Publications

Numerous studies have reported that women have a lipoprotein profile suggestive of a reduced risk of coronary heart disease (CHD). We have therefore tested whether the “protective” lipoprotein profile of women could be explained by differences in hepatic lipase (HL) or lipoprotein lipase (LPL) activities. In the present study, 14 non-obese healthy premenopausal women had higher plasma concentrations of high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL3-C, and HDL—apolipoprotein (apo) Al, and a higher ratio of HDL-C to low-density lipoprotein cholesterol (LDL-C) than 17 non-obese healthy men. Women also had lower plasma triglyceride (TG), HDL-TG, and apo B levels than men. Plasma postheparin LPL (PH-LPL) and HL activities showed no significant sex dimorphism, whereas abdominal and femoral adipose tissue (AT)-LPL activities were significantly higher in women (P < .005). In men, PH-LPL activity correlated significantly with plasma HDL2-C (r = .52, P < .05), LDL-C (r = −.47, P < .05), and apo B (r = −.56, P < .01) levels, as well as with the HDL-C LDL-C ratio (r = .67, P < .005). No such relationships were found in women, with the exception of HL activity, which was negatively correlated with HDL—apo Al levels. In both genders, abdominal AT-LPL activity showed no significant association with plasma lipoprotein levels. In contrast, femoral AT-LPL activity in women was positively correlated with plasma HDL-C, HDL2-C (r = .53, P < .05 and r = .69, P < .01, respectively), and HDL—apo Al (r = .52, P < .01) levels, as well as with the HDL-C LDL-C ratio (r = .62, P < .01). These associations were not found in men. Analysis of covariance (ANCOVA) showed that adjustment for HL activity could not explain sex differences in lipoprotein levels. When correction for PH-LPL activity was performed, gender differences observed in plasma lipoprotein levels remained significant. In ANCOVA with inclusion of abdominal AT-LPL activity as a covariate, men still had plasma TG levels significantly higher than women, whereas HDL-C, HDL2-C, HDL—apo Al, and HDL3-C concentrations were lower. Finally, femoral AT-LPL activity was the most powerful covariate explaining gender differences in plasma lipoprotein levels. Indeed, adjustment for femoral AT-LPL activity eliminated gender differences in plasma TG, HDL-C, HDL2-C, HDL—apo Al, and apo B levels and the HDL-C LDL-C ratio , with the exception being the HDL3-C level. Although these results do not provide evidence for a cause-and-effect relationship, they suggest that the high femoral AT-LPL activity is a significant correlate of the favorable plasma lipoprotein-lipid profile in women.

Abdominal obesity is associated with high plasma triglyceride (TG) and with low plasma high density lipoprotein (HDL)-cholesterol (CHOL) levels. As plasma TG and HDL-CHOL are negatively correlated, the associations between obesity, the regional distribution of body fat, plasma TG levels, and plasma lipoprotein concentration and composition were studied in a sample of 76 premenopausal women (52 obese and 24 non-obese). Obese women had significantly higher plasma levels of VLDL-TG, low density lipoprotein (LDL)-CHOL, LDL-TG, LDL-apolipoprotein (apo) B and reduced HDL-CHOL levels compared to non-obese controls (p less than 0.01). However, plasma concentrations of HDL-apo A-I and HDL-TG were not different between obese and non-obese women. Partial correlation analyses revealed that both fat mass and abdominal fat accumulation significantly contributed to VLDL-TG and HDL-CHOL variances. After control for body fat mass, the waist-to-hip circumference ratio (WHR) remained significantly correlated with plasma LDL-apo B levels and with the LDL-apo B/LDL-CHOL ratio (0.01 greater than p less than 0.05). Body fat mass was, however, associated with TG enrichment of LDL (p less than 0.01). After control for WHR, body fat mass showed no significant association with plasma HDL-TG levels, whereas the WHR was positively correlated with HDL-TG levels (p less than 0.05). Partial correlation analyses indicated that adjustment for fat mass or for the WHR failed to eliminate the associations between plasma VLDL-TG levels and lipoprotein lipid composition. This study emphasizes the importance of plasma VLDL-TG level as a correlate of plasma LDL and HDL lipid composition in abdominal obesity.

The aim of the present study was to evaluate changes in participation in physical activity and in fat and alcohol intake associated with ageing. This issue was examined in adults ( n 207) who were tested between 1978 and 1982 and re-tested 12 years later. These adults were 42.3 ( sd 4.9) years of age at baseline. Their children ( n 122) were tested over the same follow-up period. They were, on average, 12.5 ( sd 1.9) years at entry into the study. A decrease in the proportion of daily energy intake as fat and an increase in participation in vigorous physical activities were observed over the 12-year period in both groups. The proportion of dietary energy as alcohol remained stable in adults whereas it increased markedly in children. Correlation analyses between baseline and follow-up levels were significant for dietary fat and alcohol intake in adults. In children, the levels of these variables in the growing years did not predict the levels attained 12 years later. Even though the adults displayed changes in fat balance generally following current public health recommendations, a substantial increase in skinfold thicknesses was observed in these subjects during follow-up. This observation suggests that there is a strong effect of age-related factors on fat balance.

An analysis of the data collected in the Quebec Overfeeding Study of identical twins was undertaken to determine any evidence of a genotype effect on plasma levels of adrenal and gonadal steroids arising from long term positive energy balance. Plasma levels of sex hormone-binding globulin (SHBG), testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEA-S), androsterone glucuronide, androstane-3α,17β-diol glucuronide (3α-DIOL-G), and cortisol were measured in 12 pairs of young, sedentary, male monozygotic twins before and after 100 days of overfeeding. The dietary energy excess of 4.2 MJ/day (1000 Cal), 6 days a week, resulted in a total positive energy balance of 353 MJ (84,000 Cal). Overfeeding induced significant changes (P &amp;lt; 0.0001) in body weight and other measures of body composition. Within-twin pair resemblance was observed at baseline in all steroids, except cortisol [intraclass correlation range: DHEA-S, 0.50 (P &amp;lt; 0.05); DHT, 0.77 (P &amp;lt; 0.001)] and was lost with overfeeding, except for DHT and SHBG (P &amp;lt; 0.05). SHBG levels fell and 3α-DIOL-G rose with the gain in body fatness. The change in testosterone was a significant correlate of the change in upper body fat (r = −0.48; P &amp;lt; 0.05). The change in 3α-DIOL-G correlated positively with increases in all measures of central adiposity (r = 0.52; P &amp;lt; 0.01). A decrease in DHEA-S occurred with a higher, but not with a lower, gain in abdominal visceral fat (P &amp;lt; 0.05). Thus, analysis of adrenal and gonadal steroids and of conjugated metabolites before and after overfeeding in monozygous twins supports the idea that there is a genotype effect on steroid circulating steroid levels and that these blood levels are correlated with the pattern of body fat distribution. Moreover, the baseline within-twin pairs similarity in steroid levels was attenuated by prolonged positive energy balance and body fat gain.

PURPOSE A genome-wide linkage scan was performed to identify genes affecting maximal heart rate (HRmax) and heart rate reserve (HRrsv) in the sedentary state and their responses to a standardized 20–week endurance training program. METHODS A total of 654 polymorphic markers were used and 353 pairs of siblings from 99 White nuclear families and 102 sibling pairs from 114 Black family units were available. HR was measured by ECG at rest and during maximal exercise and HRrsv was calculated as HRmax - resting HR. Baseline phenotypes were adjusted for age, sex and body mass index, and the training responses (post-training - baseline) were adjusted for age, sex, baseline BMI and baseline value of the response phenotype. Multi-point linkage analyses were done using both regression and variance components-based methods. RESULTS In Whites, baseline HRmax showed the strongest evidence of linkage (LOD=2.54, p=0.0003) with markers on chromosome 10p13. The maximum linkage was detected at 9.4 Mb from pter and a 1-LOD region covered about 7.2 Mb. HRrsv training response QTLs were detected on chromosomes 8q22-q23 (LOD=2.24, p=0.00065 at 107 Mb) and 20q13.1 (LOD=2.51, p=0.00034 at 43.9 Mb). In Blacks, strong evidence of linkage was found for baseline HRrsv on chromosome 7q35 (LOD=3.03, p=0.00009 at 143.2 Mb). CONCLUSIONS All these chromosomal regions include several potential candidate genes and therefore warrant further studies in the HERITAGE cohort and other studies.

Familial aggregation and possible major gene effects were evaluated for the baseline serum dehydroepiandrosterone sulfate (DHEAS) level and the change in DHEAS in response to a 20-week exercise training program in a sample of 481 individuals from 99 Caucasian families who were sedentary at baseline and who participated in the HERITAGE Family Study. Baseline DHEAS levels were not normally distributed, and were therefore logarithmically transformed and adjusted for the effects of age and sex prior to genetic analysis. The DHEAS response to training was computed as the simple difference, post-training minus baseline, and was adjusted for the baseline DHEAS level, age, and sex. Maximal (genetic and familial environmental) heritabilities (using a familial correlation model) reached 58% and 30% for the baseline and the response to training, respectively. Our estimate for the baseline is generally in agreement with previous reports, suggesting that the magnitude of the familial effect underlying this phenotype in these sedentary families is similar to that in the general population. However, segregation analysis showed no evidence for a multifactorial familial component in data for either the baseline or the response to training. Rather, a major additive gene controlling the baseline was found. For the response to training in the complete sample, transmission of the major effect from parents to offspring was ambiguous, but in a subset of 56 “responsive” families (with at least 1 family member whose response to training was greater than 1 standard deviation) this major effect was Mendelian in nature. The putative major genes accounted for 50% and 33% of the variance for the baseline and the response to training, respectively. The novel finding in this study is that the baseline DHEAS level and the change in DHEAS in response to training may be influenced by major gene effects.

Adiponectin, a cytokine released by adipose tissue, has insulin-sensitizing and anti-atherosclerotic properties. PURPOSE: Since circulatory concentrations of adiponectin are typically lower in obese subjects, this study was performed to determine if endurance exercise training-induced reduction of adiposity resulted in increased serum adiponectin concentration in a sample of black and white men and women aged 17 to 65 years (n=667). METHODS: Serum adiponectin concentrations from before and after a 20-week endurance exercise program were analyzed via enzyme-linked immunoassay. RESULTS: After adjustment for age, serum adiponectin at baseline was not related to VO2max in any race/sex group (range: r=−0.153 in black men, r=−0.016 in white women, p>0.05). Unexpectedly, although mean subcutaneous and intra-abdominal fat area decreased, adiponectin decreased with exercise training (before vs. after: 7.45±0.18 vs. 6.39±0.17 ugmL1, p<0.001). Training-induced change in intra-abdominal fat area was not related to change in adiponectin (r=−0.009, p>0.05). Changes in fat mass and subcutaneous abdominal fat area were inversely related to serum adiponectin change (r=−0.107 and −0.098, respectively, p<0.05), i.e., a larger reduction in adiposity was associated with a slightly smaller decrease in adiponectin. These relationships were small and only significant in black women and white men. In addition, change in VO2max was not related to adiponectin change in any of the race/sex groups (overall r=−0.055, p>0.05). At baseline, adiponectin was related to fasting insulin concentration (r=−0.264, p<0.001) and insulin sensitivity derived from minimal modeling following an intravenous glucose tolerance test (r=+0.266, p<0.001). Although fasting insulin decreased and insulin sensitivity increased in response to exercise training, changes in neither of these vabiables were related to the decrease in adiponectin (r=−0.006 and −0.017, respectively, p>0.05). CONCLUSIONS: Although adiposity decreased slightly, twenty weeks of exercise training resulted in an unexpected decrease in serum adiponectin concentration. Relationships between changes in adiposity indices and adiponectin were very modest. Furthermore, since insulin sensitivity increased in spite of the decrease in adiponectin, adiponectin does not appear to play a major role in the improved insulin sensitivity found with exercise training. Funded by the American Heart Association (Mid-Atlantic Affiliate) and multiple grants from NIH-NHLBI.

There is consistent evidence from cross-sectional studies for significant familial resemblance in body fatness; however, longitudinal familial resemblance in adiposity remains unclear. The purpose of this study was to determine the familial aggregation in baseline and 7-y changes in adiposity in the Canadian population. Measures of adiposity were collected on 655 females and 661 males 7–69 y of age who participated in both the 1981 Canada Fitness Survey and 1988 Campbell's Survey of Well Being. The sample was distributed across 521 nuclear families with a mean family size of 2.5 people. Four indicators of adiposity were measured and used in change score calculations: body mass (kg); body mass index, BMI, (kg/m2); sum of 5 skinfolds, SF5, (mm); and waist circumference, WC, (mm). Data were adjusted for age in both the mean and variance by regression in four sex-by-generation groups (father, mother, son, daughter) and standardized to zero mean and unit variance. Familial correlations and maximal heritabilities were determined from path analysis using SEGPATH software. The maximal heritabilities for baseline measures of body mass, BMI, SF5 and WC were 56%, 39%, 41% and 39%, respectively, while the estimates for the 7-y change scores in body mass, BMI, SF5 and WC were 23%, 14%, 12% and 45%, respectively. The estimates of maximal heritability suggest that familial factors explain more of the variance in baseline body mass, BMI and SF5 than changes over time; however, the change in WC had a comparable heritability. The finding that familial factors appear to be more important cross-sectionally than longitudinally suggests that other lifestyle factors may be important determinants of changes in adiposity. This research was supported by the Heart and Stroke Foundation of Canada.

Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (S i ) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on S i . An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline S i and ∆S i , focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆S i further strengthens the relevance of calcium signalling in EET mediated S i response.

No abstract is provided for this article.

We investigated the role of the angiotensinogen (AGT) gene M235T polymorphism in determining blood pressure (BP) response to moderate intensity exercise in a 6-yr randomized controlled trial in 140 middle-aged men. Sitting, supine, and standing blood pressures were measured annually. Of the randomized men, 86% participated in the trial for 6 yr. Submaximal cardiorespiratory fitness increased by 16% in the exercise group. In the M homozygotes, sitting systolic BP decreased by 1.0 mmHg in the exercise but increased by 14.6 mmHg in the reference group ( P = 0.007 for net effect). Sitting and supine diastolic BP decreased by 6.2 and 3.3 mmHg in the exercise but increased by 2.8 and 3.2 mmHg in the reference group ( P = 0.026 and 0.024 for net effects), respectively. Regular moderate intensity exercise attenuates aging-related increase in systolic BP and decreases diastolic BP among the M homozygotes of the AGT gene M235T polymorphism.

No abstract is provided for this article.

This is the tenth update of the human obesity gene map, incorporating published results up to the end of October 2003 and continuing the previous format. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome‐wide scans and animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. Transgenic and knockout murine models relevant to obesity are also incorporated ( N = 55). As of October 2003, 41 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. QTLs reported from animal models currently number 183. There are 208 human QTLs for obesity phenotypes from genome‐wide scans and candidate regions in targeted studies. A total of 35 genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 272 studies reporting positive associations with 90 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, more than 430 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http:obesitygene.pbrc.edu .

Short-term studies show that bariatric surgery causes remission of diabetes. The long-term outcomes for remission and diabetes-related complications are not known.To determine the long-term diabetes remission rates and the cumulative incidence of microvascular and macrovascular diabetes complications after bariatric surgery.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.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.Diabetes remission, relapse, and diabetes complications. Remission was defined as blood glucose <110 mg/dL and no diabetes medication.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 < .001). At 15 years, the diabetes remission rates decreased to 6.5% (4/62) for control patients and to 30.4% (35/115) for bariatric surgery patients (OR, 6.3; 95% CI, 2.1-18.9; P < .001). With long-term follow-up, the cumulative incidence of microvascular complications was 41.8 per 1000 person-years (95% CI, 35.3-49.5) for control patients and 20.6 per 1000 person-years (95% CI, 17.0-24.9) in the surgery group (hazard ratio [HR], 0.44; 95% CI, 0.34-0.56; P < .001). Macrovascular complications were observed in 44.2 per 1000 person-years (95% CI, 37.5-52.1) in control patients and 31.7 per 1000 person-years (95% CI, 27.0-37.2) for the surgical group (HR, 0.68; 95% CI, 0.54-0.85; P = .001).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.