Caroline Rhéaume

Omental Adipose Tissue Type 1 11β-Hydroxysteroid Dehydrogenase Oxoreductase Activity, Body Fat Distribution, and Metabolic Alterations in Women

CONTEXT Modulation of adipose tissue exposure to active glucocorticoids by type 1 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1) is involved in abdominal obesity of rodent models, but only a few studies have related 11 beta-HSD1 oxoreductase activity to fat distribution in humans. OBJECTIVE The objective of the study was to examine the link between 11 beta-HSD1 oxoreductase activity, fat distribution patterns, and the metabolic profile in women. METHODS Omental (OM) and sc adipose tissue samples were obtained from 36 lean to obese women (aged 47.2 +/- 5.3 yr; body mass index 29.1 +/- 5.2 kg/m(2)) undergoing gynecological surgery. Measures of body composition, fat distribution, blood lipids, and insulin sensitivity were obtained. 11 beta-HSD1 oxoreductase activity was measured over a 24-h period by the reduction of [(14)C]cortisone in adipose tissue homogenates. RESULTS 11 beta-HSD1 oxoreductase activity was higher in OM compared with sc adipose tissue (9.6 +/- 4.9 vs. 7.9 +/- 4.2 pmol/mg x h, P < 0.01). OM 11 beta-HSD1 oxoreductase activity was positively associated with OM adipocyte size (r = 0.67, P < 0.0001) and visceral adipose tissue area (r = 0.57, P < 0.0003). A positive correlation was also observed between the OM/sc 11 beta-HSD1 oxoreductase activity ratio and the OM/sc adipocyte size ratio (r = 0.37, P < 0.05) as well as the visceral/sc adipose tissue area ratio (r = 0.36, P < 0.05). Women in the highest tertile of OM 11 beta-HSD1 oxoreductase activity had larger OM adipocytes, increased OM lipolysis, increased lipoprotein lipase activity, decreased high-density lipoprotein cholesterol, decreased adiponectin levels, and an increased homeostasis model assessment of insulin resistance index compared with women in the lower tertile (P < 0.05). CONCLUSIONS These results suggest that a relatively higher 11 beta-HSD1 activity in OM vs. sc adipose tissue is associated with preferential visceral fat accumulation and concomitant metabolic alterations.

Low Cardiorespiratory Fitness Levels and Elevated Blood Pressure. What Is the Contribution of Visceral Adiposity

Individuals with poor cardiorespiratory fitness have higher blood pressure than fit individuals. Individuals with low fitness levels also tend to be characterized by higher visceral adiposity compared with physically fit individuals. We tested the hypothesis that the relationship between low fitness and elevated blood pressure could be related, at least in part, to the higher level of visceral adipose tissue often found among unfit individuals. This study included 407 asymptomatic, nondiabetic participants. Visceral adipose tissue was assessed by computed tomography, and fitness was measured by a progressive submaximal physical working capacity test. Participants in the highest visceral adipose tissue tertile showed the highest systolic and diastolic blood pressures, whereas participants in the highest fitness tertile had the lowest blood pressure values (P<0.001). When participants were classified into fitness tertiles and then subdivided on the basis of visceral adipose tissue (high versus low), participants with a high visceral adipose tissue had higher systolic and diastolic blood pressure values (P=0.01), independent of their fitness category. Linear regression analyses showed that age and visceral adipose tissue, but not fitness, predicted systolic blood pressure (r2=0.11 [P<0.001], 0.12 [P<0.001], and 0.01 [P value nonsignificant], for age, visceral adipose tissue, and fitness, respectively) and diastolic blood pressure (r2=0.17 [P<0.001], 0.14 [P<0.001], and 0.01 [P value nonsignificant], for age, visceral adipose tissue, and fitness, respectively). Individuals with high visceral adipose tissue levels have higher blood pressure, independent of their fitness. Visceral adipose tissue may represent an important clinical target in the management of elevated blood pressure.

Glucose transporter 4 and insulin receptor substrate–1 messenger RNA expression in omental and subcutaneous adipose tissue in women

Insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) expression may provide an indirect reflection of the capacity of adipocytes to respond to insulin stimulation. We examined messenger RNA (mRNA) expression of these genes in omental and subcutaneous adipose tissue of women. Paired omental and subcutaneous adipose tissue samples were obtained from 36 women (age, 47 +/- 5 years; body mass index, 28.0 +/- 5.4 kg/m(2)) undergoing gynecologic surgeries. Total adiposity and visceral adiposity were assessed by dual-energy x-ray absorptiometry and computed tomography. The GLUT4 and IRS-1 mRNA expression levels were both significantly higher in subcutaneous compared with omental adipose tissue. A negative correlation was observed between body fat percentage and subcutaneous adipose tissue GLUT4 (r = -0.39, P < .05) and IRS-1 (r = -0.30, P < .08) mRNA abundance. However, in omental fat, only GLUT4 mRNA was inversely associated with body fat percentage (r = -0.53, P < .001). Moreover, the homeostasis model assessment of insulin resistance index was associated with mRNA expression of subcutaneous GLUT4 (r = -0.56, P < .001), subcutaneous IRS-1 (r = -0.51, P < .01), and omental GLUT4 (r = -0.54, P < .001), but not omental IRS-1. Interestingly, plasma adiponectin was only associated with subcutaneous GLUT4 (r = 0.48, P < .01) and IRS-1 (r = 0.48, P < .05) mRNA expression. The GLUT4 protein, unlike mRNA expression, was higher in omental than in subcutaneous adipose tissue. However, abdominal obesity-related differences in protein or mRNA expression were similar. Omental IRS-1 expression was low and unaffected by visceral obesity. In contrast, omental and subcutaneous GLUT4 as well as subcutaneous IRS-1 were reduced in visceral obesity. This divergent pattern of expression may reflect a lower capacity of omental adipose tissue to respond to insulin stimulation at all adiposity levels.

Contributions of Cardiorespiratory Fitness and Visceral Adiposity to Six-Year Changes in Cardiometabolic Risk Markers in Apparently Healthy Men and Women

CONTEXT Both excess visceral adipose tissue (VAT) and low cardiorespiratory fitness (CRF) levels are associated with a deteriorated cardiometabolic risk profile. OBJECTIVE The aim of the study was to examine the respective contributions of changes in VAT accumulation vs. changes in CRF to 6-yr longitudinal changes in cardiometabolic risk markers. DESIGN, SETTINGS, AND PARTICIPANTS We conducted a prospective, population-based study with an average follow-up of 5.9 ± 0.8 yr. We followed 132 middle-aged participants from the Quebec Family Study (mean age, 35.3 ± 13.9 yr). VAT was measured by computed tomography, whereas the level of CRF was assessed by a submaximal physical working capacity test at baseline and at follow-up. A complete cardiometabolic risk profile, including systolic and diastolic blood pressure, fasting glucose and insulin levels, C-reactive protein (n = 72), as well as a standard lipoprotein-lipid profile, was obtained at baseline and at follow-up. MAIN OUTCOME MEASURES We measured changes in CRF, VAT, and cardiometabolic risk profile over 6 yr. RESULTS After adjusting for age and sex, 6-yr changes in VAT were negatively correlated with changes in CRF (r = -0.38; P < 0.001). In a multivariate model that included age, sex, changes in VAT, changes in CRF, as well as baseline levels of the above cardiometabolic risk factors, 6-yr changes in VAT were the most important predictor of the change in the metabolic syndrome score (R(2) = 13.2%; P < 0.001). Adding 6-yr changes in CRF levels significantly improved the predictability of the model (R(2) = 19.7%; P = 0.002). CONCLUSIONS Changes in both VAT and CRF levels observed over 6 yr are associated with changes in parameters of the lipoprotein-lipid profile, glucose-insulin homeostasis, and inflammatory markers. Thus, maintaining a low level of VAT and a high level of CRF are important targets for maintenance of cardiometabolic health.

Progesterone metabolism in adipose cells.

The aim of the present study was to investigate pathways of progesterone metabolism in human adipose cells. Adipose tissue samples from the omental (OM) and subcutaneous (SC) fat compartments were surgically obtained in women. In isolated mature adipocytes, progesterone was converted to 20alpha-hydroxyprogesterone as the main metabolite, most likely through the activity of aldo-keto reductases 1C1, 2 and 3 (20alpha-HSD, 3alpha-HSD type 3 and 17beta-HSD type 5, respectively). In cultured preadipocytes, progesterone was converted to several metabolites identified using bidimensional thin layer chromatography, with or without the dual inhibitor of 5alpha-reductase type 1 and 2 (17beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5alpha-androstan-3-one (4-MA)). Major metabolites identified in OM and SC preadipocytes which were incubated for 24h with (14)C-labelled progesterone were 20alpha-hydroxyprogesterone, 5alpha-pregnane-3alpha/beta-ol-20-one, 5alpha- and 5beta-pregnanedione, 5alpha- and 5beta-pregnane-20alpha-ol-3-one, 5alpha-pregnane-3alpha/beta-ol-20-one and 5beta-pregnane-3alpha/beta-20alpha-diol. Induction of preadipocyte differentiation increased expression levels of AKR1C1 and modified the pattern of progesterone metabolism substantially, leaving 20alpha-hydroxyprogesterone as the main metabolite generated. On the other hand, progesterone itself showed no consistent effect on adipocyte differentiation. In conclusion, preadipocytes and lipid-storing, mature adipocytes efficiently generate progesterone metabolites in women, which is consistent with rather modest effects progesterone on abdominal fat cell differentiation.

Visceral adipose tissue zinc finger protein 36 mRNA levels are correlated with insulin, insulin resistance index, and adiponectinemia in women

INTRODUCTION Adipose tissue is now recognized as an endocrine organ and secretes numerous molecules and proteins potentially involved in the physiopathology of the metabolic syndrome. Recently, we have determined the transcriptome of omental adipose tissue, leading to the identification of a new candidate gene for obesity-related metabolic complications, zinc finger protein 36 (ZFP36), which is known to down-regulate tumor necrosis factor-alpha TNF-alpha) expression. OBJECTIVE The objective of this study was to further examine the relationship between ZFP36 gene expression levels, obesity-related phenotypes, and adipokines. METHODS Abdominal subcutaneous and omental adipose tissue samples were obtained from 46 women undergoing elective gynecological surgery. Adipose tissue ZFP36 mRNA abundance was assessed by quantitative real-time PCR. Body fat accumulation and distribution were measured by dual X-ray absorptiometry and computed tomography. Fasting blood levels of glucose, insulin, and lipids, and circulating TNF-alpha, interleukin-6 (IL-6), resistin, and adiponectin were also measured. RESULTS No correlation was observed between s.c. ZFP36 mRNA levels and any of the phenotypes tested. However, although omental ZFP36 mRNA levels were not correlated with measures of body fatness and lipid profile, they were negatively correlated with fasting insulin levels (R = -0.31; P = 0.05), the insulin resistance index (HOMA-IR; R = -0.31; P = 0.05), and 2-h post-glucose insulinemia (R = -0.32; P = 0.05). Omental ZFP36 mRNA abundance was also positively correlated with adiponectinemia (R = 0.35; P = 0.03) but not with circulating TNF-alpha, IL-6, and resistin concentrations. CONCLUSION These results suggest that ZFP36 gene expression in omental adipose tissue, but not in abdominal s.c. fat, may offer partial protection against the development of insulin resistance and diabetes.

Adiposity assessment: explaining the association between obesity, hypertension and stroke

Obesity is associated with a greater prevalence of cardiovascular risk factors and a higher risk of cardiovascular events, and contributes to the rise in cardiovascular morbidity and mortality worldwide. Increased BMI is established as an independent risk factor for cardiovascular disease (CVD). Attention has recently been drawn to alternate measures of adiposity/obesity, such as waist circumference, waist-to-hip ratio and waist-to-height ratio, that provide information regarding body fat distribution. Although BMI is the established clinical measurement to estimate CVD risk associated with excess bodyweight, there is evidence suggesting that abdominal obesity could represent a better marker of CVD risk than BMI. It is now recognized that abdominally obese individuals tend to have higher blood pressure. A major cardiovascular risk factor associated with stroke is systemic hypertension followed closely by obesity. Clinical adiposity indices used to describe obesity linked with systemic hypertension and stroke incidence are reviewed in this article. In summary, BMI, waist circumference, waist-to-hip ratio and waist-to-height ratio measurements are all useful tools for assessing adiposity/obesity in clinical practice, and should be evaluated with other cardiometabolic risk factors to refine cardiovascular risk stratification.

Effects of Mild Exercise on Insulin Sensitivity in Hypertensive Subjects

Physical exercise increases insulin sensitivity in conditions associated with insulin resistance, such as obesity and diabetes, but little is known in this regard in hypertension. Whether postexercise changes in hemodynamics and/or changes in insulin-induced vasodilatation could contribute to a postexercise increase in insulin sensitivity in hypertensive subjects is unknown. We investigated the effects of acute physical exercise on insulin sensitivity in 10 hypertensive and 10 normotensive subjects during a control evaluation (CTRL), during lower body negative pressure (LBNP), after 30 minutes of mild bicycle exercise (POSTEX), and during LBNP after exercise (POSTEX+LBNP). Insulin-induced vasodilatation was assessed from peak forearm blood flow during the intravenous glucose tolerance test. Cardiac output (4.9±0.3 versus 5.3±0.4 L/min, mean±SEM) and insulin sensitivity (the glucose disappearance rate over insulin area under the curve: 0.91±0.07 versus 1.38±0.25 min−1/[pmol · L−1] · minute) were lower (both P <0.05) in hypertensive than in normotensive subjects, respectively. Cardiac output decreased during LBNP, increased during POSTEX, and was similar to control during POSTEX+LBNP in both groups. Insulin sensitivity was unchanged during LBNP, increased during POSTEX, and remained elevated during POSTEX+LBNP in hypertensive subjects, whereas it remained unchanged in normotensives. Peak forearm blood flow was significantly lower in hypertensive than in normotensive subjects, despite higher insulin levels in hypertensives, and was not modified by LBNP or exercise. In conclusion, insulin sensitivity increases after exercise in hypertensive subjects, and the increase in cardiac output does not contribute to this effect. Endogenous insulin-induced vasodilatation is reduced in hypertensive subjects, and this insulin action is not affected by physical exercise.

A 12-Week Exercise Program for Pregnant Women with Obesity to Improve Physical Activity Levels: An Open Randomised Preliminary Study

Objective To evaluate whether a 12-week supervised exercise program promotes an active lifestyle throughout pregnancy in pregnant women with obesity. Methods In this preliminary randomised trial, pregnant women (body mass index ≥ 30 kg/m2) were allocated to either standard care or supervised training, from 15 to 27 weeks of gestation. Physical activity was measured by accelerometry at 14, 28 and 36 weeks, while fitness (oxygen consumption (VO2) at the anaerobic threshold), nutrition (caloric intake and macronutrients percentage) and anthropometry were assessed at 14 and 28 weeks of gestation. Analyses were performed using repeated measures ANOVA. Results A total of fifty (50) women were randomised, 25 in each group. There was no time-group interaction for time spent at moderate and vigorous activity (pinteraction = 0.064), but the exercise group’s levels were higher than controls’ at all times (pgroup effect = 0.014). A significant time-group interaction was found for daily physical activity (p = 0.023); similar at baseline ((22.0 ± 6.7 vs 21.8 ± 7.3) x 104 counts/day) the exercise group had higher levels than the control group following the intervention ((22.8 ± 8.3 vs 19.2 ± 4.5) x 104 counts/day, p = 0.020) and at 36 weeks of gestation ((19.2 ± 1.5 vs 14.9 ± 1.5) x 104 counts/day, p = 0.034). Exercisers also gained less weight than controls during the intervention period despite similar nutritional intakes (difference in weight change = -0.1 kg/week, 95% CI -0.2; -0.02, p = 0.016) and improved cardiorespiratory fitness (difference in fitness change = 8.1%, 95% CI 0.7; 9.5, p = 0.041). Conclusions Compared with standard care, a supervised exercise program allows pregnant women with obesity to maintain fitness, limit weight gain and attenuate the decrease in physical activity levels observed in late pregnancy. Trial Registration ClinicalTrials.gov NCT01610323

Insulin Resistance, Low Cardiorespiratory Fitness, and Increased Exercise Blood Pressure Contribution of Abdominal Obesity

Individuals with insulin resistance and low cardiorespiratory fitness are frequently found to have an increased waist circumference and high exercise blood pressure. We tested the hypothesis that the relationships among insulin resistance, low cardiorespiratory fitness, and increased exercise blood pressure may be mediated by an elevated waist circumference. This study included 317 apparently healthy men and women (mean age: 34.8±12.8 years; mean body mass index: 26.1±5.2 kg/m2). Exercise blood pressure values were measured using a submaximal ergometer test evaluating physical working capacity. Plasma insulin and glucose levels were measured during a 3-hour oral glucose tolerance test. Multivariate regression analyses showed that waist circumference accounted for 32.8% (P<0.0001) and 45.1% (P<0.0001) of the variance in exercise systolic blood pressure in men and women, respectively. Participants were classified into tertiles according to either insulin response, measured during the oral glucose tolerance test, or fitness levels and then further subdivided into 2 subgroups using sex-specific waist circumference thresholds. Individuals with an increased waist circumference (≥94 cm and ≥80 cm for men and women, respectively) had higher exercise systolic blood pressure compared with individuals with low waist circumference, irrespective of their level of insulin resistance (10.6 versus 6.8, 12.2 versus 7.7, and 13.2 versus 8.7 mm Hg/metabolic equivalent, respectively, for the low, intermediate, and high tertiles; P<0.05) or fitness levels (13.1 versus 8.2, 12.0 versus 7.9, and 10.6 versus 7.1 mm Hg/metabolic equivalent, respectively, for the low, intermediate, and high tertiles; P<0.05). Individuals with a higher waist circumference have elevated exercise systolic blood pressure, regardless of their insulin sensitivity or level of cardiorespiratory fitness.