Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity.

BACKGROUND: Overconsumption of dietary sugars, fructose in particular, is linked to cardiovascular risk factors such as type 2 diabetes, obesity, dyslipidemia and nonalcoholic fatty liver disease. However, clinical studies have to date not clarified whether these adverse cardiometabolic effects are induced directly by dietary sugars, or whether they are secondary to weight gain. OBJECTIVES: To assess the effects of fructose (75 g day-1 ), served with their habitual diet over 12 weeks, on liver fat content and other cardiometabolic risk factors in a large cohort (n = 71) of abdominally obese men. METHODS: We analysed changes in body composition, dietary intake, an extensive panel of cardiometabolic risk markers, hepatic de novo lipogenesis (DNL), liver fat content and postprandial lipid responses after a standardized oral fat tolerance test (OFTT). RESULTS: Fructose consumption had modest adverse effects on cardiometabolic risk factors. However, fructose consumption significantly increased liver fat content and hepatic DNL and decreased ß-hydroxybutyrate (a measure of ß-oxidation). The individual changes in liver fat were highly variable in subjects matched for the same level of weight change. The increase in liver fat content was significantly more pronounced than the weight gain. The increase in DNL correlated positively with triglyceride area under the curve responses after an OFTT. CONCLUSION: Our data demonstrated adverse effects of moderate fructose consumption for 12 weeks on multiple cardiometabolic risk factors in particular on liver fat content despite only relative low increases in weight and waist circumference. Our study also indicates that there are remarkable individual differences in susceptibility to visceral adiposity/liver fat after real-world daily consumption of fructose-sweetened beverages over 12 weeks.

Fructose intervention for 12 weeks does not impair glycemic control or incretin hormone responses during oral glucose or mixed meal tests in obese men.

BACKGROUND AND AIMS: Incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown. METHODS AND RESULTS: As many as 66 obese (BMI 26-40 kg/m2) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049). CONCLUSION: In obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge.

Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat.

BACKGROUND: To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). SUBJECTS AND METHODS: Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available. RESULTS: A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P<1.0 × 10(-6)) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 × 10(-7)), an association that was replicated (P=0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; P=2.42 × 10(-7)). Our sex-specific analyses identified one genome-wide significant (P<5.0 × 10(-8)) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 × 10(-8) to 1.13 × 10(-8)). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. CONCLUSIONS: Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women.

Effect of adipose tissue volume loss on circulating 25-hydroxyvitamin D levels: results from a 1-year lifestyle intervention in viscerally obese men.

BACKGROUND/OBJECTIVES: Although weight loss has been associated with changes in circulating 25-hydroxyvitamin D (25(OH)D) levels, the quantification of the increase in 25(OH)D levels as a function of adipose tissue volume loss precisely assessed by imaging has not been reported before. The objective of this substudy was to describe the effects of a 1-year lifestyle intervention on plasma 25(OH)D levels. The relationships between changes in 25(OH)D levels and changes in adiposity volume (total and by adipose tissue compartment) were studied. SUBJECTS/METHODS: This intervention study was performed between 2004 and 2006 and participants were recruited from the general community. Sedentary, abdominally obese and dyslipidemic men (n=103) were involved in a 1-year lifestyle modification program. Subjects were individually counseled by a kinesiologist and a nutritionist once every 2 weeks during the first 4 months with subsequent monthly visits in order to elicit a 500-kcal daily energy deficit and to increase physical activity/exercise habits. Body weight, body composition and fat distribution were assessed by dual-energy X-ray absorptiometry and computed tomography, whereas the 25(OH)D levels were measured with an automated assay. RESULTS: The 1-year intervention resulted in a 26% increase in circulating 25(OH)D (from 48±2 nmol l(-1) or 19±0.8 ng ml(-1) (±s.e.m.) to 58±2 nmol l(-1) or 23±0.8 ng ml(-1), P<0.0001) along with a 26% decrease in visceral adiposity volume (from 1947±458 to 1459±532 cm3). One-year increases in 25(OH)D levels correlated inversely with changes in all adiposity indices, especially Δvisceral (r=-0.36, P<0.0005) and Δtotal abdominal (r=-0.37, P<0.0005) adipose tissue volumes. CONCLUSIONS: These results indicate that there is a linear increase in circulating 25(OH)D levels as a function of adiposity volume loss, and therefore suggest a role of adiposity reduction in the management of obesity-associated vitamin D insufficiency.

Visceral, subcutaneous abdominal adiposity and liver fat content distribution in normal glucose tolerance, impaired fasting glucose and/or impaired glucose tolerance.

OBJECTIVES: To examine the specific distribution of liver fat content, visceral and subcutaneous adiposity in normal glucose tolerance (NGT/NGT), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined conditions (IFG+IGT), as well as with newly diagnosed type 2 diabetes (nT2D). DESIGN: Multicenter, international observational study: cross-sectional analysis. SUBJECTS: Two thousand five hundred and fifteen patients (50.0% women, 54.5% non-Caucasian) without previously known diabetes were recruited from 29 countries. Abdominal fat distribution was measured by computed tomography (CT). Liver fat was estimated using the CT-liver mean attenuation. RESULTS: Compared with NGT/NGT patients, increased visceral adiposity was found in iIFG, iIGT, IFG+IGT and nT2D; estimated liver fat progressively increased across these conditions. A one-s.d. increase in visceral adiposity was associated with an increased risk of having iIFG (men: odds ratio (OR) 1.41 (95% confidence interval (CI) 1.15-1.74), women: OR 1.62 (1.29-2.04)), iIGT (men: OR 1.59 (1.15-2.01), women: OR 1.30 (0.96-1.76)), IFG+IGT (men: OR 1.64 (1.27-2.13), women: OR 1.83 (1.36-2.48)) and nT2D (men: OR 1.80 (1.35-2.42), women: OR 1.73 (1.25-2.41)). A one-s.d. increase in estimated liver fat was associated with iIGT (men: OR 1.46 (1.12-1.90), women: OR 1.81 (1.41-2.35)), IFG+IGT (men: OR 1.42 (1.14-1.77), women: OR 1.74 (1.35-2.26)) and nT2D (men: OR 1.77 (1.40-2.27), women: OR 2.38 (1.81-3.18)). Subcutaneous abdominal adipose tissue showed an inverse relationship with nT2D in women (OR 0.63 (0.45-0.88)). CONCLUSIONS: Liver fat was associated with iIGT but not with iIFG, whereas visceral adiposity was associated with both. Liver fat and visceral adiposity were associated with nT2D, whereas subcutaneous adiposity showed an inverse relationship with nT2D in women.

Impact of rosiglitazone on body composition, hepatic fat, fatty acids, adipokines and glucose in persons with impaired fasting glucose or impaired glucose tolerance: a sub-study of the DREAM trial.

AIMS: Thiazolidinediones reduce ectopic fat, increase adiponectin and reduce inflammatory adipokines, fatty acids and glucose in people with Type 2 diabetes. We aimed to measure these effects in people with impaired fasting glucose and/or impaired glucose tolerance. METHODS: After approximately 3.5 years of exposure to rosiglitazone 8 mg (n = 88) or placebo (n = 102), 190 DREAM trial participants underwent abdominal computed tomography and dual-energy X-ray absorptiometry scans. Visceral and subcutaneous adipose tissue areas, estimated hepatic fat content, total fat and lean mass were calculated and changes in levels of fasting adipokines, free fatty acids, glucose and post-load glucose were assessed. RESULTS: Compared with the placebo, participants on rosiglitazone had no difference in lean mass, had 4.1 kg more body fat (P < 0.0001) and 31 cm(2) more subcutaneous abdominal adipose tissue area (P = 0.007). Only after adjusting for total fat, participants on rosiglitazone had 23 cm² less visceral adipose tissue area (P = 0.01) and an 0.08-unit higher liver:spleen attenuation ratio (i.e. less hepatic fat; P = 0.02) than those on the placebo. Adiponectin increased by 15.0 µg/ml with rosiglitazone and by 0.4 µg/ml with placebo (P < 0.0001). Rosiglitazone's effect on fat distribution was not independent of changes in adiponectin. Rosiglitazone's effects on fasting (-0.36 mmol/l; P = 0.0004) and 2-h post-load glucose (-1.21 mmol/l; P = 0.0008) were not affected by adjustment for fat distribution or changes in adiponectin or free fatty acids. CONCLUSIONS: In people with impaired fasting glucose/impaired glucose tolerance, rosiglitazone is associated with relatively less hepatic and visceral fat, increased subcutaneous fat and increased adiponectin levels. These effects do not appear to explain the glucose-lowering effect of rosiglitazone.

Parental eating behavior traits are related to offspring BMI in the Québec Family Study.

OBJECTIVE: Parental eating behavior traits have been shown to be related to the adiposity of their young children. It is unknown whether this relationship persists in older offspring or whether rigid or flexible control are involved. The objective of this study was to test the hypothesis that parental eating behavior traits, as measured by the Three-Factor Eating Questionnaire (TFEQ), are related to offspring body weight. METHODS: Cross-sectional anthropometric and TFEQ data from phase 2 and 3 of the Québec Family Study generated 192 parent-offspring dyads (offspring age range: 10-37 years). Relationships were adjusted for offspring age, sex and reported physical activity, number of offspring per family and parent body mass index (BMI). RESULTS: In all parent-offspring dyads, parental rigid control and disinhibition scores were positively related to offspring BMI (r=0.17, P=0.02; r=0.18, P<0.01, respectively). There were no significant relationships between cognitive restraint (P=0.75) or flexible control (P=0.06) with offspring BMI. Regression models revealed that parent disinhibition mediated the relationship between parent and offspring BMI, whereas rigid control of the parent moderated this relationship. The interaction effect between parental rigid control and disinhibition was a significant predictor of offspring BMI (ß=0.13, P=0.05). CONCLUSION: Family environmental factors, such as parental eating behavior traits, are related to BMI of older offspring, and should be a focus in the prevention of obesity transmission within families.

Assessment of cardiometabolic risk and prevalence of meeting treatment guidelines among patients with type 2 diabetes stratified according to their use of insulin and/or other diabetic medications: results from INSPIRE ME IAA.

AIM: Visceral adipose tissue (VAT) and liver fat (LF) are strongly associated with type 2 diabetes. It is not known, however, how diabetes treatment and/or risk factor management modulates the association between VAT, LF and diabetes. The aim was to determine the level of VAT and LF in patients with type 2 diabetes according to their treatment status and achievement of the American Diabetes Association's (ADA) diabetes management goals. METHODS: We performed a cross-sectional analysis of the baseline data of the International Study of the Prediction of Intra-Abdominal Adiposity and its Relationship with Cardiometabolic risk/Intra-Abdominal Adiposity (INSPIRE ME IAA), a 3-year prospective cardiometabolic imaging study conducted in 29 countries. Patients (n = 3991) were divided into four groups: (i) those without type 2 diabetes (noT2D n = 1003 men, n = 1027 women); (ii) those with type 2 diabetes but not treated with diabetes medications (T2Dnomeds n = 248 men, n = 198 women); (iii) those with type 2 diabetes and treated with diabetes medications but not yet using insulin (T2Dmeds-ins n = 591 men, n = 484 women) and (iv) those with type 2 diabetes and treated with insulin (T2Dmeds+ins n = 233 men, n = 207 women). Abdominal and liver adiposity were measured by computed tomography. RESULTS: Fewer patients with high VAT or LF achieved the ADA's goals for high-density lipoprotein cholesterol (HDL-C) or triglycerides compared to patients with low VAT or LF. Visceral adiposity (p = 0.02 men, p = 0.003 women) and LF (p = 0.0002 men, p = 0.0004 women) increased among patients who met fewer of the ADA treatment criteria, regardless of type 2 diabetes treatment. CONCLUSION: Residual cardiometabolic risk exists among patients with type 2 diabetes characterized by elevated VAT and LF.

A comparison of the assessment and management of cardiometabolic risk in patients with and without type 2 diabetes mellitus in Canadian primary care.

AIM: To investigate the cardiometabolic risk (CMR) assessment and management patterns for individuals with and without type 2 diabetes mellitus (T2DM) in Canadian primary care practices. METHODS: Between April 2011 and March 2012, physicians from 9 primary care teams and 88 traditional non-team practices completed a practice assessment on the management of 2461 patients >40 years old with no clinical evidence of cardiovascular disease and diagnosed with at least one of the following risk factor-T2DM, dyslipidaemia or hypertension. RESULTS: There were 1304 individuals with T2DM and 1157 without. Pharmacotherapy to manage hyperglycaemia, dyslipidaemia and hypertension was widely prescribed. Fifty-eight percent of individuals with T2DM had a glycated haemoglobin (HbA1c) ≤7.0%. Amongst individuals with dyslipidaemia, median low-density lipoprotein cholesterol (LDL-C) was 1.8 mmol/l for those with T2DM and 2.8 mmol/l for those without. Amongst individuals with hypertension, 30% of those with T2DM achieved the <130/80 mmHg target, whereas 60% of those without met the <140/90 mmHg target. The composite glycaemic, LDL-C and blood pressure (BP) target outcome was achieved by 12% of individuals with T2DM. Only 17% of individuals with T2DM and 11% without were advised to increase their physical activity. Dietary modifications were recommended to 32 and 10% of those with and without T2DM, respectively. CONCLUSIONS: Patients at elevated CMR were suboptimally managed in the primary care practices surveyed. There was low attainment of recommended therapeutic glycaemic, lipid and BP targets. Advice on healthy lifestyle changes was infrequently dispensed, representing a missed opportunity to educate patients on the long-term benefits of lifestyle modification.

Behavioural and metabolic characterisation of the low satiety phenotype.

Some individuals report weak appetite sensations and thus, have higher susceptibility to overeating. The aim of this study was (1) to evaluate the reliability of the satiety quotient (SQ), a marker of satiety efficiency; (2) to characterize the biopsychobehavioural profiles of individual presenting low satiety efficiency, i.e. the low satiety phenotype and (3) to document the impact of a weight loss program on these profiles. Sixty-nine obese men (BMI 33.6±3.0 kg/m², age 41.5±5.7 years) participated in a 16-week, non-restrictive weight loss intervention. Visual analog scales for appetite sensations in response to a test-meal were completed twice at baseline. Blood samples were collected before and during one test-meal. Questionnaires were administered before and after the intervention. The mean SQ showed good reliability (ICC=0.67). Baseline SQ scores tended to be negatively correlated with external hunger, anxiety and night eating symptoms (p<0.10). Moreover, the low satiety phenotype showed a lower cortisol response to the test-meal (p<0.05). The SQ seems to be a reliable marker of weaker appetite sensation responses. Stress/anxiety could be involved in the low satiety phenotype but did not influence the biopsychobehavioural changes in response to the intervention.

Bayesian networks and imaging-derived phenotypes highlight the role of fat deposition in COVID-19 hospitalisation risk.

Objective: Obesity is a significant risk factor for adverse outcomes following coronavirus infection (COVID-19). However, BMI fails to capture differences in the body fat distribution, the critical driver of metabolic health. Conventional statistical methodologies lack functionality to investigate the causality between fat distribution and disease outcomes. Methods: We applied Bayesian network (BN) modelling to explore the mechanistic link between body fat deposition and hospitalisation risk in 459 participants with COVID-19 (395 non-hospitalised and 64 hospitalised). MRI-derived measures of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat were included. Conditional probability queries were performed to estimate the probability of hospitalisation after fixing the value of specific network variables. Results: The probability of hospitalisation was 18% higher in people living with obesity than those with normal weight, with elevated VAT being the primary determinant of obesity-related risk. Across all BMI categories, elevated VAT and liver fat (>10%) were associated with a 39% mean increase in the probability of hospitalisation. Among those with normal weight, reducing liver fat content from >10% to <5% reduced hospitalisation risk by 29%. Conclusion: Body fat distribution is a critical determinant of COVID-19 hospitalisation risk. BN modelling and probabilistic inferences assist our understanding of the mechanistic associations between imaging-derived phenotypes and COVID-19 hospitalisation risk.

Longer sleep duration associates with lower adiposity gain in adult short sleepers.

The objective of this longitudinal, observational study was to verify whether a favorable change in sleep duration over 6 years could impact objective indicators of adiposity in adults aged 18-64 years. Short-duration sleepers (≤6 h per day; n=43) at baseline were divided into two groups: (i) those who increased their sleep duration to a 'healthy' length of 7-8 h per day at year 6 (mean increase: 1.52±0.66 h per day; n=23); and (ii) those who maintained their short sleep duration habits (mean change: -0.11±0.38 h per day; n=20). Adult individuals who reported sleeping 7-8 h per day at both baseline and year 6 (n=173) were used as a control group. Change in adiposity indicators for each sleep-duration group was compared by analysis of covariance. We observed that the two short-sleep-duration groups had similar baseline characteristics. However, short-duration sleepers who maintained their short sleep duration experienced a greater increase in body mass index (BMI) (difference: 1.1±0.36 kg m(-2), P<0.05) and fat mass (difference: 2.4±0.64 kg, P<0.05) over the 6-year follow-up period than short-duration sleepers who increased their sleep duration, even after adjustment for relevant covariates. We did not observe any significant difference in adiposity changes between the control group and short-duration sleepers who increased their sleep duration. This study suggests for the first time that shifting sleep duration from a short to a healthier length is associated with an attenuation of fat mass gain.

Evaluation of Adiposity and Cognitive Function in Adults.

Importance: Excess adipose tissue increases other cardiovascular risk factors, which may be associated with vascular brain injury and cognitive impairment. However, the extent to which the amount and distribution of adipose tissue may be associated with lower cognitive scores, independent of its association with cardiovascular risk factors, is not well characterized. Objective: To investigate the association of adiposity on vascular brain injury and cognitive scores. Design, Setting, and Participants: A total of 9189 participants from the Canadian Alliance for Healthy Hearts and Minds (CAHHM) and the Prospective Urban Rural Epidemiological-Mind (PURE-MIND) cohort studies were included in this cross-sectional analysis. Of these adults, 9166 underwent bioelectrical impedance analysis to assess body fat (BF) percentage, and 6773 underwent magnetic resonance imaging to assess vascular brain injury and measure visceral adipose tissue (VAT) volume. Participants from CAHHM were recruited from January 1, 2014, to December 31, 2018, and PURE-MIND participants were recruited from January 1, 2010, to December 31, 2018. Both CAHHM and PURE-MIND comprise multisite, population-based cohorts. Participants from CAHHM are from Canada, and PURE-MIND participants are from Canada or Poland. Data analysis was performed from May 3 to November 24, 2021. Exposures: The percentage of BF and VAT were modeled as sex-specific quartiles. Vascular brain injury was defined as high white matter hyperintensities or silent brain infarction. Multivariable mixed models were used to examine factors associated with reduced cognitive scores. Main Outcomes and Measures: Cognitive function was assessed using the Digital Symbol Substitution Test (DSST; scores range from 0 to 133, with lower scores indicating lower cognitive function) and Montreal Cognitive Assessment (scores range from 0 to 30, with a score of ≥26 denoting normal cognitive function). Reduced cognition was defined as a DSST score less than 1 SD below the mean. Cardiovascular risk was assessed using the INTERHEART Risk Score (IHRS; scores range from 0 to 48; low risk is defined as a score of 0 to 9, moderate risk as 10 to 16, and high risk as 17 or higher). Results: A total of 9189 adults (mean [SD] age, 57.8 [8.8] years; 5179 [56.4%] women; and 1013 [11.0%] East and Southeast Asian; 295 [3.2%] South Asian; 7702 [83.8%] White European; and 179 [1.9%] other, including Black, Indigenous, mixed, and unknown ethnicity) participated in the study. Visceral adipose tissue was highly correlated with body adiposity measured by BF percentage (r = 0.76 in women; r = 0.70 in men). Cardiovascular risk factors increased with increasing BF percentage with the fourth quartile IHRS at 13.8 (95% CI, 13.5-14.0; P < .001 for trend) and with VAT with the fourth quartile IHRS at 13.3 (95% CI, 13.0-13.5; P < .001 for trend). Vascular brain injury increased with increasing BF percentage with the fourth quartile value at 8.6% (95% CI, 7.5%-9.8%; P = .007 for trend) and with increasing VAT with fourth quartile value at 7.2% (95% CI, 6.0-8.4; P = .05 for trend). Cognitive scores were lower with increasing BF percentage with the fourth quartile score of 70.9 (95% CI, 70.4-71.5; P < .001 for trend) and for VAT with the fourth quartile score of 72.8 (95% CI, 72.1-73.4; P < .001 for trend). For every 1-SD increase in BF percentage (9.2%) or VAT (36 mL), the DSST score was lower by 0.8 points (95% CI, 0.4-1.1; P < .001) for BF percentage and lower by 0.8 points (95% CI, 0.4-1.2; P < .001) for VAT, adjusted for cardiovascular risk factors and vascular brain injury. The population attributable risk for reduced DSST score for higher BF percentage was 20.5% (95% CI, 7.0%-33.2%) and for VAT was 19.6% (95% CI, 2.0%-36.0%). Higher BF percentage and VAT were not associated with Montreal Cognitive Assessment scores. Conclusions and Relevance: In this cross-sectional study, generalized and visceral adiposity were associated with reduced cognitive scores, after adjustment for cardiovascular risk factors, educational level, and vascular brain injury. These results suggest that strategies to prevent or reduce adiposity may preserve cognitive function.

Investigation of LRP8 gene in 1p31 QTL linked to LDL peak particle diameter in the Quebec family study.

The small, dense LDL phenotype is associated with an increased cardiovascular disease risk. A genome-wide scan performed on 236 nuclear families of the Quebec Family Study (QFS) revealed a quantitative trait locus affecting LDL peak particle diameter (LDL-PPD) and density on the 1p31 region. This region contains the low-density lipoprotein receptor-related protein 8 (LRP8) gene. LRP8, a receptor for apolipoprotein (apo) E, modulates apoE levels, thus contributing to plasma cholesterol and triglyceride (TG) concentrations. We investigate the effects of LRP8 polymorphisms on LDL-PPD, on the relative proportion of small LDL (<255Å) and the absolute concentration of cholesterol among the small LDL particles. LRP8 rs5174 was associated with LDL-PPD and estimated cholesterol concentrations in the small LDL particles adjusted for the effects of age and sex (p=0.008, p=0.04, respectively). LRP8 rs3820198 was associated with total and LDL-cholesterol levels as well as with apoB concentrations adjusted for the effects of age and sex (p=0.005, p=0.004 and p=0.01, respectively) but not with LDL size-related variables. These results suggest that LRP8 gene polymorphisms influence plasma cholesterol levels as well as size and composition of LDL particles.

Hypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis.

OBJECTIVES: Adiponectin is a protein secreted by adipocytes which has anti-inflammatory properties. The objective of this study was to examine the relationship between adiponectinemia and the hemodynamic progression of aortic stenosis (AS) as well as the degree of inflammation in the valve explanted at the time of aortic valve replacement (AVR). METHODS: The plasma level of adiponectin was measured in 122 patients undergoing AVR. The explanted aortic valves were analyzed and the density of leukocytes (CD45+), T cells (CD3+) and blood vessels (von Willebrand factor positive; vWF+) was documented. Also, a subset of patients (n = 67) had ≥2 echocardiographic studies separated by at least 6 months, thereby allowing assessment of the rate of progression of stenosis during the preoperative period. RESULTS: Patients with lower plasma levels of adiponectin (<5.4 µg/ml) had a faster progression rate of the mean transvalvular gradient before surgery than those with higher levels (9 ± 1 vs. 4 ± 1 mm Hg/year; p = 0.008). Moreover, these patients with hypoadiponectinemia had significantly more leukocytes (CD45+), T cells and blood vessels (vWF+) in their explanted valves compared to those with higher adiponectin levels. CONCLUSION: These findings support the concept that adiponectin may play a protective role against the inflammatory process and progression of calcific AS.

Physical inactivity, abdominal obesity and risk of coronary heart disease in apparently healthy men and women.

OBJECTIVE: To test the hypothesis that for any given body mass index (BMI) category, active individuals would have a smaller waist circumference than inactive individuals. Our second objective was to examine the respective contribution of waist circumference and physical inactivity on coronary heart disease (CHD) risk. DESIGN: Prospective, population-based study with an 11.4-year follow-up. SUBJECTS: A total of 21 729 men and women aged 45-79 years, residing in Norfolk, UK. METHODS: During follow-up, 2191 CHD events were recorded. Physical activity was evaluated using a validated lifestyle questionnaire that takes into account both leisure-time and work-related physical activity. Waist circumference was measured and BMI was calculated for each participant. RESULTS: For both men and women, we observed that within each BMI category (<25.0, 25-30 and >or=30.0 kg m(-2)), active participants had a lower waist circumference than inactive participants (P<0.001). In contrast, within each waist circumference tertile, BMI did not change across physical activity categories (except for women with an elevated waist circumference). Compared with active men with a low waist circumference, inactive men with an elevated waist circumference had a hazard ratio (HR) for future CHD of 1.74 (95% confidence interval (CI), 1.34-2.27) after adjusting for age, smoking, alcohol intake and parental history of CHD. In the same model and after further adjusting for hormone replacement therapy use, compared with active women with a low waist circumference, inactive women with an elevated waist circumference had an HR for future CHD of 4.00 (95% CI, 2.04-7.86). CONCLUSION: In any BMI category, inactive participants were characterized by an increased waist circumference, a marker of abdominal adiposity, compared with active individuals. Physical inactivity and abdominal obesity were both independently associated with an increased risk of future CHD.

The Three-Factor Eating Questionnaire and BMI in adolescents: results from the Québec family study.

Eating behaviour traits are associated with body weight variations in adults. The Three-Factor Eating Questionnaire (TFEQ) measures cognitive restraint, disinhibition and hunger, as well as their corresponding subscales, e.g. rigid and flexible control. The TFEQ has not been widely used in adolescents to investigate eating behaviour traits associated with body weight. The aim of the present study was to assess whether eating behaviour traits were associated with BMI in male and female adolescents. Sixty adolescents (thirty females and thirty males; mean age 15.0 (sd 2.4) years) from the Québec Family Study completed the TFEQ and 3 d dietary records. There were no sex differences in the TFEQ scores. Rigid control, disinhibition and emotional susceptibility (to overeat) were positively related to BMI z-scores for the entire sample (r 0.3, P < 0.05). There was a positive relationship between BMI z-scores and rigid control (r 0.39, P < 0.05) in females, while BMI z-scores were positively related to emotional susceptibility (r 0.42, P < 0.02) and disinhibition (r 0.41, P < 0.03) in males. Adolescents characterised by both high disinhibition and high rigid control had significantly higher BMI z-scores than those by both low disinhibition and low rigid control. There were no significant differences in BMI z-scores between the flexible control categories. Dietary macronutrient content was not consistently related to eating behaviour traits. These results show that the eating behaviour traits of disinhibition and rigid control are independently related to BMI z-scores in this group of adolescents.

Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors.

AIMS/HYPOTHESIS: We previously reported that the plasma levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in a cohort of viscerally obese men are directly correlated with visceral adipose tissue (VAT) accumulation and metabolic risk factors including low HDL-cholesterol and high triacylglycerol. It is not known, however, if such correlations persist after vigorous lifestyle interventions that reduce metabolic risk factors. We analysed the changes in endocannabinoid levels in a subsample from the same cohort following a 1 year lifestyle modification programme, and correlated them with changes in VAT and metabolic risk factors. METHODS: Forty-nine viscerally obese men (average age 49 years, BMI 30.9 kg/m(2), waist 107.3 cm) underwent a 1 year lifestyle modification programme including healthy eating and physical activity. Plasma levels of 2-AG and the other most studied endocannabinoid, anandamide, were measured by liquid chromatography-mass spectrometry. Anthropometric and metabolic risk factors, including VAT, insulin resistance and glucose intolerance, HDL-cholesterol and triacylglycerol, were measured. RESULTS: Most risk factors were improved by the intervention, which led to a significant decrease in body weight (-6.4 kg, p < 0.0001), waist circumference (-8.0 cm, p < 0.0001) and VAT (-30%, p < 0.0001), and in plasma 2-AG (-62.3%, p < 0.0001) and anandamide (-7.1%, p = 0.005) levels. The decrease in levels of 2-AG but not those of anandamide correlated with decreases in VAT and triacylglycerol levels, and with the increase in HDL(3)-cholesterol levels. Multivariate analyses suggested that decreases in 2-AG and VAT were both independently associated with decreases in triacylglycerol. CONCLUSIONS/INTERPRETATION: This study shows that a strong correlation exists between 2-AG levels and high plasma triacylglycerol and low HDL(3)-cholesterol in viscerally obese men.

Lipid-mediated inflammation and degeneration of bioprosthetic heart valves.

BACKGROUND: The durability of bioprosthetic valves is limited by structural valve degeneration (SVD) leading to bioprostheses (BPs) stenosis or regurgitation. We hypothesized that a lipid-mediated inflammatory mechanism is involved in the SVD of BPs. MATERIAL AND METHODS: Eighteen Freestyle stentless BP valves were explanted for SVD at a mean time of 5.9 +/- 3 years after implantation and were analysed by immunohistochemistry and transmission electron microscopy (TEM). RESULTS: The mean age of the patients was 65 +/- 8 years and there were 11 male and seven female patients. Two of the 18 BPs had macroscopic calcification, whereas the other valves had minimal or no macroscopic calcification. Tears at the commissures leading to regurgitation was present in 16 BPs. Immunohistochemistry showed the presence of oxidized low-density lipoprotein (ox-LDL) and glycosaminoglycans in the fibrosa layer of 13 BPs. Areas with ox-LDL were infiltrated by macrophages (CD68(+)) co-expressing the scavenger receptor CD36 and metalloproteinase-9 (MMP-9). Zymogram showed the active form of MMP-9 within explanted BPs. EM studies revealed the presence of lipid-laden cells featuring foam cells and fragmented collagen. Nonimplanted control BPs obtained from the manufacturer (n = 4) had no evidence of lipid accumulation, inflammatory cell infiltration or expression of MMP9 within the leaflets. CONCLUSIONS: These results support the concept that lipid-mediated inflammatory mechanisms may contribute to the SVD of BPs. These findings suggest that modification of atherosclerotic risk factors with the use of behavioural or pharmacological interventions could help to reduce the incidence of SVD.

Genetic and nongenetic determinants of regional fat distribution.

The role of inherited and nongenetic factors in individual differences observed in the level of sc fat on the trunk and abdominal areas and in the abdominal visceral deposit is reviewed. First, the metabolic and clinical implications of variation in body fat topography are summarized. Second, the results of genetic epidemiology studies on the heritability and other evidence for a role of the genotype in the amount of truncal-abdominal sc fat and abdominal visceral fat are reviewed. Third, the impact of total body fat, age, and gender on regional fat distribution is highlighted. Fourth, adipose tissue lipoprotein lipase activity is considered as a determinant of fat topography, with a discussion of site and gender differences, the effects of steroid hormones, and evidence from genetic epidemiology. Fifth, the contribution of adipose tissue lipolysis is reviewed with an emphasis on the various regulatory factors of the lipolytic pathways including catecholamines, insulin, adenosine, steroids, and other modulators. The role of lipolytic characteristics on fat topography is further assessed by considering changes with age, differences between men and women, effects of excess body fat, and data from heritability studies. Although the study of regional variation of in vitro adipose tissue metabolism has provided valuable information, a better understanding of variation in fat topography and of the role played by adipose tissue in the regulation of whole body carbohydrate and lipid metabolism will likely require extensive in situ and in vivo investigations. Sixth, as enlargement of a specific fat deposit is associated with increases in fat cell size and number, these topics are considered with an emphasis on the role of adipose cell differentiation. Seventh, the importance of blood levels of sex steroids and glucocorticoids for regional fat distribution is discussed. Then, a unifying hypothesis, defined as the hypothalamic arousal and neuroendocrine dysregulation model, is briefly described. Finally, the issue of whether body fat distribution can be altered by caloric restriction or regular exercise is addressed.