Zdenka Pausova

In industrialized countries, prenatal exposure to maternal cigarette smoking (PEMCS) is the most common environmental insult to the fetus. Here, we tested the hypothesis that PEMCS amplifies accumulation of abdominal fat during the accelerated weight gain occurring in late puberty. This hypothesis was tested in 508 adolescents (12–18 years, 237 exposed prenatally to maternal cigarette smoking) in whom subcutaneous and intra‐abdominal fat were quantified with magnetic resonance imaging (MRI). We found that, in early puberty, exposed and nonexposed adolescents did not differ in MRI‐based measures of adiposity. In late puberty, on the other hand, exposed compared with nonexposed adolescents demonstrated markedly higher quantities of both subcutaneous fat (by 26%,P= 0.004) and intra‐abdominal fat (by 33%,P= 0.001). These group differences remained virtually unchanged after adjusting for sex and potential confounders, including birth weight and breastfeeding. As such, our results suggest that PEMCS may represent a major risk factor for the development of abdominal obesity at the later stages of puberty.

Intra-abdominal accumulation of fat is a hallmark of male body-fat distribution and a major risk factor for hypertension. Sympathoactivation may be one of the mechanisms linking intra-abdominal obesity to hypertension. The aim of the present study was to investigate whether a functional variation in the androgen-receptor gene (AR, a variable number of CAG repeats in exon 1) is associated with intra-abdominal adiposity, sympathetic modulation of vasomotor tone, and blood pressure in adolescent boys but not girls. We studied 223 boys and 259 girls (age 12 to 18 years) from a French-Canadian founder population. Intra-abdominal fat and subcutaneous-abdominal fat were quantified with an MRI. Blood pressure was recorded beat-to-beat during an hour-long protocol including physical and mental challenges, and these blood pressure time series were used to assess sympathetic modulation of vasomotor tone by power spectral analysis. The results showed that boys with a "low" versus "intermediate" or "high" CAG-repeat number in AR demonstrated higher intra-abdominal fat (by 28% and 48%, respectively) but not subcutaneous-abdominal fat. These intra-abdominal fat differences remained significant after adjusting for serum levels of sex hormones and subcutaneous-abdominal fat. Furthermore, boys with low versus intermediate or high CAG-repeat numbers also showed higher blood pressure, with the differences being most pronounced during mental stress (8.0 and 8.5 mm Hg, respectively) and higher sympathetic modulation of vasomotor tone. As expected, no such differences were seen among girls. In adolescent boys, low CAG-repeat numbers in AR may be a genetic risk factor for intra-abdominal obesity and hypertension; sympathoactivation may be an underlying link between the 2 conditions.

Objectives To investigate during adolescence (1) sex differences in blood pressure (BP) and hemodynamic factors at rest and during physical and mental challenges and (2) whether these differences are mediated by body composition and glucose and lipid metabolism. Design Cross-sectional study of a population-based cohort. Setting Saguenay Youth Study, Quebec, Canada, from November 2003 to June 2007. Participants A total of 425 adolescents (225 girls aged 12-18 years). Outcome Measures Systolic and diastolic BP measured using a Finometer. Secondary outcome measures were (1) hemodynamic parameters also measured with a Finometer, (2) body composition assessed with magnetic resonance imaging, bioimpedance, and anthropometry, and (3) metabolic indices determined from a fasting blood sample. Results Girls vs boys demonstrated lower systolic and diastolic BP at rest and during challenges, with the differences being greatest during a math-stress test (adjusted difference, 7 mm Hg; 95% confidence interval [CI], 4-10 mm Hg and adjusted difference, 6 mm Hg; 95% CI, 4-8 mm Hg, respectively). The differences were mainly due to girls vs boys having lower stroke volume while lying down, standing (adjusted difference, 4 mL; 95% CI, 1-7 mL), and sitting, and lower total peripheral resistance during the math-stress test (adjusted difference, 0.14 mm Hg · s/mL; 95% CI, 0.09-0.21 mm Hg · s/mL). Intra-abdominal fat was positively associated with BP, but less in girls than in boys, and fat-free mass, fat mass, and insulin resistance were also positively associated with BP, similarly in boys and girls. Conclusions In adolescence, BP is lower in girls than boys, with the difference being determined mainly by lower stroke volume during physical challenges and by lower total peripheral resistance during mental challenges. Body composition and insulin resistance contribute to these differences.

Background— FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO -risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone. Methods and Results— The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO- risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP. Conclusions— These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone.

Obesity is a leading cause of diabetes mellitus and hypertension. Molecular signals produced by adipose tissue may contribute to the pathogenesis of these two disorders. We showed previously that a specific segment of rat chromosome 20 (RNO20) contains a gene(s) regulating the degree of obesity, glucose intolerance, and hypertension in response to a chronic high-fat diet (HFD). Here we examined microarray gene expression profiles and cellular morphology of adipose tissues and whole body energy expenditure in this model. Adult male spontaneously hypertensive rats (SHR) and a congenic strain (SHR.1N) that differs from SHR by the above-mentioned segment of RNO20 were fed for 12 wk with HFD or a normal diet. At the end of this period, whole body energy expenditure was measured with indirect calorimetry. In response to HFD, body weight, fat pad weights, adipocyte size, and serum leptin levels increased significantly more in SHR.1N than SHR. Microarray gene expression profiles [Affymetrix, 15,923 genes and expressed sequence tags (ESTs)] showed that multiple genes of molecular pathways involved in lipogenesis were downregulated to a similar level in both strains, whereas genes involved in fatty acid oxidation and energy dissipation were upregulated less in SHR.1N than SHR. This was associated with lower whole body energy expenditure in SHR.1N than SHR at the end of the 12-wk HFD. Our results suggest that a gene(s) within the RNO20 segment regulate(s) HFD-induced increases in adiposity, and that this effect may be mediated, at least in part, by the impact of that gene(s) on fat burning and energy expenditure.

Research from JAMA Pediatrics — Intra-abdominal Adiposity and Individual Components of the Metabolic Syndrome in Adolescence — Sex Differences and Underlying Mechanisms

The search for genes of complex traits is aided by the availability of multiple quantitative phenotypes collected in geographically isolated populations. Here we provide rationale for a large‐scale study of gene‐environment interactions influencing brain and behavior and cardiovascular and metabolic health in adolescence, namely the Saguenay Youth Study (SYS). The SYS is a retrospective study of long‐term consequences of prenatal exposure to maternal cigarette smoking (PEMCS) in which multiple quantitative phenotypes are acquired over five sessions (telephone interview, home, hospital, laboratory, and school). To facilitate the search for genes that modify an individual's response to an in utero environment (i.e. PEMCS), the study is family‐based (adolescent sibships) and is carried out in a relatively geographically isolated population of the Saguenay Lac‐Saint‐Jean (SLSJ) region in Quebec, Canada. DNA is acquired in both biological parents and in adolescent siblings. A genome‐wide scan will be carried out with sib‐pair linkage analyses, and fine mapping of identified loci will be done with family‐based association analyses. Adolescent sibships (12–18 years of age; two or more siblings per family) are recruited in high schools throughout the SLSJ region; only children of French‐Canadian origin are included. Based on a telephone interview, potential participants are classified as exposed or nonexposed prenatally to maternal cigarette smoking; the two groups are matched for the level of maternal education and the attended school. A total of 500 adolescent participants in each group will be recruited and phenotyped. The following types of datasets are collected in all adolescent participants: (1) magnetic resonance images of brain, abdominal fat, and kidneys, (2) standardized and computer‐based neuropsychological tests, (3) hospital‐based cardiovascular, body‐composition and metabolic assessments, and (4) questionnaire‐derived measures (e.g. life habits such as eating and physical activity; drug, alcohol use and delinquency; psychiatric symptoms; personality; home and school environment; academic and vocational attitudes). Parents complete a medical questionnaire, home‐environment questionnaire, a handedness questionnaire, and a questionnaire about their current alcohol and drug use, depression, anxiety, and current and past antisocial behavior. To date, we have fully phenotyped a total of 408 adolescent participants. Here we provide the description of the SYS and, using the initial sample, we present information on ascertainment, demographics of the exposed and nonexposed adolescents and their parents, and the initial MRI‐based assessment of familiality in the brain size and the volumes of grey and white matter. Hum Brain Mapp 2007.

This article describes a suite of computational approaches suitable for deriving various quantitative phenotypes from structural magnetic resonance (MR) images obtained in rodents and used subsequently in genetic studies of complex traits. We begin by introducing the basic principles of genetic studies of complex traits in experimental models. We then illustrate the use of MR‐based computational anatomy in vivo and ex vivo, and in combination with histology. This work was carried out in two inbred strains of rats, namely spontaneously hypertensive rats and Brown Norway rats; these are parental strains of the only existing panel of recombinant inbred strains of rats. The rats were scanned in vivo at two time points (at 8 and 12 weeks of age) and ex vivo (at 12 weeks of age). We describe between‐strain differences and across‐time changes in brain and kidney volumes, as well as regional variations in brain structure using surface‐ and deformation‐based approaches. We conclude by discussing the power of the population‐based computational analysis of MR images, and their fusion with histology, in studies of complex traits. Hum Brain Mapp, 2007.

The environment created by modern industrialized societies has caused an unprecedented rise in the prevalence of obesity and obesity-related disorders, including hypertension. Mechanisms that underlie the development of hypertension in obese individuals are not very well understood; they are thought to involve activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and oxidative stress. Recent research suggests that obesity-associated hypertension may be causally related to the accumulation of 'dysfunctional' adipose tissue characterized by the presence of 'large' lipid-laden adipocytes. Excess energy-intake leads to an expansion of adipose tissue, a hallmark of obesity. But morphology of the expanded adipose tissue differs across individuals, including the size of adipocytes. The presence of 'large' rather than 'small' adipocytes is associated with functional and structural abnormalities of adipose tissue. These include increased production of bioactive molecules, such as leptin, angiotensinogen, pro-inflammatory cytokines, and reactive oxygen species; insufficient capacity to accommodate excess energy-intake leading to ectopic fat storage in tissues and in turn insulin resistance and hyperinsulinemia; and augmented macrophage infiltration enhancing the production of pro-inflammatory cytokines and reactive oxygen species. Such a 'dysfunctional' adipose tissue may, in turn, induce activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and oxidative stress and, hence, promote the development of obesity-associated hypertension.

Essential hypertension is a heterogeneous disorder that is thought to develop because of several overlapping subsets of underlying mechanisms. One such causal pathway may involve pathophysiological alterations induced by obesity. In the present study, we examined whether investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, facilitates the search for its genes. Fifty-five extended families were selected on the basis of having ≥2 siblings affected by hypertension from a geographically remote French-Canadian population. Fifteen of these families showed a high prevalence (≥70%) of obesity. Genome-wide scan using qualitative multipoint linkage analysis (GeneHunter 2.1; marker density <10 cM) was performed in the entire set of hypertensive families and the subset with high prevalence of obesity. In the scan involving all 55 families, the most significant loci (logarithm of odds [LOD] score=2.5) were identified on chromosomes 1 (D1S1597) and 11 (D11S1999). In the scan including only the subset of families with obesity-hypertension, the most significant locus (LOD score=3.1) was found on chromosome 1 in the same region as the scan involving all families (D1S1597). Genotyping additional markers increased the significance of this locus (LOD score=3.5) and refined its position (D1S2672). Several candidate genes of obesity-hypertension are located in close proximity; these include the tumor necrosis factor receptor 2 and atrial natriuretic peptide genes. These results suggest that investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, may facilitate the search for genes of this complex disorder.