Showing papers by "Claude Bouchard published in 2002"

The effect of sex, age and race on estimating percentage body fat from body mass index: The Heritage Family Study.

Abstract: Objective To study the effects of sex, age and race on the relation between body mass index (BMI) and measured percent body fat (%fat) Design Cross-sectional validation study of sedentary individuals Subjects The Heritage Family Study cohort of 665 black and white men and women who ranged in age from 17 to 65 y Measurements Body density determined from hydrostatic weighing Percentage body fat determined with gender and race-specific, two-compartment models BMI determined from height and weight, and sex and race in dummy coded form Results Polynomial regression showed that the relationship between %fat and BMI was quadratic for both men and women A natural log transformation of BMI adjusted for the non-linearity Test for homogeneity of log transformed BMI and gender showed that the male-female slopes were within random variance, but the intercepts differed For the same BMI, the %fat of females was 104% higher than that of males General linear models analysis of the women's data showed that age, race and race-by-BMI interaction were independently related to %fat The same analysis applied to the men's data showed that %fat was not just a function of BMI, but also age and age-by-BMI interaction Multiple regression analyses provided models that defined the bias Conclusions These data and results published in the literature show that BMI and %fat relationship are not independent of age and gender These data showed a race effect for women, but not men The failure to adjust for these sources of bias resulted in substantial differences in the proportion of subjects defined as obese by measured %fat

The Human Obesity Gene Map: The 2001 Update

Abstract: This report constitutes the eighth update of the human obesity gene map, incorporating published results up to the end of October 2001. Evidence from the rodent and human obesity cases caused by single-gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) uncovered in human genome-wide scans and in crossbreeding experiments in various animal models, association and linkage studies with candidate genes and other markers is reviewed. The human cases of obesity related in some way to single-gene mutations in six different genes are incorporated. Twenty-five Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different QTLs reported from animal models currently reaches 165. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 174 studies reporting positive associations with 58 candidate genes. Finally, 59 loci have been linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity-related phenotypes can be found on all chromosomes except chromosome Y. A total of 54 new loci have been added to the map in the past 12 months, and the number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes is now above 250. Likewise, the number of negative studies, which are only partially reviewed here, is also on the rise.

Role of ghrelin polymorphisms in obesity based on three different studies.

Abstract: Objective: Associations between preproghrelin DNA variants and obesity-related phenotypes were studied in 3004 subjects from the Quebec Family Study (QFS), the HERITAGE Family Study (HERITAGE), and the Swedish Obese Subjects (SOS) Study. Research Methods and Procedures: Body mass index (BMI), fat mass (FM) from underwater weighing, and abdominal fat from computerized tomography were measured. The ghrelin polymorphisms were identified by polymerase chain reaction. Results: Arg51Gln QFS subjects (n = 6) had lower ghrelin concentrations (p = 0.007) than Arg51Arg subjects (n = 14). White preproghrelin Met72Met subjects in HERITAGE had the lowest BMI (p = 0.020), and those in the QFS cohort had the lowest FM (p 25 kg/m2 (14.8%). SOS Met72+ obese women had a lower (11.4%; p = 0.032) prevalence of hypertension than noncarriers (23.9%). Discussion: Arg51Gln mutation was associated with lower plasma ghrelin levels but not with obesity. The preproghrelin Met72 carrier status seems to be protective against fat accumulation and associated metabolic comorbidities.

A 12-year follow-up study of treated obese children in Japan.

Abstract: Objective: To assess tracking for body weight from childhood to adulthood in obese Japanese children who were treated for obesity, investigate the relation between the changes in body weight status and morbidity, and identify correlates of the changes in body weight status. Study Design: Twelve-year retrospective cohort study. Subjects: A sample of 276 subjects (age 23.9±4.1, 176 males and 100 females) who responded to a questionnaire mailed in 1998 to 1047 children (age 10.6±2.2) treated for obesity at Mie National Hospital in Japan between 1976 and 1992. Measurements: Based on height and weight from medical records during childhood, the relative weight (RW; weight expressed as a percentage of the standard body weight for age, height, and sex) was calculated. Degrees of childhood obesity were based on RW: slight obesity (120%≤RW<130%; n=17), moderate obesity (130%≤RW<150%; n=131), and severe obesity (RW≥150%; n=128). Adult body mass index (BMI), which was obtained from the mailed questionnaires, was classified as normal, overweight and obese according to the WHO/NIH criteria. Body weight tracking by degree of obesity was evaluated. Subjects with severe obesity during childhood (n=128) were examined for their weight status in adulthood, prevalence of chronic diseases in adulthood, and factors such as parental obesity, dietary and exercise habits and obesity treatment during childhood. Results: Childhood obesity tracked into adulthood obesity or overweight in 54.7% of all cases. Severely obese children (36.7%) were more likely to be obese as an adult than moderately obese children (16.8%). The prevalence of adult obesity tended to be greater in boys with moderate childhood obesity than in girls (29.7% in boys vs 14.9% in girls, P=0.058). Among the severely obese children who became normal-weight adults, the prevalence of chronic diseases was about one-fifth of those who remained obese in adulthood (P=0.041). Four factors were associated with changes in body weight status: maternal BMI at entry (P=0.044), the changes in dietary and exercise habits after treatment (P=0.014, P=0.030, respectively), and satisfaction with obesity treatment in childhood (P=0.035). Conclusions: Severely obese children have a higher risk of becoming obese adults even when they received obesity treatment in childhood. The risk of adulthood obesity was twice as high in moderately obese boys than in girls. On the other hand, many cases of childhood obesity can be corrected with obesity treatment, which in turn can decrease the risk for adult chronic diseases.

Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort.

Abstract: The prevalence of mutations within and in the flanking regions of the gene encoding the melanocortin 4 receptor was investigated in severely obese and normal-weight subjects from the Swedish Obese Subjects study, the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family study, and a Memphis cohort. A total of 433 white and 95 black subjects (94% females) were screened for mutations by direct sequencing. Three previously described missense variants and nine novel (three missense, six silent) variants were detected. None of them showed significant association with obesity or related phenotypes. In addition, two novel deletions were found in two heterozygous obese women: a 65_64delTG mutation within the 5 noncoding region and a 171delC frameshift mutation predicted to result in a truncated nonfunctional receptor. No pathogenic mutations were found among obese blacks or nonobese controls. Furthermore, none of the null mutations found in other populations was present in this sample. In conclusion, our results do not support the prevailing notion that sequence variation in the melanocortin 4 receptor gene is a frequent cause of human obesity. (J Clin Endocrinol Metab 87: 4442–4446, 2002)

Variability in the response of HDL cholesterol to exercise training in the HERITAGE Family Study.

Abstract: In the HERITAGE Family Study, 675 sedentary, healthy, white and black men and women, aged 17 to 65 years, performed 20 weeks of supervised cycle ergometer exercise at the same relative intensity and weekly volume. As a group, subjects had normal mean baseline lipid levels for North Americans with the exception of below average high density lipoprotein cholesterol (HDL-C) levels. A significant mean increase in plasma HDL-C of 3.6 % was observed; however, there was marked variability in responsiveness to training, ranging from a mean 9.3 % decrease in Quartile 1 of HDL-C response to a mean 18 % increase in Quartile 4 (P < 0.0001 by ANOVA). Parallel changes in HDL(2)-C and HDL(3)-C, apolipoprotein A-I levels, and lipoprotein lipase activity were noted across quartiles. The change in HDL-C across quartiles was inversely related to baseline HDL-C (p < 0.0001) and to changes with training in plasma triglycerides (p = 0.0007). No significant differences in HDL-C response were observed across quartiles by sex, race, age, or increase in VO(2)max with training; however, weak positive associations were observed with age-adjusted education level and with reduction in abdominal fat and increase in VO(2)max at the ventilatory threshold following training. Multivariate regression analysis including baseline variables and training responses only accounted for 15.5 % of the variability in the HDL-C response to training. Thus, marked variability was found in the HDL-C response to the same endurance exercise training stimulus with only a modest amount of the response predictable by identified nongenetic factors.

A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference.

Abstract: Methods: We analyzed data pooled from nine studies on the human leptin receptor (LEPR) gene for the association of three alleles (K109R, Q223R and K656N) of LEPR with body mass index (BMI; kg/m2) and waist circumference (WC). A total of 3263 related and unrelated subjects from diverse ethnic backgrounds including African-American, Caucasian, Danish, Finnish, French Canadian and Nigerian were studied. We tested effects of individual alleles, joint effects of alleles at multiple loci, epistatic effects among alleles at different loci, effect modification by age, sex, diabetes and ethnicity, and pleiotropic genotype effects on BMI and WC. Results: We found that none of the effects were significant at the 0.05 level. Heterogeneity tests showed that the variations of the non-significant effects are within the range of sampling variation. Conclusions: We conclude that, although certain genotypic effects could be population-specific, there was no statistically compelling evidence that any of the three LEPR alleles is associated with BMI or WC in the overall population.

A Genomewide Linkage Scan for Abdominal Subcutaneous and Visceral Fat in Black and White Families: The HERITAGE Family Study

Abstract: Abdominal visceral fat (AVF), abdominal subcutaneous fat (ASF), and abdominal total fat (ATF) were measured using a computed tomography scan, both before (baseline) and after (post) a 20-week endurance exercise training protocol in the HERITAGE Family Study. Each of the baseline and response (post minus baseline) measures was adjusted for several covariates, including total fat mass, and responses to training were further adjusted for baseline levels. Multipoint variance components linkage analysis using a genomewide scan of 344 markers was conducted separately by race using race-specific allele frequencies. Several promising results (P < 0.0023) were obtained. For baseline AVF, the best evidence was on 2q22.1 and 2q33.2-q36.3 (including the IRS1 locus) in whites, with suggestive findings on 7q22.2-q31.3 (including the LEP locus) in blacks. Although several regions were indicated for baseline ASF, only 4q31.22-q32.2 and 11p15.4-p11.2 replicated the results of another study. For responses to training, promising results were limited to ASF and ATF primarily on 7q36.2 (including NOS3) in blacks, with suggestive regions (P < 0.01) on 1q21.2-q24.1 (S100A, ATP1A2, and ATP1B1), 10q25.2 (ADRA2A), and 11p15.5 (IGF2). In summary, the 4q and 11p regions have now been implicated in two independent studies for ASF; further research is warranted to identify the genes and mutations in these regions that are responsible for fat accumulation in the abdominal depot. Additional work in an independent sample is needed to verify the linkages for baseline AVF as well as the response measures.

Genomewide Linkage Scan of Resting Blood Pressure HERITAGE Family Study

Abstract: The purpose of this study was to search for genomic regions influencing resting systolic (SBP) and diastolic (DBP) blood pressure (BP) in sedentary families (baseline), and for resting BP responses (changes) resulting from a 20-week exercise training intervention (post-training–baseline) in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study. A genome-wide scan was conducted on 317 black individuals from 114 families and 519 white individuals from 99 families using a multipoint variance-components linkage model and a panel of 509 markers. Promising results were primarily, but not exclusively, found in the black families. Linkage evidence ( P P

A Polymorphism in the Human Agouti-Related Protein Is Associated with Late-Onset Obesity

Abstract: The mouse agouti-related protein (AGRP) is a powerful appetite effector that results in hyperphagia and the development of obesity when administered intracerebroventricularly or when overexpressed in transgenic mice. Animal studies have also shown that exogenous administration of AGRP predisposes toward hedonic intake of high fat and high sucrose diets. The human ortholog (hAGRP) maps on chromosome 16q22 and has similar physiological properties, as tested in animal models. A polymorphism was identified in the third exon of hAGRP, c.199G3 A, that resulted in a nonconservative amino acid substitution, Ala 67 Thr. Computational analysis of the protein showed significant differences in the coils of the two polymorphic isoforms of the protein. Human studies showed no genotype effects in individuals with a mean age of 25 yr. However, the G/G genotype was significantly associated with fatness and abdominal adiposity in the parental population with a mean age of 53 yr. The c.199G3 A polymorphism in hAGRP could, therefore, play a role in the development of human obesity in an age-dependent fashion. (J Clin Endocrinol Metab 87: 4198 – 4202, 2002)

Heritability of HR and BP response to exercise training in the HERITAGE Family Study

Abstract: PURPOSE The heritability of the response to exercise training in resting blood pressure (BP) and heart rate (HR) was assessed in 482 Caucasian individuals comprising 98 families participating in the HERITAGE Family Study. METHODS All individuals were sedentary at the baseline visit (time 1 measurement). After completing a 20-wk exercise-training program, subjects were measured again (time 2). A familial correlation model was used to assess the heritability (genetic plus familial environmental) of the response in resting systolic BP (SBP), diastolic BP (DBP), and HR, computed as the difference between the two measurement times. This response was adjusted for the effects of baseline levels and age within sex and generation groups. Analyses were conducted separately in a subsample of families in which at least one family member was considered to have elevated BP (95th percentile; SBP > or = 135 or DBP > or = 80). RESULTS Several novel findings emerged from this study. First, the SBP and HR response may be influenced by genetic factors. The maximal heritabilities were 20% (SBP) and 36% (HR) in the elevated BP, 18% and 24% in the complete, and not significant in the normotensive samples. For DBP, there were cohort effects (significant sibling and spouse but not parent-offspring correlations) in the complete and normotensive samples that may be due to generation-specific environmental influences. CONCLUSION The trainability of SBP and HR in families with elevated BP appears to be determined in part by genetic factors, whereas DBP trainability may be more a function of environmental effects.

Genetic factors as predictors of weight gain in young adult Dutch men and women.

Abstract: OBJECTIVE: To investigate the association between DNA polymorphisms in several candidate genes for obesity and weight gain. Polymorphisms in these genes may contribute to weight gain through effects on energy intake, energy expenditure or adipogenesis. DESIGN AND METHODS: From two large cohorts in The Netherlands (total 17,500 adult men and women), we compared 286 subjects aged 20-40 y who gained an average of 12.8 kg (range 5.5-47 kg) during a mean follow-up of 6.8 y with 296 subjects who remained relatively constant over the same period with respect to occurrence of several polymorphisms in candidate genes of obesity and some lifestyle factors. Subjects who were dieting, were high alcohol consumers, were pregnant, changed their smoking status recently, or those who suffered from serious illnesses were excluded. Polymorphisms were determined in the LEPR-gene (LEPR Lys109Arg, LEPR Gln223Arg, LEPR Lys656Asn), in the UCP1 gene (A-G mutation at position-3826 5' region), in the UCP2 gene (Ala55Val, 45 bp Ins/Del), in the PPARG2 gene (Pro12Ala) and in the ADRB2 gene (Gly16Arg and Gln27Glu). RESULTS: With the exception of the Gly16Arg polymorphism in the ADRB2 gene in men (P = 0.04) and women (P = 0.05), and the Lys109Arg polymorphism in the LEPR gene in women, no statistically significant differences in the genotype and allele frequencies were observed between weight gainers and non-weight gainers. Weight gainers differed in some aspects of dietary habits and physical activity patterns: weight gainers consumed relatively more savory snacks and were less active during leisure time compared with non-weight gainers. CONCLUSION: Only variations in the ADRB2 gene and LEPR gene, may contribute to susceptibility to weight gain. None of the other studied genetic markers were clearly associated with weight gain. Further research is necessary to establish the role of lifestyle factors, or interactions between genes or between genes and lifestyle factors on weight gain with age.

5-HT2A receptor gene promoter polymorphism in relation to abdominal obesity and cortisol.

Abstract: Objective: There is considerable evidence that cortisol secretion is associated with obesity. The regulation of the 5-hydroxytryptamine receptor 2A (5-HT2A) gene might play an essential role because it is involved in the control of cortisol secretion. Therefore, we examined the potential impact of the 5-HT2A −1438G/A promoter polymorphism on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol, in 284 unrelated Swedish men born in 1944. Research Methods and Procedures: The subjects were genotyped by using polymerase chain reaction amplification of the promoter region of the gene for 5-HT2A followed by digestion of the reaction product with the restriction enzyme MspI. Results: The frequencies were 0.39 for allele −1438A and 0.61 for allele −1438G. Homozygotes for the −1438G allele had, in comparison with −1438A/A subjects, higher body mass index, waist-to-hip ratio, and abdominal sagittal diameter. Moreover, cortisol escape from 0.25-mg dexamethasone suppression was found in subjects with the −1438A/G genotype. Serum leptin, fasting insulin, and glucose, as well as serum lipids, were not different across the −1438G/A genotype groups. Discussion: From these results, we suggest the possibility that an abnormal production rate of the 5-HT2A gene product might lead to the development of abdominal obesity. The pathophysiology could involve stress factors that destabilize the serotonin-hypothalamic-pituitary-adrenal system in those with genetic vulnerability in the serotonin receptor gene.

Familial Aggregation of Blood Lipid Response to Exercise Training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study

Abstract: Background— Fasting levels of plasma lipids and lipoproteins are reported to improve with regular exercise training. However, little is known on whether the training responses are influenced by heritable factors. Methods and Results— The lipid profile was assessed in 115 black (224 individuals) and 99 white families (469 individuals), who participated in the HERITAGE Family Study, while in a sedentary state (baseline visit) and after exercise training for 20 weeks (post visit). Variables included total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, and HDL-C subfractions 2 (HDL2-C) and 3 (HDL3-C). Familial correlations for the training responses (Δ=post−baseline) were significant for most variables, and the percent variance accounted for by familial factors (ie, maximal heritabilities) ranged from 25% to 38%. Exceptions were for higher heritabilities near 60% for ΔApoB in blacks and ΔHDL2-C ...

A C-1291G polymorphism in the alpha2A-adrenergic receptor gene (ADRA2A) promoter is associated with cortisol escape from dexamethasone and elevated glucose levels.

Abstract: . Rosmond R, Bouchard C, Bjorntorp P (Sahlgrenska University Hospital, Goteborg, Sweden; Pennington Biomedical Research Center, LA, USA). A C-1291G polymorphism in the α2A-adrenergic receptor gene (ADRA2A) promoter is associated with cortisol escape from dexamethasone and elevated glucose levels. J Intern Med 2002; 251: 252–257. Objectives. The objective of the current study was to examine the potential impact of a C G substitution at position −1291 of the α2A-adrenergic receptor gene (ADRA2A) promoter on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol in 284 unrelated Swedish men born in 1944. Main outcome measures. The subjects were genotyped by using PCR amplification of the promoter region of the ADRA2A gene followed by digestion with the restriction enzyme MspI. Results. The frequencies were 0.23 for allele C and 0.77 for allele G. The observed genotype frequencies were 45.8 and 54.2% for C/G and G/G, respectively. Heterozygotes (n=121) had significantly (P=0.009) higher salivary cortisol levels after 0.5 mg dexamethasone compared with G/G homozygotes (n=143). Fasting glucose was found to be significantly (P=0.017) higher in heterozygotes than in G/G homozygotes. The latter group had also a borderline significantly (P=0.080) higher mean diastolic blood pressure. These results were all adjusted for the potential confounding effect of body mass index (BMI) and waist-to-hip ratio (WHR). Other measurements such as BMI, WHR, abdominal sagittal diameter, total testosterone, insulin-like growth factor I, serum leptin, fasting insulin and serum lipids were not different across the ADRA2A genotype groups. Conclusions. In conclusion, we have shown that an C G polymorphism at position −1291 of the ADRA2A gene is associated with a subnormal cortisol response to dexamethasone, elevated glucose levels and perhaps increased diastolic blood pressure. The pathophysiology could involve an altered density of the α2A-AR that destabilizes the sympathetic–hypothalamic–pituitary–adrenal systems in those with genetic vulnerability in the α2A-adrenergic receptor gene promoter.

Is adiposity at normal body weight relevant for cardiovascular disease risk

Abstract: OBJECTIVE: To examine the relation between adiposity and risk factors for cardiovascular disease (CVD) in normal weight (NW) individuals. METHODS: Cross-sectional study using the sample of white people, aged from 17 to 60 y from the Quebec Family Study and the Heritage Family Study. NW subjects with a body mass index (BMI) between 18.5 and 25 kg/m2 (181 males and 265 females) and overweight (OW) subjects with a BMI between 25 and 30 kg/m2 (133 males and 114 females) were retained for this study. NW subjects were divided into quintiles of each adiposity variable, then the quintiles and the OW group were evaluated for the presence of CVD risk factors. Using logistic regression analysis, the odds ratio (OR) for the prevalence of risk factors for each quintile of each adiposity variable and the OW group was estimated relative to the first quintile in NW subjects. Mean values of adiposity variables were compared between the subjects with and without risk factors. In these analyses, age and study cohort effects were taken into account. MEASUREMENTS: Percentage body fat (%fat) and fat mass (FM) measured by underwater weighing were available as adiposity variables. Risk factors included systolic and diastolic blood pressure, LDL and HDL cholesterol, triglycerides and fasting glucose. RESULTS: Wide ranges of values were observed for adiposity variables. HDL cholesterol, triglycerides and fasting glucose in NW males and HDL cholesterol in NW females were significantly correlated with all adiposity variables. For males, higher quintiles of adiposity variables in the NW group and the OW group tended to have higher ORs compared to the first quintiles for the risk factor variables. The fifth quintiles of all adiposity variables had the highest ORs (3.15 for %fat and 3.77 for FM) and they were significantly different from the first quintiles. OW males had ORs similar to those of the fifth quintiles for the risk factor variables. On the other hand, for females, the relatively linear associations were less clear in the NW group. In NW males, the subjects with at least one risk factor had significantly higher %fat and FM than the subjects without risk factors. In NW females, no significant difference was observed for these adiposity variables between the subjects with and without risk factors. CONCLUSION: NW males with elevated adiposity had higher prevalence of risk factors than NW males with less adiposity and the prevalence in the former was rather similar to that seen in OW males. On the other hand, measures of adiposity added little additional information to the BMI classification of NW on CVD risk factors in females.

Uncoupling protein 3 gene is associated with body composition changes with training in HERITAGE study

Abstract: The uncoupling protein 3 (UCP3) is a mitochondrial membrane transporter mainly expressed in skeletal muscle that we have shown to be associated with obesity. We have analyzed UCP3 polymorphisms, Va...

Skeletal muscle characteristics predict body fat gain in response to overfeeding in never-obese young men☆

Abstract: The associations between skeletal muscle morphological and metabolic properties and the changes in body composition and metabolic rates in response to long-term overfeeding were investigated in 24 healthy young male identical twins (12 pairs). The proportions of muscle fiber types (type I, type IIA, and type IIB) and the activities of creatine kinase (CK), oxoglutarate dehydrogenase (OGDH), and phosphofructokinase (PFK) were determined from biopsies of the vastus lateralis before and after the overfeeding protocol. Body weight, fat mass (FM), fat-free mass (FFM), percent body fat (%FAT), resting metabolic rate (RMR), and thermic effect of a standardized meal (TEM) were also measured before and after 100 days of overfeeding. Type I muscle fiber proportions correlated inversely with the changes of FM and %FAT ( r = [minus ]0.43, P = .035; r = [minus ]0.49, P = .01), and type IIA positively with the same overfeeding-induced changes ( r = 0.43, P = .035; r = 0.47, P = .021). Baseline CK and PFK activities correlated negatively with the changes of RMR ( r = [minus ]0.49, P = .017; r = [minus ]0.53, P = .01). OGDH activity at baseline correlated negatively with the changes of FM ( r = [minus ]0.47, P = 0.02) but the ratio of PFK/OGDH correlated positively with the change of FM ( r = 0.46, P = .02). We conclude that overfeeding induced a lower gain of FM in individuals with higher proportions of type I fiber, lower proportions of type IIA fiber, and higher OGDH activities at baseline. CK and PFK activities at baseline were associated with an attenuated increase in RMR when challenged by overfeeding. The significant correlations range from 0.43 to 0.53, and account for 18% to 28% of the variance in the response to overfeeding. The results suggest that an elevated skeletal muscle oxidative capacity plays a protective role in the response to long-term positive energy balance.

Familial Resemblance of 7-Year Changes in Body Mass and Adiposity

Abstract: Objective: To investigate the familial resemblance of 7-year changes in body mass and adiposity among Canadian families. Research Methods and Procedures: The sample consisted of 655 women and 660 men from 521 families who participated in the Canada Fitness Survey in 1981 and the follow-up Campbell's Survey in 1988. Indicators of baseline and 7-year changes in body mass and adiposity included body mass (kilograms), body mass index (BMI; kilograms per square meter), sum of five skinfolds (SF5; millimeters), and waist circumference (WC; millimeters). The data were adjusted for the effects of age and sex, and the change scores were adjusted for baseline levels. A familial correlation model was used to determine the heritability of each phenotype using maximum likelihood techniques. Results: Significant familial resemblance was observed at baseline and for 7-year changes in all phenotypes. At baseline, moderate heritabilities were observed [body mass: heritability coefficient (h2) = 56%; BMI, h2 = 39%; SF5, h2 = 41%; and WC, h2 = 39%], whereas values were attenuated for each change score except for WC (Δbody mass, h2 = 23%; ΔBMI, h2 = 14%; ΔSF5, h2 = 12%; and ΔWC, h2 = 45%). Discussion: Changes in body mass and adiposity significantly aggregate within families over 7 years. However, baseline values are characterized by higher heritability levels except WC. The significant heritabilities observed for change scores suggest that lifestyle, transient environmental factors, and possibly age-related gene effects are important determinants of changes in body mass and adiposity.

The alpha2-adrenergic receptor gene and body fat content and distribution: The HERITAGE family study

Abstract: Among adrenergic receptor subtypes that regulate lipid mobilization, the α2-adrenergic receptor is involved in the inhibition of fatty acid mobilization from adipose tissue. A C-1291G polymorphism is located in the α2-adrenergic receptor gene (ADRA2A) but no association with body fat accumulation has been reported yet. Body mass index (BMI), fat mass (FAT), percentage body fat (%FAT), trunk-to-extremity skinfold ratio (TER), sum of eight skinfolds (SF8), and abdominal subcutaneous (ASF), visceral (AVF), and total (ATF) fat areas assessed by CT scan have been measured in adult sedentary white (n = 503) and black (n = 276) subjects participating in the HERITAGE Family Study. Association between the C-1291G polymorphism and each phenotype was tested separately in men and women of each race using ANCOVA with the effects of age as covariate in addition to the effects of BMI for TER and of FAT for AVF, ASF, and ATF. The allele frequencies of the ADRA2A C-1291G polymorphism differed between races. No association was observed in white subjects, except for a moderate effect of the polymorphism accounting for less than 1% of the variance in AVF and ATF in women. In black subjects, however, the G-1291 allele was found to be associated with an increase of TER in men (3.8% of variance accounted for by the polymorphism), while in black women it was associated with a decrease in TER (2.9%) and in AVF (2.5%). These results suggest a role for the ADRA2A gene in determining the propensity to store fat in the abdominal area, independently of total body fatness.

Leptin Levels, Leptin Receptor Gene Polymorphisms, and Energy Metabolism in Women

Abstract: Objective: Resting metabolic rate (RMR) is mainly determined by fat-free mass and additionally by age, sex, hormones, and possibly genetic differences. We evaluated whether leptin levels and polymorphisms in the leptin receptor (LEPR) gene were associated with energy expenditure phenotypes. Methods: RMR, body composition, and leptin levels were measured in 125 overweight and obese women. Three LEPR polymorphisms, Lys109Arg, Gln223Arg, and Lys656Asn, were typed on genomic DNA of another group of 192 women in whom RMR was measured. Fat, protein, and carbohydrate oxidation were calculated for 103 of these subjects. In 38 subjects, glucose-induced thermogenesis was measured over 3 hours. Results: In the first study group, a negative correlation between RMR and leptin levels was found after controlling for fat and fat-free mass. In multiple regression analysis, leptin contributed significantly to RMR, independent of body composition. In the second study group, RMR was not associated with LEPR polymorphisms. Differences in substrate oxidation rates were found among genotypes at the Lys656Asn site. In fasting conditions, Lys656Lys showed a trend to oxidize more carbohydrates and less fat than Asn656 carriers, a trend which became significant after the glucose load when carbohydrate oxidation rate in Lys656Lys was 15% higher than in Asn656 carriers (p = 0.04), and fat oxidation rate was 44% lower (p = 0.02). Discussion: These results suggest that DNA sequence variations in the LEPR gene could affect substrate oxidation. We hypothesize that this might be caused by differences in glucose levels, leading to differences in glucose oxidation rates.

G protein β3 polymorphism and hemodynamic and body composition phenotypes in the HERITAGE Family Study

Abstract: A C825T polymorphism of the G protein β3 (GNB3) gene has been reported to be associated with hypertension and obesity. We analyzed the associations between the GNB3 C825T polymorphism and hemodynam...

A genome-wide linkage scan for steroids and SHBG levels in black and white families: the HERITAGE Family Study.

Abstract: To identify loci-harboring genes affecting steroid hormone and SHBG plasma levels, a genomic-wide scan was performed in the HERITAGE Family Study at baseline. The following steroid hormones were assayed: androstane-3α, 17β-diol glucuronide, androsterone glucuronide, cortisol, dihydrotestosterone, estradiol, 17-hydroxyprogesterone (OH-PROG), progesterone (PROG), pregnenolone ester, and testosterone. A total of 509 markers on the 22 autosomes were genotyped, and a maximum of 357 pairs of siblings from white families and 103 from black families were available for the study. Significant linkages with LOD scores over 3.6 (P < 2.2 × 10−5) for SHBG were observed in blacks on 1q44 (D1S321), 5p13.3 (D5S1986), 10q24.1 (D10S1239), and 12q12 (D12S1653) in both singlepoint and multipoint analyses. Promising evidence of linkage (1.75 < LOD < 3.6; 2.2 × 10−5 < P < 0.0023) for SHBG was observed on 1q44 in singlepoint analysis in whites. In addition, several other loci in blacks exhibited promising evidence of linkage, su...

Spousal resemblance in the Canadian population: implications for the obesity epidemic.

Abstract: OBJECTIVE: To determine the extent of the spousal resemblance for adiposity and leanness in the Canadian population. DESIGN: Cross-sectional population survey. METHODS: The sample comprised parents and offspring from 1341 families (n=4023) of the Canada Fitness Survey. Indicators of adiposity included the body mass index (BMI) and the sum of five skinfolds (SF5). Both offspring and parents were ranked by their BMI and SF5 percentile position in the population using the entire Canada Fitness Survey database (n=15 818). RESULTS: Pearson correlations indicated significant spousal resemblance for both BMI (r=0.14; P<0.0001) and SF5 (r=0.13; P<0.0001). However, the magnitude of the spousal correlations varied by the adiposity status of the offspring, with spousal correlations tending to be stronger in parents of lean or obese children and lower among parents of ‘average’ children. Bivariate histograms indicated that among lean (≤5th percentile) and obese offspring (≥95th percentile), the parental pairs tended to cluster among the lower and higher percentiles of adiposity, respectively. CONCLUSIONS: There are spousal similarities in adiposity, particularly among parents of lean or obese offspring in the Canadian population. The degree to which these similarities are due to a loading of spouses with genes predisposing to obesity or a shared household environment cannot be determined from the present study. However, these results are compatible with the notion that genes and mutations predisposing to obesity are more prevalent among obese parents while those for pronounced leanness are more prevalent among lean parents.

The hormone-sensitive lipase gene and body composition: The Heritage Family Study

Abstract: OBJECTIVE: To investigate whether the C-60G polymorphism and other markers in the hormone-sensitive lipase (LIPE) gene are associated with baseline body composition and free-fatty acid (FFA) concentrations measured at rest and during low-intensity exercise in white and black subjects participating in the HERITAGE Family Study. SUBJECTS: Adult sedentary white (245 men and 258 women) and black (91 men and 185 women) subjects. MEASUREMENTS: body mass index (BMI); fat mass (FAT); percentage body fat (%FAT); fat-free mass (FATFR); sum of eight skinfolds (SF8); subcutaneous (ASF), visceral (AVF) and total (ATF) abdominal fat areas assessed by CT scan; plasma FFA concentrations measured at rest (FFAR), at a power output of 50 W (FFA50) and at a relative power output of 60% of VO2max (FFA60%); and fasting insulin (INS). STATISTICAL ANALYSIS: Association between the C-60G polymorphism of the LIPE gene and each phenotype was tested separately in men and women using ANCOVA with the effects of age and race as covariates and with further adjustment for FAT for ASF, AVF, ATF, FFAR, FFA50 and FFA60%. Secondly, owing to significant gene-by-race interaction, associations were investigated separately in each of the two race groups. Linkage was tested with the C-60G polymorphism, a dinucleotide repeat polymorphism in the intron 7 of the LIPE gene and two microsatellites markers (D19S178 and D19S903) flanking the LIPE gene. RESULTS: There were no race differences in the allele frequencies of the C-60G polymorphism of the LIPE gene. No association or gene-by-race interaction was observed in men. However, in women, strong gene-by-race interactions were observed for BMI (P=0.0005), FAT (P=0.0007), %FAT (P=0.0003), SF8 (P=0.0001), ASF (P=0.03) and ATF (P=0.01). When the analysis was performed separately in each race, white women carriers of the -60G allele exhibited lower %FAT (P=0.005) and SF8 (P=0.01) than non-carriers, while in black women, the -60G allele was associated with higher BMI (P=0.004), FAT (P=0.009), %FAT (P=0.01) and SF8 (P=0.0009). These associations were no longer significant after adjusting for INS. Evidence of linkage was observed in whites with ATF, FFAR, FFA50 and FFA60%. CONCLUSION: These results suggest that the C-60G polymorphism in the LIPE gene plays a role in determining body composition and that its effect is sex-, race- and insulin-dependent.

Adiposity, adipose tissue distribution and mortality rates in the Canada Fitness Survey follow-up study.

Abstract: OBJECTIVE: To compare mortality rates across indicators of adiposity and relative adipose tissue distribution in the Canadian population. SUBJECTS: The sample included 10 323 adult participants 20–69 y of age from the Canada Fitness Survey who were monitored for all-cause mortality over 13 y. METHODS: BMI, waist circumference (WC) and the sum of five skinfolds (SF5) were indicators of adiposity, and the first principal component of skinfold residuals (PC1) represented subcutaneous adipose tissue distribution. Proportional hazards regression was used to estimate relative mortality risk from mortality rates across levels of adiposity and adipose tissue distribution, controlling for the confounding effects of age, smoking status and alcohol consumption. RESULTS: Significant curvilinear (J-shaped) relationships in men and linear relationships in women were observed between BMI, WC and SF5 and all-cause mortality rates. PC1 was not related to mortality rates in either men or women. In women, the inclusion of the other indicators of adiposity and adipose tissue distribution did not significantly add to the prediction of mortality rates beyond BMI; however, combinations of BMI and both WC and SF5 produced significant models in men. CONCLUSION: The results support the hypothesis that overall level of adiposity is an important predictor of all-cause mortality, more so than the relative distribution of subcutaneous body fat, once overall level of body fatness has been accounted for.

Physical exercise and blood pressure with reference to the angiotensinogen M235T polymorphism.

Abstract: 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.

Menopause, estrogen, and training effects on exercise hemodynamics: the HERITAGE study.

Abstract: GREEN, J. S., P. R. STANFORTH, J. GAGNON, A. S. LEON, D. C. RAO, J. S. SKINNER, C. BOUCHARD, T. RANKINEN, and J. H. WILMORE. Menopause, estrogen, and training effects on exercise hemodynamics: the HERITAGE study. Med. Sci. Sports Exerc., Vol. 34, No. 1, 2002, pp. 74–82.PurposeTo investigate the infl

A +2138InsCAGACC polymorphism of the melanocortin receptor 3 gene is associated in human with fat level and partitioning in interaction with body corpulence.

Abstract: The melanocortin system includes five receptors (MC1R to MC5R), and mouse and human MC4R has been shown to be involved in the regulation of feeding, and mouse MC3R in body composition. To verify a possible similar effect of MC3R in humans, we analyzed one insertion and one single nucleotide polymorphism by restriction fragment length polymorphisms (RFLP), and a microsatellite (D20S32e) in relation to body composition and glucose metabolism. Eight hundred twelve subjects of the Quebec Family Study (QFS) cohort were analyzed for body composition, food intake, and energy metabolism phenotypes. Southern Blot with the complete MC3R cDNA was used to detect a new +2138InsCAGACC variant by Pst1 restriction. PCR-RFLP with BsaJ1 was used to type amino acid polymorphism V81I arising from a G241A nucleotide change. PCR and automatic DNA sequencers were used for the analysis of the TG dinucleotide repeat D20S32e located between −1933/ −1892 of MC3R. In a covariance analysis among genotypes, phenotypes were adjusted for age and sex as covariates. Food intake and energy metabolism phenotypes were also adjusted for body mass index (BMI), and leptin and abdominal fat, as assessed by a computed tomography scan, for fatness using six skinfold thicknesses. An association between the +2138InsCAGACC MC3R polymorphism was observed with fat mass (FM), percent body fat (%FAT), and total abdominal fat (ATF). Homozygote subjects for the + 2138 insertion variant allele in normal weight (BMI < 25 kg/m2) and overweight (25 ≤ BMI < 30 kg/m2) subjects showed a similar level of fatness despite the overall difference in BMI. In normal weight, homozygotes for the insertion allele showed higher mean values than heterozygotes and homozygotes for wild-type allele without insertion (%FAT: 24.0 ± 1.1 versus 19.3 ± 0.9 and 20.5 ± 0.8, p = 0.0005; FM: 15.7 ± 0.9 kg versus 11.7 ± 0.7 kg and 12.6 ± 0.6 kg, p = 0.0003). In contrast, overweight subjects homozygote for the variant allele showed lower mean values (%FAT: 27.0 ± 1.2 versus 31.4 ± 0.8 and 30.9 ± 0.7, p = 0.002; FM: 18.3 ± 1.0 kg versus 22.8 ± 0.8 kg and 22.0 ± 0.6 kg, p = 0.0001). This resulted in a similar level of body fat between both BMI groups for subjects homozygote for the insertion allele versus wild-type allele carriers (%FAT: ±2–3% versus ±10–12%; FM: ±2 kg versus ±9–11 kg). In obese subjects (BMI ≥ 30 kg/m2), a lower level of ATF was seen (−15%, p = 0.002). Other polymorphisms and phenotypes tested showed no association. A new +2138InsCAGACC MC3R polymorphism is associated with the level of adiposity and with body fat partitioning in interaction with corpulence in humans.

Plasma leptin response to an epinephrine infusion in lean and obese women.

Abstract: Objective: Because leptin production by adipose tissue is under hormonal control, we examined the impact of epinephrine administration on plasma leptin concentrations. Research Methods and Procedures: We measured plasma leptin, insulin, and free fatty acid (FFA) responses after a 60-minute epinephrine infusion (0.010 μg/kg fat free mass/min) followed by a 30-minute recovery period (no infusion) in a group of 11 lean (mean body mass index ± SD: 22.6 ± 1.1 kg/m2) and 15 obese (30.0 ± 1.3 kg/m2) premenopausal women. Leptin, insulin, and FFA levels were measured in plasma before (−15 and 0 minutes) and at every 30 minutes over the 90-minute period. Results: In both lean and obese individuals, plasma leptin was significantly reduced by epinephrine (p < 0.0001). Body fat mass was associated with fasting leptin levels (r = 0.64, p < 0.0005) as well as with the decrease in leptinemia (r = −0.51, p < 0.01) produced by epinephrine administration. Furthermore, we noted a large range of leptin response to epinephrine among our subjects, especially in obese women (from −12 to −570 ng/mL per 60 minutes). However, there was no association between postepinephrine leptin and FFA levels (r = −0.14, p = 0.55). Discussion: Results of this study indicate that leptin levels decrease after epinephrine administration in both lean and obese premenopausal women. However, the heterogeneity in the response of leptin to catecholamines suggests potential alterations of the leptin axis that may contribute to generate a positive energy balance and, thus, may favor weight gain in some obese individuals.