Impact of maternal cardiometabolic status after bariatric surgery on the association between telomere length and adiposity in offspring.

The impact of bariatric surgery on metabolic and inflammatory status are reflected in the epigenetic profile and telomere length mediated by the changes in the metabolic status of the patients. This study compared the telomere length of children born before versus after maternal bariatric surgery as a surrogate to test the influence of the mother's metabolic status on children's telomere length. DNA methylation telomere length (DNAmTL) was estimated from Methylation-EPIC BeadChip array data from a total of 24 children born before and after maternal bariatric surgery in the greater Quebec City area. DNAmTL was inversely associated with chronological age in children (r = - 0.80, p < 0.001) and significant differences were observed on age-adjusted DNAmTL between children born before versus after the maternal bariatric surgery. The associations found between body mass index and body fat percentage with DNAmTL in children born after the surgery were influenced by maternal triglycerides, TG/HDL-C ratio and TyG index. This study reports the impact of maternal bariatric surgery on offspring telomere length. The influence of maternal metabolic status on the association between telomere length and markers of adiposity in children suggests a putative modulating effect of bariatric surgery on the cardiometabolic risk in offspring.

Relationship between lifestyle habits and cardiovascular risk factors in familial hypercholesterolemia.

BACKGROUND AND AIM: Little is known about the cardioprotective potential of a healthy lifestyle in familial hypercholesterolemia (FH). The objective of this study was to evaluate the relationship between lifestyle and cardiovascular risk factors in adults with FH. METHODS AND RESULTS: This cross-sectional study leveraged data from the CARTaGENE Quebec population-based cohort (Canada). Participants with FH were identified using the validated Simplified Canadian Definition for FH. A healthy lifestyle score (HLS), ranging from 0 to 5, was calculated per adherence to 5 lifestyle habits: 1) not smoking; 2) being physically active (≥150 min/week of moderate or vigorous physical activity); 3) eating a healthy diet (Alternate Healthy Eating Index ≥50%); 4) having a light to moderate alcohol consumption (men: 1-30 g/day; women: 1-15 g/day); and 5) sleeping 7-8 h/day. Among the 122 included individuals (women, n = 78; men, n = 44; mean age ± SD: 57.3 ± 6.7 years), 92 (75.4%) had a HLS ≤3/5, while only 5 (4.1%) had a HLS of 5/5. After adjustments for sex, age, body mass index, and lipid-lowering medication use, we found no evidence of an association between the HLS and concentrations of LDL-cholesterol (ß = 0.04, 95% CI = -0.08, 0.15 mmol/L; P = 0.54). However, the HLS was favorably associated with HbA1c levels (ß = -0.07, 95% CI = -0.13, -0.01%; P = 0.02), and statistical trends suggested favorable associations with HDL-cholesterol (ß = 0.06, 95% CI = -0.02, 0.14 mmol/L; P = 0.06) and waist circumference (ß = -2.22, 95% CI = -4.62, 0.17 cm; P = 0.07). CONCLUSION: This study suggests that a healthy lifestyle is favorably associated with CVD risk factors in adults with FH.

The fit-active profile to better reflect the benefits of a lifelong vigorous physical activity participation: mini-review of literature and population data.

Physical activity is favourably considered for its effect on metabolic fitness and body composition. This observation is generally supported by observational studies and is concordant with endurance-trained individuals' metabolic and morphological profiles. However, in some contexts, the measurement of physical activity habits may not provide an adequate representation of its benefits. In this paper, we review relevant literature on the respective effects of fitness and physical activity on anthropometric and metabolic variables and the informative potential of a classification based on aerobic fitness and activity indicators. The relevance to defining a profile based on both fitness and activity is reinforced by data from the Quebec Family Study showing that, in both men and women, "fit-active" individuals displayed a much more favourable morphological and metabolic profile than "unfit-inactive" individuals. Moreover, these benefits seemed to be more related to variations in fitness than in physical activity. In summary, evidence suggests that a profile combining information on aerobic fitness and physical activity may better reflect the lifelong impact of physical activity on body composition and health. Novelty: The fit-active profile better reflects the long-term benefits of vigorous physical activity participation on health. The reported benefits seem to be more related to variations in aerobic fitness than to those in physical activity.

Polygenic risk score for predicting weight loss after bariatric surgery.

BACKGROUND: The extent of weight loss among patients undergoing bariatric surgery is highly variable. Herein, we tested the contribution of genetic background to such interindividual variability after biliopancreatic diversion with duodenal switch. METHODS: Percentage of excess body weight loss (%EBWL) was monitored in 865 patients over a period of 48 months after bariatric surgery, and two polygenic risk scores were constructed with 186 and 11 (PRS186 and PRS11) single nucleotide polymorphisms previously associated with body mass index (BMI). RESULTS: The accuracy of the %EBWL logistic prediction model - including initial BMI, age, sex, and surgery modality, and assessed as the area under the receiver operating characteristics (ROC) curve adjusted for optimism (AUCadj = 0.867) - significantly increased after the inclusion of PRS186 (ΔAUCadj = 0.021; 95% CI of the difference [95% CIdiff] = 0.005-0.038) but not PRS11 (ΔAUCadj= 0.008; 95% CIdiff= -0.003-0.019). The overall fit of the longitudinal linear mixed model for %EBWL showed a significant increase after addition of PRS186 (-2 log-likelihood = 12.3; P = 0.002) and PRS11 (-2 log-likelihood = 9.9; P = 0.007). A significant interaction with postsurgery time was found for PRS186 (ß = -0.003; P = 0.008) and PRS11 (ß = -0.008; P = 0.03). The inclusion of PRS186 and PRS11 in the model improved the cost-effectiveness of bariatric surgery by reducing the percentage of false negatives from 20.4% to 10.9% and 10.2%, respectively. CONCLUSION: These results revealed that genetic background has a significant impact on weight loss after biliopancreatic diversion with duodenal switch. Likewise, the improvement in weight loss prediction after addition of polygenic risk scores is cost-effective, suggesting that genetic testing could potentially be used in the presurgical assessment of patients with severe obesity. FUNDING: Heart and Stroke Foundation of Canada (G-17-0016627) and Canada Research Chair in Genomics Applied to Nutrition and Metabolic Health (no. 950-231-580).

No Evidence of a Common DNA Variant Profile Specific to World Class Endurance Athletes.

There are strong genetic components to cardiorespiratory fitness and its response to exercise training. It would be useful to understand the differences in the genomic profile of highly trained endurance athletes of world class caliber and sedentary controls. An international consortium (GAMES) was established in order to compare elite endurance athletes and ethnicity-matched controls in a case-control study design. Genome-wide association studies were undertaken on two cohorts of elite endurance athletes and controls (GENATHLETE and Japanese endurance runners), from which a panel of 45 promising markers was identified. These markers were tested for replication in seven additional cohorts of endurance athletes and controls: from Australia, Ethiopia, Japan, Kenya, Poland, Russia and Spain. The study is based on a total of 1520 endurance athletes (835 who took part in endurance events in World Championships and/or Olympic Games) and 2760 controls. We hypothesized that world-class athletes are likely to be characterized by an even higher concentration of endurance performance alleles and we performed separate analyses on this subsample. The meta-analysis of all available studies revealed one statistically significant marker (rs558129 at GALNTL6 locus, p = 0.0002), even after correcting for multiple testing. As shown by the low heterogeneity index (I2 = 0), all eight cohorts showed the same direction of association with rs558129, even though p-values varied across the individual studies. In summary, this study did not identify a panel of genomic variants common to these elite endurance athlete groups. Since GAMES was underpowered to identify alleles with small effect sizes, some of the suggestive leads identified should be explored in expanded comparisons of world-class endurance athletes and sedentary controls and in tightly controlled exercise training studies. Such studies have the potential to illuminate the biology not only of world class endurance performance but also of compromised cardiac functions and cardiometabolic diseases.

SREBF1 gene variations modulate insulin sensitivity in response to a fish oil supplementation.

BACKGROUND: An important inter-individual variability in the response of insulin sensitivity following a fish oil supplementation has been observed. The objective was to examine the associations between single nucleotide polymorphisms (SNPs) within sterol regulatory element binding transcription factor 1 (SREBF1) gene and the response of insulin sensitivity to a fish oil supplementation. METHODS: Participants (n = 210) were recruited in the greater Quebec City area and followed a 6-week fish oil supplementation protocol (5 g/day: 1.9-2.2 g EPA; 1.1 g DHA). Insulin sensitivity was assessed by the quantitative insulin sensitivity check index (QUICKI). Three tag SNPs (tSNPs) within SREBF1 gene were genotyped according to TAQMAN methodology. RESULTS: Three tSNPs (rs12953299, rs4925118 and rs4925115) covered 100% of the known genetic variability within SREBF1 gene. None of the three tSNPs was associated with either baseline fasting insulin concentrations (rs12953299, rs4925118 and rs4925115) (p = 0.29, p = 0.20 and p = 0.70, respectively) or QUICKI (p = 0.20, p = 0.18 and p = 0.76, respectively). The three tSNPs (rs12953299, rs4925118 and rs4925115) were associated with differences in the response of plasma insulin levels (p = 0.01, p = 0.005 and p = 0.004, respectively) and rs12953299 as well as rs4925115 were associated with the insulin sensitivity response (p = 0.009 and p = 0.01, respectively) to the fish oil supplementation, independently of the effects of age, sex and BMI. CONCLUSIONS: The genetic variability within SREBF1 gene has an impact on the insulin sensitivity in response to a fish oil supplementation. TRIAL REGISTRATION: clinicaltrials.gov: NCT01343342.

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

OBJECTIVE: 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/m(2) ) 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.

A variant in the LRRFIP1 gene is associated with adiposity and inflammation.

UNLABELLED: Inflammation is an important factor linking abdominal obesity with insulin resistance and related cardiometabolic risk. A genome-wide association study of adiposity-related traits performed in the Quebec Family Study (QFS) revealed that a single-nucleotide polymorphism (SNP) in the LRRFIP1 gene (rs11680012) was associated with abdominal adiposity (P = 4.6 × 10(-6)). OBJECTIVE: The objective of this study was to assess the relationship between polymorphisms in LRRFIP1 gene and adiposity (BMI, fat mass (FM), waist circumference (WC), and computed tomography-derived areas of total, subcutaneous and visceral abdominal adipose tissue) and markers of inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)). DESIGN AND METHODS: Using Sequenom, 16 tag SNPs in the LRRFIP1 gene, capturing 78% of the genetic variation, were genotyped in 926 participants of the QFS. RESULTS: Eight SNPs (rs7575941, rs3769053, rs11689421, rs3820808, rs11680012, rs3806505, rs6739130, and rs11686141) showed evidence of association with at least two adiposity phenotypes and plasma levels of one marker of inflammation. The strongest evidence of association was observed with rs11680012, which explained 1.8-3.4% of the variance in areas of abdominal adiposity and 2.0% of the variation in CRP levels. Carriers of the rare allele of rs11680012 had ≈ 30% more abdominal adiposity (P values between 2.7 × 10(-4) and 3.8 × 10(-6)) and 75% higher CRP levels (P = 1.6 × 10(-4)) than the common allele in age and sex adjusted data. Rs11680012 is a G/C SNP converting an arginine into a threonine and this amino acid substitution may potentially alter exonic splicing. CONCLUSION: This gene may therefore represent a potential interesting target to investigate in further functional studies on adiposity and inflammation.

LINE-1 methylation in visceral adipose tissue of severely obese individuals is associated with metabolic syndrome status and related phenotypes.

BACKGROUND: Epigenetic mechanisms may be involved in the regulation of genes found to be differentially expressed in the visceral adipose tissue (VAT) of severely obese subjects with (MetS+) versus without (MetS-) metabolic syndrome (MetS). Long interspersed nuclear element 1 (LINE-1) elements DNA methylation levels (%meth) in blood, a marker of global DNA methylation, have recently been associated with fasting glucose, blood lipids, heart diseases and stroke. AIM: To test whether LINE-1%meth levels in VAT are associated with MetS phenotypes and whether they can predict MetS risk in severely obese individuals. METHODS: DNA was extracted from VAT of 34 men (MetS-: n = 14, MetS+: n = 20) and 152 premenopausal women (MetS-: n = 84; MetS+: n = 68) undergoing biliopancreatic diversion for the treatment of obesity. LINE-1%meth levels were assessed by pyrosequencing of sodium bisulfite-treated DNA. RESULTS: The mean LINE-1%meth in VAT was of 75.8% (SD = 3.0%). Multiple linear regression analyses revealed that LINE-1%meth was negatively associated with fasting glucose levels (ß = -0.04; P = 0.03), diastolic blood pressure (ß = -0.65; P = 0.03) and MetS status (ß = -0.04; P = 0.004) after adjustments for the effects of age, sex, waist circumference (except for MetS status) and smoking. While dividing subjects into quartiles based on their LINE-1%meth (Q1 to Q4: lower %meth to higher %meth levels), greater risk were observed in the first (Q1: odds ratio (OR) = 4.37, P = 0.004) and the second (Q2: OR = 4.76, P = 0.002) quartiles compared to Q4 (1.00) when adjusting for age, sex and smoking. CONCLUSIONS: These results suggest that lower global DNA methylation, assessed by LINE-1 repetitive elements methylation analysis, would be associated with a greater risk for MetS in the presence of obesity.

Association of LIPA gene polymorphisms with obesity-related metabolic complications among severely obese patients.

The lipase A, lysosomal acid, cholesterol esterase enzyme (LIPA) is involved in the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) delivered to lysosomes. LIPA deficiency in human causes two distinct phenotypes characterized by intracellular storage of CE and derangements in the control of cholesterol production, namely the Wolman disease (WD) and the CE storage disease (CESD). To test the potential association of LIPA gene polymorphisms with obesity-related metabolic complications, promoter, exons, and intronic flanking regions of the LIPA gene were first sequenced in 25 individuals. From the 14 common polymorphisms identified, 12 tagging single-nucleotide polymorphisms (tSNPs) were genotyped in a cohort of 1,751 obese individuals. After adjustments for the effect of age, sex, diabetes, and medication, the C allele of SNP rs1051338 was associated with lower blood pressure (BP; systolic (SBP) P = 0.004; diastolic (DBP) P = 0.006). Three of the tested SNPs were associated with modifications of the plasma lipid profile. The G/G genotype of rs2071509 was associated with higher high-density lipoprotein cholesterol (HDL-C) levels (P = 0.009) and minor allele of rs1131706 was also associated with higher HDL-C (P = 0.004) and an association between rs3802656 and total cholesterol (total-C)/HDL-C ratio was identified (P = 0.04). These results thus suggest that LIPA polymorphisms contribute to the interindividual variability observed in obesity-related metabolic complications.

Thymic stromal lymphopoietin: an immune cytokine gene associated with the metabolic syndrome and blood pressure in severe obesity.

A previous expression profiling of VAT (visceral adipose tissue) revealed that the TSLP (thymic stromal lymphopoietin) gene was less expressed in severely obese men with (n=7) compared with without (n=7) the MetS (metabolic syndrome). We hypothesized that TSLP SNPs (single nucleotide polymorphisms) are associated with TSLP gene expression in VAT and with MetS phenotypes. Following validation of lower TSLP expression (P=0.003) in VAT of severely obese men and women with (n=70) compared with without (n=60) the MetS, a detailed genetic investigation was performed at the TSLP locus by sequencing its promoter, exons and intron-exon splicing boundaries using DNA of 25 severely obese subjects. Five tagging SNPs were genotyped in the 130 subjects from the expression analysis to test whether these SNPs contributed to TSLP expression variability (ANOVAs) and then genotyped in two independent samples of severely obese men (total, n=389) and women (total, n=894). In a sex-stratified multistage experimental design, ANOVAs were performed to test whether tagging SNPs were associated with MetS components treated as continuous variables. We observed that the non-coding SNP rs2289277 was associated with TSLP mRNA abundance (P=0.04), as well as with SBP [systolic BP (blood pressure)] (P=0.004) and DBP (diastolic BP) (P=0.0003) in men when adjusting for age, waist circumference, smoking and medication treating hypertension. These novel observations suggest that TSLP expression in VAT may partly explain the inter-individual variability for metabolic impairments in the presence of obesity and that specific SNPs (rs2289277 and/or correlating SNPs) may influence TSLP gene expression as well as BP in obese men.

The effect of mere-measurement of cognitions on physical activity behavior: a randomized controlled trial among overweight and obese individuals.

BACKGROUND: The promotion of physical activity among an overweight/obese population is an important challenge for clinical practitioners and researchers. In this regard, completing a questionnaire on cognitions could be a simple and easy strategy to increase levels of physical activity. Thus, the aim of the present study was to test the effect of completing a questionnaire based on the Theory of Planned Behavior (TPB) on the level of physical activity. METHODS: Overall, 452 overweight/obese adults were recruited and randomized to the experimental or control group. At baseline, participants completed a questionnaire on cognitions regarding their participation in leisure-time physical activity (experimental condition) versus a questionnaire on fruit and vegetable consumption (control condition). The questionnaires assessed the TPB variables that are beliefs, attitude, norm, perception of control, intention and a few additional variables from other theories. At three-month follow-up, leisure-time physical activity was self-reported by means of a short questionnaire. An analysis of covariance with baseline physical activity level as covariate was used to verify the effect of the intervention. RESULTS: At follow-up, 373 participants completed the leisure-time physical activity questionnaire. The statistical analysis showed that physical activity participation was greater among participants in the experimental condition than those in the control condition (F(1,370)=6.85, p=.009, d=0.20). CONCLUSIONS: Findings indicate that completing a TPB questionnaire has a significant positive impact on subsequent participation in physical activity. Consequently, asking individuals to complete such a questionnaire is a simple, inexpensive and easy strategy to increase the level of physical activity among overweight/obese adults.

DPP4 gene DNA methylation in the omentum is associated with its gene expression and plasma lipid profile in severe obesity.

Severely obese subjects with the metabolic syndrome (MS) have higher dipeptidyl peptidase-4 (DPP4) expression in their visceral adipose tissue (VAT) compared to obese individuals without MS. We tested the hypothesis that methylation level of CpG sites in the DPP4 promoter CpG island in VAT was genotype-dependent and associated with DPP4 mRNA abundance and MS-related phenotypes. The VAT DNA was extracted in 92 severely obese premenopausal women undergoing biliopancreatic derivation for the treatment of obesity. Women were nondiabetic and none of them used medication to treat MS features. Cytosine methylation rates (%) of 102 CpG sites in the DPP4 CpG island were assessed by pyrosequencing of sodium bisulfite-treated DNA. Methylation rates were >10% for CpG sites 94-102. Their mean methylation rate (%Meth(94-102)) was different between genotypes for DPP4 polymorphisms rs13015258 (P = 0.001), rs17848915 (P = 0.0004), and c.1926 G>A (P = 0.001). The %Meth(94-102) correlated negatively with DPP4 mRNA abundance (r = -0.25, P < 0.05) and positively with plasma high-density lipoprotein (HDL) cholesterol concentrations (r = 0.22, P < 0.05), whereas DPP4 mRNA abundance correlated positively with plasma total-/HDL-cholesterol ratio (r = 0.25; P < 0.05). In the VAT of nondiabetic severely obese women, genotype-dependent methylation levels of specific CpG sites in the DPP4 promoter CpG island were associated with DPP4 gene expression and variability in the plasma lipid profile. Higher DPP4 gene expression in VAT and its relationship with the plasma lipid profile may be explained by actually unknown DPP4 biological effect or, to another extent, may also be a marker of VAT inflammation known to be associated with metabolic disturbances.

Combining genetic markers and clinical risk factors improves the risk assessment of impaired glucose metabolism.

BACKGROUND: Although several candidate gene polymorphisms (SNPs) have been associated with increased risk of type 2 diabetes mellitus (T2DM), relatively few studies have assessed the ability of T2DM candidate genes to assess the risk of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and T2DM beyond the information provided by clinical risk factors. OBJECTIVE: To test whether the inclusion of genetic markers in a regression model provides a better assessment of the risk of IFG, IGT, and T2DM than a model based only on non-genetic risk factors commonly assessed in clinical settings. METHODS: Subjects (n = 485; 213 parents, 272 offspring) from the Quebec Family Study, not known to haveT2DM, were measured for several risk factors and underwent an oral glucose tolerance test. Thirty-eight SNPs in 25 susceptibility/ candidate genes previously reported to be associated with T2DM were genotyped. In order to identify risk factors associated with IFG/IGT/T2DM, two logistic regression models were tested: a full model (FM) including age, sex, body mass index (BMI), systolic and diastolic blood pressure, smoking status, and the 38 SNPs; and a reduced model (RM), in which the SNPs were dropped, which allowed us to test the null-hypothesis that the markers are not associated with the risk of IFG/IGT/T2DM. Performances of the models were compared by using a likelihood ratio test and the receiver-operating characteristic curves (ROC).The area under the curve (AUC) was calculated from the ROC curve. RESULTS: The analyses showed that age (P < 0.0001), BMI (P < 0.0001), and six variants (IGF2BP2 rs4402960, P = 0.002; ADIPOQ+276 G>T, P = 0.004; UCP2Ala55Val, P = 0.01; CDKN2AI2B rs3731201, P = 0.02; rs495490, P = 0.02, and rsl 0811661, P = 0.03) were significantly associated with the risk of IFG/IGT/T2DM. Dropping genetic markers from the analysis significantly reduced the fit of the model to the data (chi-square = 38.98, P < 0.00001 contrasting RM to FM), suggesting that the genetic markers are significantly associated with the risk of IFG/IGT/T2DM. Furthermore, the AUC was higher for FM than for RM (0.85 (95% CI 0.81-0.89) versus 0.81 (95% CI 0.76-0.85), P = 0.004). CONCLUSION: Our results suggest that combining genetic markers with traditional clinical risk factors has the potential to improve our ability to assess the risk of complex diseases such as T2DM.

Prediction of daily fruit and vegetable consumption among overweight and obese individuals.

The purpose of this study is twofold: to identify the determinants of daily fruit and vegetable (F&V) consumption and the moderators of the intention-behaviour relationship. A sample of 225 overweight or obese adults completed a TPB questionnaire. F&V behaviour was assessed at baseline and three months later. Statistical analyses revealed that past behaviour, perceived behavioural control (PBC) and age were significant predictors of daily F&V consumption. In addition, intention was found to interact with anticipated regret. Interventions should encourage the development of habit and PBC. However, the age and level of anticipated regret of the targeted population should be considered when designing interventions.

Contribution of genetic and metabolic syndrome to omental adipose tissue PAI-1 gene mRNA and plasma levels in obesity.

BACKGROUND: Plasminogen activator inhibitor type-1 (PAI-1) has already been associated with atherosclerosis; myocardial infarction; and cardiovascular disease risk factors such as obesity, insulin resistance, and dyslipidemia. However, factors regulating PAI-1 adipose tissue (AT) gene expression and plasma levels are not yet well defined. AIM: This study aims to assess the contribution of PAI-1 omental AT mRNA levels and genetic and metabolic factors to variation in plasma PAI-1 concentrations. METHODS: Ninety-one non-diabetic premenopausal severely obese women (body mass index, BMI >35 kg/m(2)) undergoing bariatric surgery were phenotyped (fasting plasma glucose, lipid-lipoprotein, and PAI-1 levels) and genotyped for four PAI-1 polymorphisms. Omental AT PAI-1 mRNA levels were determined using real-time polymerase chain reaction. Stepwise regression analysis was used to identify independent PAI-1 AT mRNA and plasma level predictors. RESULTS: Among the variables included to the stepwise regression analysis, plasma high-density lipoprotein (HDL)-cholesterol (r = 0.38; p = 0.0004) and total cholesterol (r = 0.16; p = 0.0541) levels were the only two (out of 12) independent variables retained as predictive of PAI-1 omental AT mRNA levels, whereas BMI (r = 0.35; p = 0.0039), plasma HDL-cholesterol concentrations (r = -0.31; p = 0.0375), PAI-1 omental AT mRNA levels (r = 0.19; p = 0.0532) and PAI-1-844G/A (p = 0.0023), and rs6092 (p.A15T; p = 0.0358) polymorphisms contributed independently to plasma PAI-1 concentrations. Taken together, these variables explained 17.8% and 31.0% of the variability in PAI-1 AT mRNA and plasma levels, respectively. CONCLUSION: These results suggest that PAI-1 polymorphisms contribute significantly to PAI-1 plasma levels but do not support the notion that omental AT is one of its major source.

Differential epigenomic and transcriptomic responses in subcutaneous adipose tissue between low and high responders to caloric restriction.

BACKGROUND: Caloric restriction is recommended for the treatment of obesity, but it is generally characterized by large interindividual variability in responses. The factors affecting the magnitude of weight loss remain poorly understood. Epigenetic factors (ie, heritable but reversible changes to genomic function that regulate gene expression independently of DNA sequence) may explain some of the interindividual variability seen in weight-loss responses. OBJECTIVE: The objective was to determine whether epigenetics and gene expression changes may play a role in weight-loss responsiveness. DESIGN: Overweight/obese postmenopausal women were recruited for a standard 6-mo caloric restriction intervention. Abdominal subcutaneous adipose tissue biopsy samples were collected before (n = 14) and after (n = 14) intervention, and the epigenomic and transcriptomic profiles of the high and low responders to dieting, on the basis of changes in percentage body fat, were compared by using microarray analysis. RESULTS: Significant DNA methylation differences at 35 loci were found between the high and low responders before dieting, with 3 regions showing differential methylation after intervention. Some of these regions contained genes known to be involved in weight control and insulin secretion, whereas others were localized in known imprinted genomic regions. Differences in gene expression profiles were observed only after dieting, with 644 genes being differentially expressed between the 2 groups. These included genes likely to be involved in metabolic pathways related to angiogenesis and cerebellar long-term depression. CONCLUSIONS: These data show that both DNA methylation and gene expression are responsive to caloric restriction and provide new insights about the molecular pathways involved in body weight loss as well as methylation regulation during adulthood.

Age-related differences in inflammatory markers in men: contribution of visceral adiposity.

As visceral adipose tissue (AT) accumulation and inflammatory markers are known to increase with age, we examined whether this age-related change in regional AT distribution could contribute to the increase in the concentration of some inflammatory markers found with age. Two hundred eight healthy men aged 18.6 to 72.2 years and covering a wide range of adiposity values (body mass index, 18.5-39.3 kg/m(2)) were studied. Plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels were measured by enzyme-linked immunosorbent assay. Anthropometric characteristics such as height, weight, and waist girth were measured; and body mass index was calculated. Cross-sectional areas of abdominal AT were obtained at L4-L5 by computed tomography. Fasting blood samples were collected to determine a complete lipoprotein lipid profile, and a 75-g oral glucose tolerance test was performed. Overall, visceral AT accumulation was positively correlated with age (r = 0.51, P < .0001) as well as with plasma CRP (r = 0.39, P < .0001), IL-6 (r = 0.32, P < .0001), and TNF-alpha (r = 0.14, P < .05) levels. A significant positive relationship was also observed between age and CRP (r = 0.36, P < .0001), IL-6 (r = 0.39, P < .0001), or TNF-alpha (r = 0.15, P < .05) concentrations. As middle-aged men were characterized by higher CRP (1.32 [25th percentile, 0.71; 75th percentile, 2.71] vs 0.66 [0.36, 1.62] mg/L, P < .0001) and IL-6 (1.60 [1.09, 2.28] vs 1.12 [0.77, 1.60] pg/mL, P < .0001) levels as well as by a greater amount of visceral AT (P < .0001) than young men, we have individually matched 43 young men (age, 28.6 +/- 5.82 years) with 43 middle-aged men (age, 57.6 +/- 5.15 years) on the basis of their visceral AT. Matching for visceral AT eliminated the difference between middle-aged men and younger adult men in inflammatory markers. These results suggest that the age-related variation in CRP and IL-6 is largely explained by differences in visceral AT.

Body composition, cardiorespiratory fitness, and low-grade inflammation in middle-aged men and women.

The objective of the present study was to determine the respective contributions of visceral adipose tissue (AT) accumulation and cardiorespiratory fitness to variation of inflammatory markers in men and women. Circulating levels of C-reactive protein, tumor necrosis factor-alpha, interleukin-6, and adiponectin were obtained with visceral AT (computed tomography) and fitness (physical working capacity test) levels in a sample of healthy men (n = 120) and women (n = 152) covering a wide range of adiposity. An inflammation score was developed based on gender-specific percentile values of each inflammatory marker (0 or 1), which yielded a score ranging from 0 (low) to 4 (high). Visceral AT was positively associated with C-reactive protein and interleukin-6 levels (r > or =0.35, p <0.0001), but negatively associated with adiponectin (r = -0.29, p < or =0.0003) after adjustment for fitness. After adjusting for visceral AT, fitness was not associated with variation in inflammatory markers in women and only with adiponectin in men (r = -0.20, p = 0.03). In participants with low visceral AT (<130 cm(2) for men and <100 cm(2) for women), prevalences of participants with an increased inflammation score were 23.9% and 28.0%, respectively, for participants with high and low fitness, whereas in subjects with increased visceral AT, prevalences of a high inflammation score were 60.0% and 61.7%, respectively, for participants with high and low fitness. In conclusion, these results suggest that the previously reported association between poor fitness and low-grade inflammation may be largely attributable to increased visceral AT accumulation and its associated state of insulin resistance, conditions frequently observed in subjects with poor cardiorespiratory fitness.