diabetes Federation and liver fat content by proton magnetic resonance spectroscopy were measured in 271 nondiabetic subjects (162 women, 109 men). In addition, other features of insulin resistance (serum insulin, C-peptide), intraabdominal and sc fat by magnetic resonance imaging, and liver enzymes (serum alanine aminotransferase and serum aspartate aminotransferase) were measured., Results: Liver fat was 4-fold higher in subjects with [n = 116; median 8.2% (interquartile range 3.2-18.7%)] than without [n = 155; 2.0% (1.0-5.0%); P < 0.0001] the metabolic syndrome. This increase in liver fat remained significant after adjusting for age, gender, and body mass index. All components of the metabolic syndrome correlated with liver fat content. The best correlate was waist in both women (r = 0.59, P < 0.0001) and men (r = 0.56, P < 0.0001). Liver fat correlated significantly with serum alanine aminotransferase (r = 0.39, P < 0.0001 for women; r = 0.44, P < 0.0001 for men) and aspartate aminotransferase (r = 0.27, P = 0.0005 for women; r = 0.31, P = 0.0012 for men) concentrations. The best correlates of liver fat were fasting serum insulin (r = 0.61; P < 0.0001 for both women and men) and C-peptide (r = 0.62; P < 0.0001 for both women and men)., Conclusions: Liver fat content is significantly increased in subjects with the metabolic syndrome as compared with those without the syndrome, independently of age, gender, and body mass index. Of other markers, serum C-peptide is the strongest correlate of liver fat.

Objective: To explore the association of eating styles with overweight and obesity in young adults, controlling for identical genetic background in monozygotic twins., Design: Prospective twin cohort study., Setting: Finland, 1991-2002., Subjects: Two-hundred and thirty-three women and 2060 men from the FinnTwin16 study, aged 16 years at baseline (T1), and ranging from 22 to 27 years at the time of the nutritional assessment (T4)., Methods: Eating styles (Restrictive/overeating, health-conscious, snacking, emotional and externally induced), self-reported at T4, were contrasted with body mass indices (BMIs) at T1 and T4., Results: At T4, obesity (BMI>or=30Kg/m(2)) was significantly cross-sectionally associated with restrictive eating, frequent snacks, eating in the evening, avoiding fatty foods and failure to maintain healthy eating patterns. These associations were independent of BMI at T1. Obese women self-reported more vulnerability to external eating cues and comfort eating than normal-weight women. However, in a multivariable model, only restrictive/overeating and health-conscious eating styles were significant correlates of obesity at T4, independent of gender and BMI at T1. When we controlled for genetic background restricting the analysis to the 39 female and 45 male monozygotic twin pairs discordant for obesity or overweight (BMI>or=25Kg/m(2)), restrictive/overeating eating style was still statistically significantly associated with excess weight., Conclusions: The eating styles of obese young adults differ from their normal-weight counterparts: restrictive eating, overeating and fewer healthy food choices are associated with obesity. Different eating styles may partially explain weight differences in individuals with identical genetic background.

Objectives: To investigate the contributions of genetic and environmental factors to the development of relative weight during the growth period., Design: Longitudinal twin study., Subjects: Two-hundred and thirty-one monozygotic and 144 dizygotic complete male twin pairs born between 1973 and 1979 were measured annually from birth to 18 years of age., Results: Body mass index (BMI, kg/m(2)) at age 18 correlated with BMI at age 1 (r=0.32, 95% confidence intervals (CI) 0.21-0.42), and this correlation increased steadily up to age 17 (r=0.91, 95% CI 0.89-0.93). Major part (81-95%) of these trait correlations was attributable to correlate additive genetic factors, but also unique environmental correlations were present during the whole-growth period. The correlation between ponderal index (kg/m(3)) at birth and BMI at age 18 was small (r=0.09, 95% CI 0.02-0.15) and totally because of correlated unique environmental factors., Conclusions: Our results suggest persistent genetic regulation of BMI from age 1 to 18. However, environmental factors, not shared by siblings, also affected the correlations of BMI. A small specific environmental correlation was found between ponderal index at birth and BMI at age 18, which may reflect the effect of neonatal environmental factors on adult BMI. A challenge to the future research is to identify chromosome regions and specific genes regulating the development of BMI as well as environmental factors affecting BMI through the growth period independently or interacting with genetic factors.

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.

Context: Both acquired and genetic factors regulate adipose tissue function., Objective: We determined whether adipose tissue mRNA expression is regulated by obesity, independently of genetic effects, by studying monozygotic (MZ) twins., Design: Seventeen healthy pairs of MZ twins aged 24-27 yr (body mass index 20.0-33.9 kg/m(2), intrapair differences in body weight 0.1-24.7 kg), were identified from the population-based FinnTwin16 cohort. Body fat percent was determined by dual-energy x-ray absorptiometry, sc and intraabdominal fat by magnetic resonance imaging, liver fat by proton spectroscopy, and insulin sensitivity by using the euglycemic insulin clamp technique. Adipocyte cell size and expression of 10 genes (real-time PCR) were determined in sc adipose tissue biopsies. Serum levels of some of the genes were measured using ELISA., Results: Within MZ twin pairs, acquired obesity was significantly related to increased adipocyte size and increased adipose tissue mRNA expressions of leptin, TNFalpha and the macrophage marker CD68, and decreased mRNA expressions of adiponectin and peroxisome proliferator-activated receptor-gamma. Intrapair differences in liver fat correlated directly with those in leptin and CD68 expression. CD68 expression and serum TNFalpha concentrations were correlated with insulin resistance., Conclusions: Acquired obesity independent of genetic influences is able to increase expression of macrophage and inflammatory markers and decrease adiponectin expression in adipose tissue.

Objective: To determine whether acquired obesity or accompanying metabolic changes such as adiponectin deficiency, insulin resistance, dyslipidemia, or visceral fat are associated, independent of genetic influences, with endothelial dysfunction by studying young adult monozygotic (MZ) twin pairs discordant for obesity., Research Methods and Procedures: Nine obesity-discordant (intra-pair difference in BMI, 3.8 to 10.1 kg/m(2)) and nine concordant (0 to 2.3 kg/m(2)) 24- to 27-year-old MZ twin pairs were identified from a population-based FinnTwin16-sample. Endothelial function was measured by blood flow responses to intrabrachial infusions of an endothelium-dependent (acetylcholine) and an endothelium-independent (sodium nitroprusside) vasodilator. Whole body insulin sensitivity was measured using the euglycemic insulin clamp technique, and forearm and body composition were measured with magnetic resonance imaging and DXA. In addition, serum levels of adiponectin, high-sensitivity C-reactive protein, and lipids were determined., Results: The heavier co-twins of the discordant pairs had significantly lower whole body insulin sensitivity than the leaner co-twins. Blood flows/muscle volume during infusions of acetylcholine and sodium nitroprusside were not altered by obesity. However, intra-pair differences in serum adiponectin, intra-abdominal fat, and C-reactive protein were significantly correlated with those in endothelial function. Only the relationship between intra-pair differences in adiponectin and endothelial function persisted in multiple linear regression analysis. Obesity-concordant co-twins had comparable insulin sensitivity and endothelial function., Discussion: In young adult MZ twins discordant for obesity, acquired adiponectin deficiency rather than obesity per se is an independent correlate of endothelial dysfunction.

Objective: To explore eating styles associated with intentional weight loss (IWL) and to determine whether the genetic liability in IWL is entirely shared with genetic liability affecting BMI., Research Methods and Procedures: As part of a longitudinal assessment of various health-related behaviors in a large population-based sample of twins, eating styles, BMI, and the number of times the study participants had intentionally lost > or = 5 kg were assessed by questionnaire from 4667 male and female twins (22 to 27 years of age). Associations of eating styles and IWL were explored using polytomous logistic regression models adjusted for BMI. Sex-specific bivariate structural equation modeling was used to explore genetic and environmental correlations of BMI and IWL., Results: Individuals who had engaged in IWL exhibited markedly more restricting, overeating, and alternating restricting/overeating than those in the no-IWL group. Snacking and eating in the evening were characteristic of women with at least two IWL attempts. Eating in response to visual and emotional cues was very pronounced in women who had engaged in IWL but much less so in men. IWL was estimated to have a heritability of 38% [95% confidence interval (CI), 19% to 55%] in men and 66% (95% CI, 55% to 75%) in women. The genetic covariance of BMI and IWL was 0.38 (95% CI, 0.28 to 0.47) for men and 0.45 (95% CI, 0.41 to 0.52) for women., Discussion: Distinct sex differences exist in eating styles associated with IWL and in the heritability of IWL. Most genetic factors affecting BMI are different from those affecting IWL.

We determined whether acquired obesity is associated with increases in liver or intra-abdominal fat or impaired insulin sensitivity by studying monozygotic (MZ) twin pairs discordant and concordant for obesity. We studied nineteen 24- to 27-yr-old MZ twin pairs, with intrapair differences in body weight ranging from 0.1 to 24.7 kg [body mass index (BMI) range 20.0-33.9 kg/m2], identified from a population-based FinnTwin16 sample. Fat distribution was determined by magnetic resonance imaging, percent body fat by dual-energy X-ray absorptiometry, liver fat by proton spectroscopy, insulin sensitivity by measuring the fasting insulin concentration, and whole body insulin sensitivity by the euglycemic insulin clamp technique. Intrapair differences in BMI were significantly correlated with those in intra-abdominal fat (r = 0.82, P < 0.001) and liver fat (r = 0.57, P = 0.010). Intrapair differences in fasting insulin correlated with those in subcutaneous abdominal (r = 0.60, P = 0.008), intra-abdominal (r = 0.75, P = 0.0001) and liver (r = 0.49, P = 0.048) fat. Intrapair differences in whole body insulin sensitivity correlated with those in subcutaneous abdominal (r = -0.72, P = 0.001) and intra-abdominal (r = -0.55, P = 0.015) but not liver (r = -0.20, P = 0.20) fat. We conclude that acquired obesity is associated with increases in intra-abdominal and liver fat and insulin resistance, independent of genetic factors.

Weight discordance is very rare in monozygotic (MZ) twin pairs; when found, however, such pairs are advantageous in the search for either environmental or epigenetic causes and consequences of obesity. We analyzed the growth patterns of young adult MZ pairs discordant and concordant for obesity. Screening 5 consecutive birth cohorts (1975-1979) of 22- to 27-year-old Finnish twins (the FinnTwin16 study), we found 14 obesity discordant (Body Mass Index [BMI] difference > or = 4 kg/m2) MZ pairs out of 658. Ten pairs participated in clinical studies. Nine concordant pairs (BMI difference < or = 2 kg/m2) were examined as controls. Lifetime measured heights and weights recorded in hospitals and health centers were traced manually. Height development was similar in all the co-twins of both groups. The weight differences between the co-twins of the discordant pairs began to emerge at 18 years leading to an average discordance of 16.4 kg, 5.6 kg/m2 (p for both = .005) at 25.7 years. The heavier co-twin weighed 221 g (p = .066), 1.0 kg/m2 (p = .01) more already at birth than the leaner, but the differences waned by 6 months of age and reappeared only after adolescence. Both the leaner and the heavier co-twins of the discordant pairs weighed more than expected by the singleton reference values (Cole et al., 1998) after 8 years. The concordant co-twins, on the other hand, grew similarly and after 6 months, their mean growth was not distinguishable from the singleton patterns. Young adulthood represents a critical period of gaining weight irrespective of genetic background in this twin sample.

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyzes the interconversion of inactive cortisone to active cortisol. Overexpression of 11beta-HSD-1 in murine adipose tissue results in glucocorticoid receptor (GR)alpha overexpression, central obesity, and insulin resistance. It is controversial whether 11beta-HSD-1 or GRalpha expression are increased in human adipose tissue in obesity. We studied effects of acquired obesity on 11beta-HSD-1 gene (real-time PCR) and protein (Western blotting) expression in sc adipose tissue in 17 monozygotic twin pairs aged 24-27 yr with a mean intrapair difference in body mass index (BMI) of 3.8 kg/m(2) (range 0.4-10.1 kg/m(2)). Intrapair correlations were calculated to study effects of acquired obesity on 11beta-HSD-1 expression. Western blot analysis of adipose tissue homogenates identified approximately 50- and approximately 68-kDa proteins specific for 11beta-HSD-1. Both structural forms correlated positively with 11beta-HSD-1 mRNA concentrations. Intrapair differences in 11beta-HSD-1 mRNA, and the 50- and 68-kDa proteins in sc adipose tissue correlated positively with those in BMI (kilograms per square meter) (r = 0.78 for 11beta-HSD-1 mRNA, P = 0.0002; r = 0.87 for the 11beta-HSD-1 50-kDa protein, P = 0.0003; and r = 0.62 for the 11beta-HSD-1 68-kDa protein, P = 0.033), total body fat (percent) (r = 0.65, P = 0.005; r = 0.83, P = 0.001; and r = 0.69, P = 0.013, respectively) and sc fat (cubed centimeters) (r = 0.66, P = 0.004; r = 0.94, P = 0.0001; and r = 0.71, P = 0.009, respectively). Furthermore, 11beta-HSD-1 mRNA and 50-kDa protein expression, but not 68-kDa protein expression, correlated positively with intrapair differences in intraabdominal fat mass (cubed centimeters) (r = 0.62, P = 0.008; r = 0.69, P = 0.013; r = 0.48, P = 0.112) and serum fasting insulin concentration (milliunits per liter) (r = 0.76, P = 0.0004; r = 0.60, P = 0.037; and r = 0.43, P = 0.160, respectively). Intrapair differences in GRalpha expression were significantly inversely correlated with those in BMI and total and sc fat mass. In conclusion, expression of 11beta-HSD-1 in sc adipose tissue is increased in human acquired obesity and is closely related to accumulation of sc and intraabdominal fat and features of insulin resistance.

Aims/hypothesis: Protein-mediated trans-membrane and intracellular fatty acid trafficking are becoming increasingly recognised as biochemically and physiologically important concepts. Obesity and insulin resistance are polygenic disorders, heavily influenced by environmental and life-style factors, and are virtually always associated with disturbed fatty acid metabolism in adipose and other tissues. The aim of this study was to investigate mRNA expression levels of fatty-acid-handling proteins in adipose tissue in relation to markers of genetic and acquired obesity and insulin resistance., Methods: We quantified mRNA expression of subcutaneous adipose tissue fatty-acid-handling proteins (ALBP, KLBP, FATP1, FATP4, CD36, ACS1) in 17 monozygotic twin-pairs with a range of intra-pair differences (Delta) in BMI and detailed measures of obesity and insulin resistance, allowing influences of genetic and non-genetic factors to be distinguished., Results: In acquired obesity FATP4 expression was up-regulated independently of genetic background (DeltaFATP4 versus DeltaBMI; r=0.50, p=0.04; DeltaFATP4 versus Deltabody fat; r=0.59, p=0.01). Similarly, CD36 and FATP1 expression correlated with acquired differences in HDL cholesterol and non-esterified fatty acid concentrations respectively. Moreover, FATP4 and CD36 expression levels correlated with measures of obesity and insulin resistance that are influenced by both genetic and non-genetic factors (FATP4 versus BMI: r=0.53, p=0.0001; FATP4 versus body fat: r=0.51, p=0.002; FATP4 versus homeostasis model assessment [HOMA]: r=0.49, p=0.001; CD36 versus BMI: r=0.50, p=0.02; CD36 versus body fat: r=0.63, p=0.001; CD36 versus HOMA: r=0.34, p=0.06)., Conclusions/interpretation: These findings indicate that expression of specific adipose tissue fatty-acid-handling proteins is related to obesity and insulin resistance, and that, in particular, FATP4 plays a role in acquired obesity. Our results suggest that facilitated fatty acid trafficking is a physiologically and pathologically relevant phenomenon in man.

Body mass index (BMI), a simple anthropometric measure, is the most frequently used measure of adiposity and has been instrumental in documenting the worldwide increase in the prevalence of obesity witnessed during the last decades. Although this increase in overweight and obesity is thought to be mainly due to environmental changes, i.e., sedentary lifestyles and high caloric diets, consistent evidence from twin studies demonstrates high heritability and the importance of genetic differences for normal variation in BMI. We analysed self-reported data on BMI from approximately 37,000 complete twin pairs (including opposite sex pairs) aged 20-29 and 30-39 from eight different twin registries participating in the GenomEUtwin project. Quantitative genetic analyses were conducted and sex differences were explored. Variation in BMI was greater for women than for men, and in both sexes was primarily explained by additive genetic variance in all countries. Sex differences in the variance components were consistently significant. Results from analyses of opposite sex pairs also showed evidence of sex-specific genetic effects suggesting there may be some differences between men and women in the genetic factors that influence variation in BMI. These results encourage the continued search for genes of importance to the body composition and the development of obesity. Furthermore, they suggest that strategies to identify predisposing genes may benefit from taking into account potential sex specific effects.

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.

Objective: To investigate whether girls with insulin dependent diabetes mellitus (IDDM) were more overweight than nondiabetic girls, and how diet, insulin treatment, metabolic control, age, and pubertal status were related to body weight and fat content., Design: Case-control study., Subjects and Methods: 48 IDDM girls aged 10-19 years and controls matched for age and social class participated in the study. Overweight was assessed by body mass index (BMI), relative weight, and body fat from skinfold thicknesses. Food consumption data were collected by a 48 hour recall method., Results: The girls with IDDM were more overweight than control girls according to all measures of obesity (for example, mean BMI 20.3 v 18.9 kg/m2). The daily insulin dose/body weight correlated positively with BMI and per cent body fat., Conclusions: Girls with IDDM are more overweight than their peers, which indicates that a more effective prevention of obesity is needed in the treatment of diabetes.