Showing papers by "Claude Bouchard published in 2014"

Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications

Abstract: Importance Short-term studies show that bariatric surgery causes remission of diabetes. The long-term outcomes for remission and diabetes-related complications are not known. Objectives To determine the long-term diabetes remission rates and the cumulative incidence of microvascular and macrovascular diabetes complications after bariatric surgery. Design, Setting, and Participants The Swedish Obese Subjects (SOS) is a prospective matched cohort study conducted at 25 surgical departments and 480 primary health care centers in Sweden. Of patients recruited between September 1, 1987, and January 31, 2001, 260 of 2037 control patients and 343 of 2010 surgery patients had type 2 diabetes at baseline. For the current analysis, diabetes status was determined at SOS health examinations until May 22, 2013. Information on diabetes complications was obtained from national health registers until December 31, 2012. Participation rates at the 2-, 10-, and 15-year examinations were 81%, 58%, and 41% in the control group and 90%, 76%, and 47% in the surgery group. For diabetes assessment, the median follow-up time was 10 years (interquartile range [IQR], 2-15) and 10 years (IQR, 10-15) in the control and surgery groups, respectively. For diabetes complications, the median follow-up time was 17.6 years (IQR, 14.2-19.8) and 18.1 years (IQR, 15.2-21.1) in the control and surgery groups, respectively. Interventions Adjustable or nonadjustable banding (n = 61), vertical banded gastroplasty (n = 227), or gastric bypass (n = 55) procedures were performed in the surgery group, and usual obesity and diabetes care was provided to the control group. Main Outcomes and Measures Diabetes remission, relapse, and diabetes complications. Remission was defined as blood glucose Results The diabetes remission rate 2 years after surgery was 16.4% (95% CI, 11.7%-22.2%; 34/207) for control patients and 72.3% (95% CI, 66.9%-77.2%; 219/303) for bariatric surgery patients (odds ratio [OR], 13.3; 95% CI, 8.5-20.7; P P P P = .001). Conclusions and Relevance In this very long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials. Trial Registration clinicaltrials.gov Identifier:NCT01479452

Testosterone, Sex Hormone-Binding Globulin and the Metabolic Syndrome in Men: An Individual Participant Data Meta-Analysis of Observational Studies

Abstract: Background: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. Objectives: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. Data sources: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. Study Eligibility Criteria: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. Methods: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. Results: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. Conclusions: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

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

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

Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection

Abstract: Genome-wide association studies (GWAS) may have reached their limit of detecting common type 2 diabetes (T2D)–associated genetic variation. We evaluated the performance of current polygenic T2D prediction. Using data from the Framingham Offspring (FOS) and the Coronary Artery Risk Development in Young Adults (CARDIA) studies, we tested three hypotheses: 1) a 62-locus genotype risk score (GRSt) improves T2D prediction compared with previous less inclusive GRSt; 2) separate GRS for β-cell (GRSβ) and insulin resistance (GRSIR) independently predict T2D; and 3) the relationships between T2D and GRSt, GRSβ, or GRSIR do not differ between blacks and whites. Among 1,650 young white adults in CARDIA, 820 young black adults in CARDIA, and 3,471 white middle-aged adults in FOS, cumulative T2D incidence was 5.9%, 14.4%, and 12.9%, respectively, over 25 years. The 62-locus GRSt was significantly associated with incident T2D in all three groups. In FOS but not CARDIA, the 62-locus GRSt improved the model C statistic (0.698 and 0.726 for models without and with GRSt, respectively; P < 0.001) but did not materially improve risk reclassification in either study. Results were similar among blacks compared with whites. The GRSβ but not GRSIR predicted incident T2D among FOS and CARDIA whites. At the end of the era of common variant discovery for T2D, polygenic scores can predict T2D in whites and blacks but do not outperform clinical models. Further optimization of polygenic prediction may require novel analytic methods, including less common as well as functional variants.

Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Abstract: Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10−8) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10−4) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

An evolving scientific basis for the prevention and treatment of pediatric obesity

Abstract: The 2013 Pennington Biomedical Research Center's Scientific Symposium focused on the treatment and management of pediatric obesity and was designed to (i) review recent scientific advances in the prevention, clinical treatment and management of pediatric obesity, (ii) integrate the latest published and unpublished findings and (iii) explore how these advances can be integrated into clinical and public health approaches. The symposium provided an overview of important new advances in the field, which led to several recommendations for incorporating the scientific evidence into practice. The science presented covered a range of topics related to pediatric obesity, including the role of genetic differences, epigenetic events influenced by in utero development, pre-pregnancy maternal obesity status, maternal nutrition and maternal weight gain on developmental programming of adiposity in offspring. Finally, the relative merits of a range of various behavioral approaches targeted at pediatric obesity were covered, together with the specific roles of pharmacotherapy and bariatric surgery in pediatric populations. In summary, pediatric obesity is a very challenging problem that is unprecedented in evolutionary terms; one which has the capacity to negate many of the health benefits that have contributed to the increased longevity observed in the developed world.

Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate–related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Competing targets of microRNA-608 affect anxiety and hypertension

Abstract: MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects others remained unclear. We found that changing a single miRNA-target interaction can simultaneously affect multiple other miRNA-target interactions and modify physiological phenotype. We show that miR-608 targets acetylcholinesterase (AChE) and demonstrate weakened miR-608 interaction with the rs17228616 AChE allele having a single-nucleotide polymorphism (SNP) in the 3'-untranslated region (3'UTR). In cultured cells, this weakened interaction potentiated miR-608-mediated suppression of other targets, including CDC42 and interleukin-6 (IL6). Postmortem human cortices homozygote for the minor rs17228616 allele showed AChE elevation and CDC42/IL6 decreases compared with major allele homozygotes. Additionally, minor allele heterozygote and homozygote subjects showed reduced cortisol and elevated blood pressure, predicting risk of anxiety and hypertension. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice. We demonstrate that SNPs in miRNA-binding regions could cause expanded downstream effects changing important biological pathways.

Findings from the Quebec Family Study on the Etiology of Obesity: Genetics and Environmental Highlights

Abstract: The Quebec Family Study (QFS) was an observational study with three cycles of data collection between 1979 and 2002 in Quebec City, Canada. The cohort is a mixture of random sampling and ascertainment through obese individuals. The study has significantly contributed to our understanding of the determinants of obesity and associated disease risk over the past 35 years. In particular, the QFS cohort was used to investigate the contribution of familial resemblance and genetic effects on body fatness and behaviors related to energy balance. Significant familial aggregation and genetic heritability were reported for total adiposity, fat-free mass, subcutaneous fat distribution, abdominal and visceral fat, resting metabolic rate, physical activity level and other behavioral traits. The resources of QFS were also used to study the contribution of several nontraditional (non-caloric) risk factors as predictors of excess body weight and gains in weight and adiposity over time, including low calcium and micronutrient intake, high disinhibition eating behavior trait, and short sleep duration. An important finding relates to the interactions between dietary macronutrient intake and exercise intensity on body mass and adiposity.

Dynamic model predicting overweight, obesity, and extreme obesity prevalence trends.

Abstract: Objective Obesity prevalence in the United States (US) appears to be leveling, but the reasons behind the plateau remain unknown. Mechanistic insights can be provided from a mathematical model. The objective of this study is to model known multiple population parameters associated with changes in body mass index (BMI) classes and to establish conditions under which obesity prevalence will plateau.

Effects of Long-Term Averaging of Quantitative Blood Pressure Traits on the Detection of Genetic Associations

Abstract: Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10−8); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

Cardiorespiratory fitness and cognitive function in middle age: The CARDIA Study

Abstract: Objective: To investigate whether greater cardiorespiratory fitness (CRF) is associated with better cognitive function 25 years later. Methods: We studied 2,747 participants in the community-based Coronary Artery Risk Development in Young Adults Study of black and white men and women aged 18 to 30 years at recruitment in 1985–1986 (baseline year 0). Symptom-limited maximal treadmill test durations at years 0 and 20 provided measures of CRF. Cognitive tests at year 25 measured verbal memory (Rey Auditory Verbal Learning Test [RAVLT]), psychomotor speed (Digit Symbol Substitution Test [DSST]), and executive function (Stroop Test). Results: Per minute of baseline CRF, the RAVLT was 0.12 words recalled higher (standard error [SE] = 0.03, p p p p = 0.07). Analysis in the subset of 1,957 participants who also completed the year-20 treadmill test showed that 20-year change in CRF was positively associated only with DSST ( p Conclusions: Better verbal memory and faster psychomotor speed at ages 43 to 55 years were clearly associated with better CRF 25 years earlier.

Replication of 6 Obesity Genes in a Meta-Analysis of Genome-Wide Association Studies from Diverse Ancestries

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

Cardiorespiratory fitness and cognitive function in middle age

Abstract: Objective: To investigate whether greater cardiorespiratory fitness (CRF) is associated with better cognitive function 25 years later. Methods: We studied 2,747 participants in the community-based Coronary Artery Risk Development in Young Adults Study of black and white men and women aged 18 to 30 years at recruitment in 1985–1986 (baseline year 0). Symptom-limited maximal treadmill test durations at years 0 and 20 provided measures of CRF. Cognitive tests at year 25 measured verbal memory (Rey Auditory Verbal Learning Test [RAVLT]), psychomotor speed (Digit Symbol Substitution Test [DSST]), and executive function (Stroop Test). Results: Per minute of baseline CRF, the RAVLT was 0.12 words recalled higher (standard error [SE] 5 0.03, p , 0.0001), the DSST was 0.92 digits higher (SE 5 0.13, p , 0.0001), and the Stroop Test score was 0.52 lower (better performance, SE 5 0.11, p , 0.0001), after accounting for race, sex, age, education, and clinical center. Compared with the lowest quartile of CRF, each cognitive test was 21% to 34% of an SD better in the highest CRF quartile. Further adjustment for lifestyle and clinical measures attenuated coefficients for RAVLT and DSST slightly, while the coefficient predicting the Stroop Test lost more than half its value (p 5 0.07). Analysis in the subset of 1,957 participants who also completed the year-20 treadmill test showed that 20-year change in CRF was positively associated only with DSST (p , 0.001).

Change in sleep duration and visceral fat accumulation over 6 years in adults.

Abstract: Objective To investigate the relationship between change in sleep duration and long-term visceral adiposity change in adults Methods A longitudinal analysis was conducted on 293 participants, aged 18-65 years, followed for a mean of 60 ± 09 years At baseline and year 6, sleep duration was self-reported and visceral adipose tissue (VAT) assessed using computed tomography Multivariable modeling was used to examine the association between change in sleep duration and VAT change over the 6-year time period, with adjustments made for age, sex, change in BMI, personal characteristics, energy intake, and physical activity Results Participants gained an average of 192 ± 373 cm2 in VAT over the follow-up period Baseline short (≤6 h/day) and long (≥9 h/day) sleepers gained significantly more VAT than those reporting sleeping 7-8 hours a night (234 and 202 cm2 vs 141 cm2, respectively, P < 005) Using continuous data, we observed that the change in sleep duration was not associated with VAT change However, a change in sleep duration from ≤6 h/day to 7-8 h/day was associated with 6 cm2 fewer VAT gain after multivariable adjustment (P < 005) Conclusions A spontaneous change in sleep duration (from a short to an adequate duration) is independently and inversely associated with long-term VAT accumulation

An empirical comparison of meta-analysis and mega-analysis of individual participant data for identifying gene-environment interactions

Abstract: For analysis of the main effects of SNPs, meta-analysis of summary results from individual studies has been shown to provide comparable results as "mega-analysis" that jointly analyzes the pooled participant data from the available studies. This fact revolutionized the genetic analysis of complex traits through large GWAS consortia. Investigations of gene-environment (G×E) interactions are on the rise since they can potentially explain a part of the missing heritability and identify individuals at high risk for disease. However, for analysis of gene-environment interactions, it is not known whether these methods yield comparable results. In this empirical study, we report that the results from both methods were largely consistent for all four tests; the standard 1 degree of freedom (df) test of main effect only, the 1 df test of the main effect (in the presence of interaction effect), the 1 df test of the interaction effect, and the joint 2 df test of main and interaction effects. They provided similar effect size and standard error estimates, leading to comparable P-values. The genomic inflation factors and the number of SNPs with various thresholds were also comparable between the two approaches. Mega-analysis is not always feasible especially in very large and diverse consortia since pooling of raw data may be limited by the terms of the informed consent. Our study illustrates that meta-analysis can be an effective approach also for identifying interactions. To our knowledge, this is the first report investigating meta-versus mega-analyses for interactions.

Where is the beef? Waist circumference is more highly correlated with BMI and total body fat than with abdominal visceral fat in children

Abstract: Medically accepted ‘facts’ sometimes become outmoded when additional research shows them to be incorrect. This Commentary evaluates the evidence for the measurement of waist circumference (WC) in children and adolescents as a good surrogate for the measurement of abdominal visceral fat (VF) and for assessing the risk for ‘metabolic syndrome’. WC correlates well with total body fat, but does not correlate any better for abdominal VF than does BMI. The use of WC as a marker for VF and for ‘metabolic syndrome’ in children no longer seems valid even in the field or for epidemiological studies.

Advances in exercise, fitness, and performance genomics in 2013.

Abstract: The most significant and scientifically sound articles in exercise genomics that were published in 2013 are reviewed in this report. No article on the genetic basis of sedentary behavior or physical activity level was identified. A calcineurin- and alpha actinin-2-based mechanism has been identified as the potential molecular basis for the observed lower muscular strength and power in alpha actinin-3-deficient individuals. Although baseline muscle transcriptomic signatures were found to be associated with strength training-induced muscle hypertrophy, no predictive genomic variants could be identified as of yet. One study found no clear evidence that the inverse relation between physical activity level and incident CHD events was influenced by 58 genomic variants clustered into four genetic scores. Lower physical activity level in North American populations may be driving the apparent risk of obesity in fat mass- and obesity-associated gene (FTO)-susceptible individuals compared with more active populations. Two large studies revealed that common genetic variants associated with baseline levels of plasma HDL cholesterol and triglycerides are not clear predictors of changes induced by interventions focused on weight loss, diet, and physical activity behavior. One large study from Japan reported that a higher fitness level attenuated the arterial stiffness-promoting effect of the Ala54 allele at the fatty acid binding protein 2 locus, which is a controversial finding because previous studies have suggested that Thr54 was the risk allele. Using transcriptomics to generate genomic targets in an unbiased manner for subsequent DNA sequence variants studies appears to be a growing trend. Moreover, exercise genomics is rapidly embracing gene and pathway analysis to better define the underlying biology and provide a foundation for the study of human variation.

Predictors of body composition and body energy changes in response to chronic overfeeding

Abstract: We have previously shown that 24 young lean men (12 pairs of identical twins) subjected to a standardized 353 MJ (84 000 kcal) overfeeding protocol over 100 days exhibited individual differences in body weight and composition gains. The mean (+s.d.) gains in fat mass (FM) and fat-free mass (FFM) were 5.4+1.9 kg and 2.7+1.5 kg for a total body energy (BE) gain of 221+75 MJ, representing 63% of the energy surplus consumed. We report here on the most important baseline correlates of these overfeeding-induced changes with the aim of identifying biomarkers of the response. Baseline maximal oxygen uptake per kg body mass was negatively correlated with gains in weight, FM and BE (all P<0.05). Enzyme activities indicative of skeletal muscle oxidative potential correlated with gains in FM and BE (all P<0.05). Baseline thyroid-stimulating hormone levels in response to thyrotropin-releasing hormone stimulation correlated positively with changes in FM-to-FFM ratio (P<0.05). Plasma concentrations of androstenediol sulfate, dehydroepiandrosterone and 17-hydroxy pregnenolone were negatively correlated with gains in FM and BE (0.01

Cross-sectional associations of acylation stimulating protein (ASP) and adipose tissue gene expression with estradiol and progesterone in pre- and postmenopausal women.

Abstract: SummaryObjective Sex steroid hormones play an important regulatory role in fat metabolism and obesity. We hypothesized involvement of interactions between ovarian hormones with acylation stimulating protein (ASP). Design, patients and measurements In 392 women with wide age (18–69 years) and body size (BMI: 17 to 90 kg/m2) ranges, fasting plasma levels of ASP, ovarian hormones, glucose, adiponectin and lipids/apolipoproteins were assessed, along with determination of metabolic syndrome (MS) features. Gene expression of C3 (ASP precursor) and related receptors C5L2, C3aR and C5aR in subcutaneous and omental adipose tissues was measured in a subset. Results Acylation stimulating protein correlated negatively with concentrations of estradiol (P < 0·0001), adiponectin (P < 0·001) and apolipoprotein A1 (P < 0·001) and positively with apolipoprotein B levels (P < 0·001), systolic blood pressure (P < 0·001), waist circumference (P < 0·001), and triglyceride concentrations (P < 0·01). In age-matched groups of lean, overweight, metabolically healthy obese (MHO) and obese with metabolic syndrome (MSO), there was a stepwise increase in ASP levels (P < 0·001) while concentrations of adiponectin (P < 0·0001) and estradiol (P < 0·001) but not those of progesterone decreased. Progesterone but not estradiol levels correlated positively with C3 gene expression in omental adipose tissue (P < 0·05) and negatively with C5L2 expression in both omental (P < 0·01) and subcutaneous (P < 0·05) adipose tissues. Conclusion Our results are consistent with the concept that sex hormones differentially influence circulating ASP and adipose tissue gene expression of its related proteins in a depot-specific manner. ASP may play a role in the regulation of regional fat metabolism through interactions with sex hormones in women.

Commonality versus specificity among adiposity traits in normal-weight and moderately overweight adults.

Abstract: Commonality versus specificity among adiposity traits in normal-weight and moderately overweight adults

Epidemiology, etiology, and physiopathology

Abstract: History, Definitions, and Prevalence Obesity Has Always Been with Us: An Historical Introduction George A. Bray Measurement of Total Adiposity, Regional Fat Depots, and Ectopic Fat Steven B. Heymsfield, Houchun Harry Hu, ZiMian Wang, Wei Shen, and Ye Jin Anthropometric Indicators in Relation to the Gold Standards Peter T. Katzmarzyk Worldwide Prevalence of Obesity in Adults Jacob C. Seidell Prevalence and Consequences of Pediatric Obesity Nazrat M. Mirza and Jack A. Yanovski Obesity in Older Adults in the United States Tala H.I. Fakhouri, Brian K. Kit, Margaret D. Carroll, Katherine M. Flegal, and Cynthia L. Ogden Gender, Ethnic, and Geographic Variation in Adiposity Timothy Olds and Carol Maher Biological Determinants of Obesity Genetic Component to Obesity: Evidence from Genetic Epidemiology Louis Perusse, Treva K. Rice, and Claude Bouchard Genes and the Predisposition to Obesity Marcel den Hoed and Ruth J. F. Loos Epigenetic Mechanisms in Obesity Robert A. Waterland Fetal and Early Postnatal Life Determinants of Adiposity Felicia M. Low, Peter D. Gluckman, and Mark A. Hanson Animal Models of Obesity: Perspectives on Evolution of Strategies for Their Development and Analysis of Their Phenotypes Heike Munzberg, Tara M. Henagan, and Thomas W. Gettys Animal Models of Obesity: Nonhuman Primates Barbara C. Hansen CNS Regulation of Energy Balance Hans-Rudolf Berthoud and Barry E. Levin Gastrointestinal Regulation of Energy Balance Timo D. Muller, Kristy Heppner, Chun-Xia Yi, Paul T. Pfluger, and Matthias H. Tschop Gut Microbiome and Obesity Patrice D. Cani Sympathetic Nervous System and Endocrine Determinants of Energy Balance Hamid R. Farshchi and Ian A. Macdonald Insulin Resistance and Obesity Charmaine S. Tam, Morvarid Kabir, Richard N. Bergman, and Eric Ravussin White and Brown Adipose Tissue Development Meghan E. McDonald and Stephen R. Farmer Adipose Tissue Metabolism, Adipokines, and Obesity Dominique Langin and Max Lafontan Visceral Adipose Tissue and Ectopic Fat Deposition Amalia Gastaldelli Skeletal Muscle Metabolism and Obesity Jeffrey J. Brault, G. Lynis Dohm, and Joseph A. Houmard Mitochondrial Bioenergetic Aspects of Obesity and Weight Loss Mary-Ellen Harper, Robert Dent, and Ruth McPherson Resting Metabolic Rate, Thermic Effect of Food, and Obesity Yves Schutz and Abdul G. Dulloo Energy Cost of Exercise, Postexercise Metabolic Rates, and Obesity Einat Shalev-Goldman, Trevor O'Neill, and Robert Ross Energy Partitioning, Substrate Oxidation Rates, and Obesity Angelo Tremblay, Yves Deshaies, and Katherine Cianflone Viral Infections and Adiposity Nikhil V. Dhurandhar, Emily J. Dhurandhar, and Richard L. Atkinson Behavioral Determinants of Obesity Obesity: Influence of the Food Environment on Ingestive Behaviors Richard D. Mattes and Sze Yen Tan Obesity and Related Eating Disorders Brooke A. Bailer, Lauren E. Bradley, and Kelly C. Allison Tobacco Use, Smoking Cessation, and Obesity Carole Clair, Semira Gonseth, Jacques Cornuz, and Ivan Berlin Breastfeeding and Later Obesity Nancy F. Butte Beverages and Obesity: Biology, History, Trends Barry M. Popkin and Frank B. Hu Sedentary Time and Obesity Neville Owen and Marc Hamilton Occupational Work and Obesity Nicholas D. Gilson and Catrine Tudor-Locke Leisure-Time Physical Activity and Obesity Thrudur Gunnarsdottir, Renee J. Rogers, John M. Jakicic, and James O. Hill Sustained Short Sleep and Risk of Obesity: Evidence in Children and Adults Michelle A. Miller, George Smith, Andrew O'Keeffe, and Francesco P. Cappuccio Environmental, Social, and Cultural Determinants of Obesity Role of Agriculture and the Food Industry in America's Obesity James E. Tillotson Transportation Policies and Obesity David R. Bassett Jr. Urban Environment, Building Design, and Obesity Reid Ewing and Gail Meakins Social and Economic Determinants of Obesity Lindsay McLaren Influence of Culture on Obesity Alison Tovar and Aviva Must Bias, Discrimination, and Obesity Rebecca M. Puhl, Kelly D. Brownell, and Jenny A. DePierre Environmental Chemicals and Obesity Amanda S. Janesick, Thaddeus T. Schug, Jerrold J. Heindel, and Bruce Blumberg Economic Costs of Obesity Ping Zhang, Sundar S. Shrestha, and Rui Li Consequences of Obesity Obesity and Mortality Rates Gary Whitlock and Rachel R. Huxley Obesity and Heart Disease Peter W.F. Wilson Obesity and Hypertension Raj S. Padwal and Arya M. Sharma Obesity and Lipoprotein Metabolism Sally Chiu and Ronald M. Krauss Obesity and Type Diabetes Henna Cederberg and Markku Laakso Obesity and Metabolic Syndrome Jean-Pierre Despres Obesity and Cancer: Clinical Epidemiology Andrew G. Renehan Inflammatory Causes of Obesity and Metabolic Diseases Ebru Erbay and Gokhan S. Hotamis,ligil Obesity and Gallbladder Disease Cynthia W. Ko and Sum P. Lee Obesity and Liver: Cell Death, Compensatory Growth, and Repair of Damage Giovanni Tarantino Obesity, Lung Function, and Lung Disease Nour A. Assad, Jesse H. Alvarado, and Akshay Sood Obesity, Arthritis, and Gout Luke Dawson, Anita E. Wluka, Yuanyuan Wang, and Flavia M. Cicuttini Obesity and Mental Health Lucy F. Faulconbridge and Anthony Fabricatore Obesity and Health-Related Quality of Life Donald A. Williamson and W. Jack Rejeski Obesity and Pregnancy Outcomes Raul Artal and Sarah Hopkins Obesity, an Inactive Lifestyle and Low Fitness: The Most Unhealthy Combination Paul A. McAuley and Steven N. Blair Index