Obesity: Tchernof A

Blouin K, Veilleux A, Luu-The V, Tchernof A. · Molecular Endocrinology and Oncology Research Center, Laval University Medical Research Center, Canada; Department of Nutrition, Laval University, Canada. · Mol Cell Endocrinol. · Pubmed #19022338 No free full text.

Abstract: Androgens modulate adipocyte function and affect the size of adipose tissue compartments in humans. Aldo-keto reductase 1C (AKR1C) enzymes, especially AKR1C2 and AKR1C3, through local synthesis and inactivation of androgens, may be involved in the fine regulation of androgen availability in adipose tissue. This review article summarizes recent findings on androgen metabolism in adipose tissue. Primary culture models and whole tissue specimens of human adipose tissue obtained from the abdominal subcutaneous and intra-abdominal (omental) fat compartments were used in our studies. The non-aromatizable androgen dihydrotestosterone (DHT) inhibits adipocyte differentiation in subcutaneous and omental adipocytes in humans. This inhibitory effect is partially reversed by anti-androgens. Activity and mRNA expression of AKR1C1, 2 and 3 were detected in SC and OM adipose tissue, in men and women, with higher levels in the SC depot than the omental depot of both sexes. The abundance of AKR1C enzyme mRNAs was particularly elevated compared to other steroid-converting enzymes. Significant positive associations were observed between AKR1C enzyme mRNA levels or DHT inactivation rates and visceral fat accumulation as well as OM adipocyte size in women and in men, at least in the normal weight to moderately obese range. Mature adipocytes had significantly higher DHT inactivation rates compared to preadipocytes. Accordingly, adipocyte differentiation significantly increased AKR1C enzyme expression and DHT inactivation rates. Treatment of preadipocytes with dexamethasone alone led to significant increases in the formation of 5alpha-androstan-3alpha,17beta-diol. This stimulation was completely abolished by RU486, suggesting that androgen inactivation is stimulated by a glucocorticoid receptor-dependent mechanism. In conclusion, higher AKR1C activity and expression in mature adipocytes may explain the associations between these enzymes and obesity. We speculate that glucocorticoid-induced androgen inactivation could locally decrease the exposure of adipose cells to active androgens and partially remove their inhibitory effect on adipogenesis. We hypothesize that body fat distribution patterns likely emerge from the local adipose tissue balance between active androgens and glucocorticoids in each fat compartment.

Morisset AS, Blouin K, Tchernof A. · Molecular Endocrinology and Oncology Laval University Medical Research Center, Quebec City, Canada. · Nutr Rev. · Pubmed #18752474 No free full text.

Abstract: This review summarizes studies on the effect of various diets on circulating androgen levels and sex hormone-binding globulin (SHBG). Reduced caloric intake leading to significant weight loss increases SHBG levels regardless of diet composition, particularly in women. Cross-sectional studies show that dietary composition is generally not associated with SHBG levels independent of obesity level. No clear conclusion can be reached regarding the effect of various eating habits or dietary composition on circulating androgens. The evidence indicates that dietary effects on circulating SHBG, and possibly androgens, can be expected if body weight or fatness and/or insulin homeostasis are modulated.

Blouin K, Boivin A, Tchernof A. · Molecular Endocrinology and Oncology Research Center, Laval University Medical Research Center, 2705 Laurier Boulevard T3-67, Québec, Que, Canada. · J Steroid Biochem Mol Biol. · Pubmed #17945484 No free full text.

Abstract: An important sex difference in body fat distribution is generally observed. Men are usually characterized by the android type of obesity, with accumulation of fat in the abdominal region, whereas women often display the gynoid type of obesity, with a greater proportion of their body fat in the gluteal-femoral region. Accordingly, the amount of fat located inside the abdominal cavity (intra-abdominal or visceral adipose tissue) is twice as high in men compared to women. This sex difference has been shown to explain a major portion of the differing metabolic profiles and cardiovascular disease risk in men and women. Association studies have shown that circulating androgens are negatively associated with intra-abdominal fat accumulation in men, which explains an important portion of the link between low androgens and features of the metabolic syndrome. In women, the low circulating sex hormone-binding globulin (SHBG) levels found in abdominal obesity may indirectly indicate that elevated free androgens are related to increased visceral fat accumulation. However, data on non SHBG-bound and total androgens are not unanimous and difficult to interpret for total androgens. These studies focusing on plasma levels of sex hormones indirectly suggest that androgens may alter adipose tissue mass in a depot-specific manner. This could occur through site-specific modulation of preadipocyte proliferation and/or differentiation as well as lipid synthesis and/or lipolysis in mature adipocytes. Recent results on the effects of androgens in cultured adipocytes and adipose tissue have been inconsistent, but may indicate decreased adipogenesis and increased lipolysis upon androgen treatment. Finally, adipose tissue has been shown to express several steroidogenic and steroid-inactivating enzymes. Their mere presence in fat indirectly supports the notion of a highly complex enzymatic system modulating steroid action on a local basis. Recent data obtained in both men and women suggest that enzymes from the aldoketoreductase 1C family are very active and may be important modulators of androgen action in adipose tissue.

Sniderman AD, Bhopal R, Prabhakaran D, Sarrafzadegan N, Tchernof A. · Mike Rosenbloom Laboratory for Cardiovascular Research, Division of Cardiology, McGill University Health Science Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada. · Int J Epidemiol. · Pubmed #17510078 links to  free full text

Abstract: The rates of coronary disease have accelerated dramatically amongst South Asians, driven to an important extent by the atherogenic dyslipidemia and type 2 diabetes that have become so common amongst them. These precursors of vascular disease appear at lower absolute amounts of adipose tissue in South Asians than in whites. In this paper, we set out a new hypothesis--the adipose tissue overflow hypothesis--to account for these findings. The adipose tissue mass within our bodies can be divided into three different compartments: superficial subcutaneous adipose tissue, deep subcutaneous adipose tissue and visceral adipose tissue. The superficial subcutaneous adipose tissue compartment is the primary compartment, is present throughout the body, and constitutes the vast majority of the adipose tissue in the lower limb. With energy excess, the secondary adipose tissue compartments--the deep subcutaneous (mainly upper body) and the visceral adipose tissue compartments--become more prominent. Superficial subcutaneous adipose tissue is relatively inert metabolically, whereas the other two compartments are characterized by higher transmembrane fatty acid flux rates and thus are more closely linked to dyslipidemia and dysglycemia. We hypothesize that the superficial subcutaneous adipose tissue compartment is larger in whites than in South Asians. If so, as obesity develops, South Asians exhaust the storage capacity of their superficial subcutaneous adipose tissue compartment before whites do and that is why they develop the metabolic complications of upper body obesity at lower absolute masses of adipose tissue than white people.

Tchernof A, Labrie F. · Molecular Endocrinology and Oncology Research Center, Laval University Hospital Research Center (CHUL Research Center) and Laval University, Quebec G1V 4G2, Canada. · Eur J Endocrinol. · Pubmed #15248817 links to  free full text

Abstract: The age-related decline in serum dehydroepiandrosterone (DHEA) and its sulfated ester (DHEA-S) has suggested that a relative deficiency of these steroids may be causally related to the development of chronic diseases generally associated with aging, including insulin resistance, obesity, cardiovascular disease, cancer, reductions of the immune defense, depression and a general deterioration in the sensation of well-being. The numerous studies which have focused on the link between DHEA and cardiovascular disease have generally been inconsistent, generating much debate and controversy on this issue. The present article is an analysis of studies on the relationship between endogenous DHEA or DHEA-S, obesity and cardiovascular disease risk, as well as DHEA treatment studies. Elevated plasma levels of free DHEA are associated with reduced obesity in both men and women, and with smaller abdominal body fat accumulations in men. However, contradictory results have been reported regarding the relationships between the sulfate ester DHEA-S and adiposity. Age differences in the populations studied may have been a confounding factor in these associations. On the other hand, DHEA-S level is not a predictor of cardiovascular disease endpoints in women, and appears to be a relatively weak one in men. DHEA intervention studies suggest that the effects of DHEA on serum lipids are, at best, modest or non-significant. The uncertainty as to whether endogenous and exogenous DHEA should be considered cardioprotective is related to discrepancies in the literature on this topic. Several studies may have been plagued by methodological problems such as low power, unreliable analytical methods, confounding factors or other differences in the populations studied. As a consequence, the original reports demonstrating dramatic effects of either endogenous or exogenous DHEA on cardiovascular disease risk have never been replicated. We propose that the effects of DHEA on cardiovascular disease risk (either favorable or unfavorable) should be considered to be much more modest than previously believed.

Bélanger C, Luu-The V, Dupont P, Tchernof A. · Molecular Endocrinology and Oncology Research Center, Quebec, Canada. · Horm Metab Res. · Pubmed #12660892 No free full text.

Abstract: The present article summarizes some of the studies available on steroid hormone conversion through the specific expression of steroidogenic enzymes in adipose tissue (adipose tissue intracrinology) and discusses the potential impact of local adipose tissue steroid metabolism on the regulation of adipocyte function and other metabolic parameters. Several studies have demonstrated significant steroid hormone uptake and conversion by adipose tissues from various body sites and in various cell fractions. Activities and/or mRNAs of aromatase, 3beta-hydroxysteroid dehydrogenase (HSD), 3alpha-HSD, 11beta-HSD, 17beta-HSD, 7alpha-hydroxylase, 17alpha-hydroxylase, 5alpha-reductase and UDP-glucuronosyltransferase 2B15 have been detected in adipose tissue or adipose cells. These studies have demonstrated potentially important roles for these enzymes in obesity, central fat accumulation, and the metabolic syndrome. Future studies on adipose tissue intracrinology will contribute further to our understanding of steroid action in adipocytes.

Tchernof A, Després JP. · Molecular Endocrinology Laboratory and Lipid Research Center, Laval University Medical Research Center, Ste-Foy, Québec, Canada. · Horm Metab Res. · Pubmed #11246820 No free full text.

Abstract: Sex steroid hormones in both males and females have been closely related to the regulation of adiposity, either through direct or indirect physiological mechanisms. Evidence also suggests a direct relationship between sex hormones and risk factors for cardiovascular disease. In the present review article, we will discuss recent studies that have examined the complex interrelationships between sex hormones, SHBG, obesity and risk factors for cardiovascular disease. Male obesity and excess abdominal adipose tissue accumulation is associated with reductions in gonadal androgen and low adrenal C19 steroid concentrations. Reduced C19 steroids are also related to an altered metabolic risk factor profile including glucose intolerance and an atherogenic dyslipidemic state. However, the concomitant visceral obese state appears as a major correlate in these associations. In women, menopause-induced estrogen deficiency and increased androgenicity are associated with increased abdominal obesity and with the concomitant alterations in the metabolic risk profile. The accelerated accretion of adipose tissue in the intra-abdominal region coincident with the onset of menopause may explain part of the increased risk of cardiovascular disease in postmenopausal women. In both men and women, plasma levels of sex hormone-binding globulin are strong correlates of obesity and risk factors for cardiovascular disease, and more importantly, the relationships between low SHBG and altered plasma lipid levels appear to be independent from the concomitant increased levels of visceral adipose tissue. SHBG concentration may, therefore, represent the most important and reliable marker of the sex hormone profile in the examination of the complex interrelation of sex steroid hormones, obesity, and cardiovascular disease risk.

Robitaille J, Fontaine-Bisson B, Couture P, Tchernof A, Vohl MC. · Lipid Research Center, CHUQ-CHUL Pavilion, Ste-Foy, Quebec, Canada. · Ann Nutr Metab. · Pubmed #15942159 No free full text.

Abstract: BACKGROUND/AIMS: A healthy diet is a key factor in the prevention of cardiovascular disease, the leading cause of death for women in industrialized countries. In this regard, soluble fibers may have beneficial effects on the plasma lipoprotein/lipid profile. The objective of the present study was to investigate the plasma lipoprotein/lipid response to dietary fibers in overweight premenopausal women within a randomized controlled trial. METHODS: Following a 2-week run-in phase, 34 premenopausal women (age: 22-53 years) were randomly assigned either to the control group (no supplement) or to the treatment group, which received 2 oat bran-enriched muffins per day (28 g/day of oat bran) during 4 weeks. RESULTS: Supplementation with oat bran had a beneficial effect on plasma HDL-C levels. Indeed, compared to the control group (n = 16), a mean increase in plasma HDL-C levels of 11.2% was observed in women eating the oat bran supplement (n = 18) (p = 0.01), whereas the total cholesterol/HDL-C ratio decreased by 7.0% (p = 0.002). Results were similar after adjustment for age, apo E genotype and weight change. CONCLUSION: These results suggest that oat bran-rich foods have beneficial effect on the metabolic profile of overweight women. Integration of these foods as part of a healthy diet may, therefore, improve the cardiovascular risk profile of women.

Blouin K, Blanchette S, Richard C, Dupont P, Luu-The V, Tchernof A. · Molecular Endocrinology and Oncology Research Center, Dept. of Nutrition, Laval University Medical Center, 2705 Laurier Boulevard, Rm. T3-67, Quebec City, Prov. Quebec, Canada G1V 4G2. · Am J Physiol Endocrinol Metab. · Pubmed #15494612 links to  free full text

Abstract: We examined expression and activity of steroid aldoketoreductase (AKR) 1C enzymes in adipose tissue in women. AKR1C1 (20alpha-hydroxysteroid dehydrogenase; 20alpha-HSD), AKR1C2 (3alpha-HSD-3), and AKR1C3 (17beta-HSD-5) are involved mainly in conversion of progesterone to 20alpha-hydroxyprogesterone and inactivation of dihydrotestosterone to 5alpha-androstane-3alpha,17beta-diol. Abdominal subcutaneous and omental adipose tissue biopsies were obtained during abdominal hysterectomies in seven women with low visceral adipose tissue (VAT) area and seven age- and total body fat mass-matched women with visceral obesity. Women with elevated VAT areas were characterized by significantly higher omental adipose tissue 20alpha-HSD and 3alpha-HSD-3 mRNA abundance compared with women with low VAT accumulations (1.4- and 1.6-fold differences, respectively; P < 0.05). Omental and subcutaneous adipose tissue 3alpha-HSD activities were significantly higher in women with high vs. low VAT areas (P < 0.05 for both comparisons). Total and visceral adiposities were positively associated with omental 20alpha-HSD mRNA level (r = 0.75, P < 0.003 for fat mass; r = 0.57, P < 0.04 for VAT area) and omental 3alpha-HSD-3 mRNA level (r = 0.68, P < 0.01 for fat mass; r = 0.74, P < 0.003 for VAT area). Enzyme activities in both depots were also positively correlated with adiposity measures. Omental adipose tissue enzyme expression and activity were positively associated with omental adipocyte size and LPL activity. In conclusion, mRNA abundance and activity of AKR1C enzymes in abdominal adipose tissue compartments are positive correlates of adiposity in women. Increased progesterone and/or dihydrotestosterone reduction in abdominal adipose tissue may impact locally on fat cell metabolism.

Brochu M, Tchernof A, Turner AN, Ades PA, Poehlman ET. · Departments of Kinesiology and Nutrition, University of Montréal, Québec, Canada. · Metabolism. · Pubmed #12759890 No free full text.

Abstract: It is presently unclear how much visceral adipose tissue (VAT) loss is needed to induce favorable metabolic changes. Cross-sectional studies have proposed that a threshold level of VAT exceeding 110 cm(2) in women induces deleterious changes in the metabolic profile. It is presently unclear, however, if significant decreases in VAT below this given threshold significantly improve the metabolic profile more as compared to decreases that remain below 110 cm(2). To examine whether achieving versus not achieving the proposed VAT threshold impacts differently on the metabolic profile in postmenopausal women, we examined the effects of a VAT loss below the 110-cm(2) threshold versus those individuals who remained higher than 110 cm(2) after a weight loss program. Twenty-five sedentary obese (baseline % body fat, 47.7% +/- 4.1%; [mean +/- SD]) postmenopausal women aged between 51 and 71 years (59.7 +/- 5.6 years) and displaying high baseline levels of VAT accumulation (223 +/- 45 cm(2)) were submitted to a 1-year weight loss program with weight stabilization periods before and after weight reduction. Based on their loss of VAT after weight loss, subjects were characterized as "attainers" (post VAT levels < 110 cm(2); average, 96 +/- 10 cm(2); n = 10) or "non-attainers" (post VAT levels > 110 cm(2); average, 171 +/- 34 cm(2); n = 15). We compared changes in (1) plasma lipid-lipoprotein levels, (2) insulin sensitivity (euglycemic/hyperinsulinemic clamp), and (3) supine resting blood pressure between groups who achieved these 2 distinct levels of VAT. Attainers showed a 2-fold greater loss of VAT compared to non-attainers (-51.5% v -27.5%, P <.001). Attainers also showed a greater loss of body weight (-19.0% v -12.5%, P <.01) and fat mass (-34.8% v -18.4%, P <.001) after the program compared to non-attainers. Despite significant differences in the loss of total fat and VAT after the weight loss program, attainers and non-attainers showed comparable improvements for plasma high-density lipoprotein-cholesterol (HDL-chol) levels (+62.5% v +50.0%, P = not significant [NS]), cholesterol/HDL-chol ratio (-45.5% v -36.5%, P = NS), insulin sensitivity (+34.1% v +23.2%, P = NS), and resting systolic (-6.9% v -5.1%, P = NS) and diastolic (-11.3% v -11.1%, P = NS) blood pressure. These results do not favor the idea that attaining levels of VAT below a threshold of 110 cm(2) is necessary to favorably improve the metabolic profile in obese postmenopausal women. Achieving or not the proposed threshold of VAT, independently of baseline values, appears to yield similar metabolic improvements in obese postmenopausal women. More moderate losses of VAT appear to yield similar metabolic improvements as large losses.

Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET. · Department of Medicine, College of Medicine, University of Vermont, Burlington. · Circulation. · Pubmed #11827920 links to  free full text

Abstract: BACKGROUND: C-reactive protein (CRP) has been proposed as an independent risk factor for cardiovascular disease and has been positively associated with body weight and body fatness. We examined the hypothesis that weight loss would reduce plasma CRP levels in obese postmenopausal women. METHODS AND RESULTS: In a sample of 61 obese (body mass index, 35.6 +/- 5.0 kg/m(2)), postmenopausal women (age, 56.4 +/- 5.2 years), we found that plasma CRP levels were positively associated with dual x-ray absorptiometry-measured total body fatness (r=0.36, P<0.005) and CT-measured intra-abdominal body fat area (r=0.30, P<0.02). Significant correlations were also found between plasma CRP and triglyceride levels (r=0.33, P<0.009) and glucose disposal measured by the hyperinsulinemic-euglycemic clamp technique (r=-0.29, P<0.03). Twenty-five of the 61 women tested at baseline completed a weight loss protocol. The average weight loss was 14.5 +/- 6.2 kg (-15.6%, P<0.0001), with losses of 10.4 +/- 5.4 kg fat mass (-25.0%, P<0.0001) and 2.8 +/- 1.4 kg fat-free mass (-6.0%, P<0.0001). Visceral and subcutaneous fat areas were reduced by -36.4% and -23.7%, respectively (P<0.0001). Plasma CRP levels were significantly reduced by weight loss: average -32.3%, from 3.06 (+0.69, -1.29) to 1.63 (+0.70, -0.75) microgram/mL (P<0.0001, medians and interquartile differences). Changes in body weight and in total body fat mass were both positively associated with plasma CRP level reductions. CONCLUSIONS: Adiposity was a significant predictor of plasma CRP in postmenopausal women on a cross-sectional basis. Moreover, caloric restriction-induced weight loss decreased plasma CRP levels. Weight loss may represent an important intervention to reduce CRP levels, which may mediate part of its cardioprotective effects in obese postmenopausal women.

Sites CK, Brochu M, Tchernof A, Poehlman ET. · Departments of Obstetrics and Gynecology and Medicine, The University of Vermont College of Medicine, Burlington, VT 05405, USA. · Metabolism. · Pubmed #11436191 No free full text.

Abstract: The aim of this study was to compare the effect of hormone replacement therapy (HRT) on insulin resistance and central adiposity in obese postmenopausal women. Forty-five obese postmenopausal women (16 HRT users and 29 nonusers), with a mean age of 56.6 +/- 5.3 years and duration of current, continuous HRT use of 4.7 +/- 2.9 years, were included in the study. Subjects were studied using oral glucose tolerance tests, euglycemic clamping, dual photon x-ray absorptiometry, computed tomography, doubly labeled water, and treadmill testing. Insulin sensitivity, total fat, visceral fat, subcutaneous abdominal fat, thigh muscle attenuation, daily physical activity energy expenditure, peak oxygen consumption (Vo(2)) were measured. HRT users had lower body weight (88.0 +/- 11.0 v 98.2 +/- 15.0 kg, P =.05), lower body mass index (33.1 +/- 3.5 v 36.8 +/- 5.2 kg/m(2), P =.05), lower fat mass (38.3 +/- 7.3 v 44.1 +/- 10 kg, P =.05), less visceral adipose tissue (157 +/- 47 v 211 +/- 81 cm(2); P =.05), and higher peak Vo(2) (21.1 +/- 4.6 v 17.6 +/- 2.2 mL/kg/min, P =.001) than nonusers. After adjustment for total fat, we noted a trend for decreased visceral adipose tissue in HRT users (P =.09). After adjustment for peak Vo(2), the decreased visceral adipose tissue persisted in HRT users (P <.01). Insulin sensitivity per kilogram of lean body mass did not differ between HRT users (0.51 +/- 0.22 mmol/kg/min) and nonusers (0.49 +/- 0.22 mmol/kg/min). It was concluded that obese postmenopausal women using HRT have a more favorable body composition and fat distribution pattern than nonusers. Although visceral adipose tissue is decreased in HRT users, insulin sensitivity does not differ between HRT users and nonusers.

Brochu M, Starling RD, Tchernof A, Matthews DE, Garcia-Rubi E, Poehlman ET. · Department of Medicine, University of Vermont College of Medicine, Burlington 05405, USA. · J Clin Endocrinol Metab. · Pubmed #10902782 links to  free full text

Abstract: Older obese postmenopausal women have an increased risk for type 2 diabetes and cardiovascular disease. Increased abdominal obesity may contribute to these comorbidities. There is considerable controversy, however, regarding the effects of visceral adipose tissue as a singular predictor of insulin resistance compared to the other constituents of adiposity. To address this issue, we examined the independent association of regional adiposity and total fat mass with glucose disposal in obese older postmenopausal women. A secondary objective examined the association between glucose disposal with markers of skeletal muscle fat content (muscle attenuation) and physical activity levels. We studied 44 healthy obese postmenopausal women between 50 and 71 yr of age (mean +/- SD, 56.5 +/- 5.3 yr). The rate of glucose disposal was measured using the euglycemic/hyperinsulinemic clamp technique. Visceral and sc adipose tissue areas and midthigh muscle attenuation were measured from computed tomography. Fat mass and lean body mass were estimated from dual energy x-ray absorptiometry. Peak VO2 was measured from a treadmill test to volitional fatigue. Physical activity energy expenditure was measured from indirect calorimetry and doubly labeled water. Pearson correlations indicated that glucose disposal was inversely related to visceral adipose tissue area (r = -0.40; P < 0.01), but not to sc adipose tissue area (r = 0.17), total fat mass (r = 0.05), midthigh muscle attenuation (r = 0.01), peak VO2 (r = -0.22), or physical activity energy expenditure (r = -0.01). The significant association persisted after adjusting visceral adipose tissue for fat mass and abdominal sc adipose tissue levels (r = -0.45; P < 0.005; in both cases). Additional analyses matched two groups of women for fat mass, but with different visceral adipose tissue levels. Results showed that obese women with high visceral adipose tissue levels (283 +/- 59 vs. 137 +/- 24 cm2; P < 0.0001) had a lower glucose disposal per kg lean body mass compared to those with low visceral adipose tissue levels (0.44 +/- 0.14 vs. 0.66 +/- 0.28 mmol/kg x min; P < 0.05). Visceral adipose tissue is an important and independent predictor of glucose disposal, whereas markers of skeletal muscle fat content or physical activity exhibit little association in obese postmenopausal women.

Tchernof A, Toth MJ, Poehlman ET. · Department of Medicine, University of Vermont, Burlington 05405, USA. · Diabetes Care. · Pubmed #10546023 links to  free full text

Abstract: OBJECTIVE: Low sex hormone-binding globulin (SHBG) levels in women are associated not only with hyperinsulinemia, increased risk for cardiovascular disease, and type 2 diabetes but also with excess body fatness and abdominal obesity. We tested the hypothesis that an elevated total or intra-abdominal adipose tissue accumulation mediates the relationship between low SHBG levels and an altered metabolic profile. RESEARCH DESIGN AND METHODS: We measured body composition (dual-energy X-ray absorptiometry [DEXA]) and body fat distribution (computed tomography) in 52 middle-aged (46.7 +/- 0.4, mean +/- SEM) premenopausal women. Insulin and glucose responses to a 75-g oral glucose load and plasma lipid-lipoprotein levels were also measured. RESULTS: Low plasma SHBG concentrations were associated with increased total body fat mass (r = -0.41, P < 0.005) and subcutaneous abdominal (r = -0.39, P < 0.005) and intra-abdominal (r = -0.37, P < 0.008) adipose tissue area. Low SHBG was also associated with a greater insulin response to oral glucose (r = -0.40, P < 0.005), higher triglyceride levels (r = -0.29, P < 0.05), higher cholesterol/HDL cholesterol ratio (r = -0.51, P < 0.005), but lower HDL cholesterol concentrations (r = 0.65, P < 0.005). When matched for intra-abdominal fat or total fat mass, subjects with either low or high SHBG showed no difference in the insulin response to an oral glucose challenge. Statistical adjustment for differences in intra-abdominal adipose tissue accumulation or total body fat mass also eliminated the associations between SHBG levels and metabolic variables, with the exception of the association between SHBG and HDL cholesterol levels (r = 0.52, P < 0.005). CONCLUSIONS: Our results suggest that the previously reported relationship between low SHBG levels and increased metabolic disease risk in women is mediated, to a large extent, by concomitant variation in body fatness and intra-abdominal adipose tissue accumulation.

Tchernof A, Starling RD, Walston JD, Shuldiner AR, Dvorak RV, Silver K, Matthews DE, Poehlman ET. · Department of Medicine, College of Medicine, University of Vermont, Burlington 05405, USA. · Diabetes. · Pubmed #10389848 links to  free full text

Abstract: We examined the hypothesis that postmenopausal women with the beta3-adrenoceptor gene variant (Trp64Arg) have reduced total daily energy expenditure (TEE), altered free fatty acid kinetics, and increased intra-abdominal fat. A secondary objective was to examine whether the obese state masks the effect of the variant on resting metabolic rate (RMR). There were 23 obese heterozygous women with the genetic variant (age 58 +/- 6 years; BMI 36 +/- 7 kg/m2) who were compared with 19 homozygous obese women with the normal allele (age 56 +/- 4 years; BMI 36 +/- 3 kg/m2). Daily energy expenditure was determined from doubly labeled water and indirect calorimetry, lipolysis from infusion of [1-13C]palmitate, and body fat distribution from computed tomography. No significant differences were found in TEE, RMR, energy expenditure of physical activity, the thermic effect of a meal, fat oxidation as estimated by fasting and postprandial respiratory quotients (RQs), or rate of lipolysis. Similarly, no difference was found in visceral adipose tissue and abdominal subcutaneous fat areas. When RMR was compared between obese (n = 23) and never-obese women with the Trp64Arg variant (n = 16), we found a 317 kcal/day lower RMR in never-obese women after controlling for fat mass, fat-free mass, and age (P < 0.0017). These results do not support the hypothesis that already obese women with the Trp64Arg polymorphism of the beta3-adrenergic receptor gene have lower daily energy expenditure, altered lipolysis, and increased abdominal obesity. On the other hand, the lower RMR in never-obese women suggests that the obese state may mask a moderate effect of the Trp64Arg variant on energy expenditure. Although these results need to be confirmed in other populations, the obese state may have been a confounding factor in previous studies of the beta3-adrenoceptor Trp64Arg variant and energy expenditure.

Veilleux A, Blouin K, Rhéaume C, Daris M, Marette A, Tchernof A. · Molecular Endocrinology and Oncology Research Center, Laval University, Québec, (Québec), Canada G1V 4G2. · Metabolism. · Pubmed #19375584 No free full text.

Abstract: 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.

Bouchard L, Faucher G, Tchernof A, Deshaies Y, Marceau S, Lescelleur O, Biron S, Bouchard C, Pérusse L, Vohl MC. · Montreal University Community Genomics Medicine Center, Chicoutimi Hospital, Université de Montreal, Chicoutimi, Québec, Canada. · Obesity (Silver Spring). · Pubmed #19325544 No free full text.

Abstract: The prevalence of morbid obesity and its associated metabolic complications has risen rapidly in the past decade. Recently, we have established the transcriptome of the visceral adipose tissue of nondiabetic severely obese men with and without metabolic syndrome (MetS) that provided new candidate genes for cardiovascular disease (CVD) risk factors. The oxysterol-binding protein-like protein 11 (OSBPL11) that belongs to the OSBP family of intracellular receptors was one of the genes found to be significantly overexpressed in the MetS group. To determine whether OSBPL11 gene polymorphisms are associated with CVD risk factors and diabetes, OSBPL11 gene promoter and coding regions were sequenced in 25 individuals and six tagging single-nucleotide polymorphisms (SNPs) capturing 85% of gene sequence-derived common genetic variability (minor allele frequency (MAF) > 5%) were genotyped in two samples for a total of 962 obese individuals. Using a multistage experimental design, chi(2)-tests and logistic regressions were applied to compare genotype frequencies and to compute odds ratios (ORs) for low and high CVD risk groups. Significant associations between rs1055419 and diastolic blood pressure (OR = 0.53; P = 0.01) were found whereas IVS12+95 T>C, a newly discovered SNP, was associated with low-density lipoprotein-cholesterol levels (OR = 1.63; P < 0.001), hyperglycemia/diabetes (OR = 1.48; P < 0.004) as well as with MetS per se (OR = 1.56; P < 0.01). These results suggest that the OSBPL11 gene is involved in cholesterol and glucose metabolism in obese individuals.Obesity (2009) 17 7, 1466-1472. doi:10.1038/oby.2009.71.

Drolet R, Bélanger C, Fortier M, Huot C, Mailloux J, Légaré D, Tchernof A. · Laval University Medical Research Center, Quebec City, Quebec, Canada. · Obesity (Silver Spring). · Pubmed #19219061 No free full text.

Abstract: Our objective was to examine omental and subcutaneous adipocyte adiponectin release in women. We tested the hypothesis that adiponectin release would be reduced to a greater extent in omental than in subcutaneous adipocytes of women with visceral obesity. Omental and subcutaneous adipose tissue samples were obtained from 52 women undergoing abdominal hysterectomies (age: 47.1 +/- 4.8 years; BMI: 26.7 +/- 4.7 kg/m(2)). Adipocytes were isolated and their adiponectin release in the medium was measured over 2 h. Measures of body fat accumulation and distribution were obtained using dual-energy X-ray absorptiometry and computed tomography, respectively. Adiponectin release by omental and subcutaneous adipocytes was similar in lean individuals; however, in subsamples of obese or visceral obese women, adiponectin release by omental adipocytes was significantly reduced while that of subcutaneous adipocytes was not affected. Omental adipocyte adiponectin release was significantly and negatively correlated with total body fat mass (r = -0.47, P < 0.01), visceral adipose tissue area (r = -0.50, P < 0.01), omental adipocyte diameter (r = -0.43, P < 0.01), triglyceride levels (r = -0.32, P < or = 0.05), cholesterol/high-density lipoprotein (HDL)-cholesterol (r = -0.31, P < or = 0.05), fasting glucose (r = -0.39, P < or = 0.01), fasting insulin (r = -0.36, P < or = 0.05), homeostasis model assessment index (r = -0.39, P < or = 0.01), and positively associated with HDL-cholesterol concentrations (r = 0.33, P < or = 0.05). Adiponectin release from subcutaneous cells was not associated with any measure of adiposity, lipid profile, or glucose homeostasis. In conclusion, compared to subcutaneous adipocyte adiponectin release, omental adipocyte adiponectin release is reduced to a greater extent in visceral obese women and better predicts obesity-associated metabolic abnormalities.

Bouchard L, Faucher G, Tchernof A, Deshaies Y, Lebel S, Hould FS, Marceau P, Vohl MC. · Lipid Research Center, Laval University, 2705 Laurier Blvd (TR93), Quebec City, QC, Canada G1V 4G2. · Acta Diabetol. · Pubmed #18682883 No free full text.

Abstract: The incretin system has been shown to stimulate insulin secretion in a glucose dependent manner and currently fosters considerable hope for the treatment of diabetes. Recently, we have shown that the dipeptidylpeptidase-4 (DPP4) gene, which is responsible for incretin inactivation, was overexpressed in omental adipose tissue of obese men with the metabolic syndrome, compared to men not characterized by this condition. Since the cardiovascular disease (CVD) risk profile shows substantial inter-individual variability in obesity, this study aimed at verifying whether DPP4 polymorphisms contribute to explain such a difference. In the first step of this multi-stage study, seven tagging SNPs were genotyped in a sample of 576 obese (BMI>40 kg/m(2)) individuals and tested for their association with blood pressure and lipids, as well as diabetes-related phenotypes. Then, in an additional sample of 572 obese individuals (stage 2), SNPs showing trends (P<0.10) for an association in the first sample were genotyped and reanalyzed. Logistic regressions were used to compute odds ratio for obesity-related metabolic complications. In sample 1, homozygotes for rs17848915 and rs7608798 minor alleles were at lower risk of hyperglycemia/diabetes (P=0.002) and elevated plasma triglyceride levels (P=0.030) respectively, whereas rs1558957 heterozygotes were at higher risk to have high plasma triglyceride (P=0.040), HDL- (P=0.021), LDL- (P=0.001) and total-cholesterol (P=0.003) levels. However, none of these associations was consistently replicated in stage 2. This first comprehensive genetic analysis does not support the notion that DPP4 polymorphisms could modulate the CVD risk profile among obese patients.

Zhang Y, Bossé Y, Marceau P, Biron S, Lebel S, Richard D, Vohl MC, Tchernof A. · Molecular Endocrinology and Oncology Research Center, Laval University Medical Research Center, Québec, Canada. · Gene Expr. · Pubmed #17933217 No free full text.

Abstract: We investigated interindividual variability in gene expression in abdominal subcutaneous (SC) and omental (OM) adipose tissue of 10 massively obese men. Affymetrix human U133A microarrays were used to measure gene expression levels. A total of 6811 probesets generated significant signal in both depots in all samples. Interindividual variability in gene expression was rather low, with more than 90% of transcripts showing a coefficient of variation (CV) lower than 23.6% and 21.7% in OM and SC adipose tissues, respectively. The distributions of CV were similar between the two fat depots. A set of highly variable genes was identified for both tissues on the basis of a high CV and elevated gene expression level. Among the set of highly regulated genes, 18 transcripts were involved in lipid metabolism and 28 transcripts were involved in cell death for SC and OM samples, respectively. In conclusion, gene expression interindividual variability was rather low and globally similar between fat compartments, and the adipose tissue transcriptome appeared as relatively stable, although specific pathways were found to be highly variable in SC and OM depots.

Bouchard L, Vohl MC, Deshaies Y, Rhéaume C, Daris M, Tchernof A. · Lipid Research Center, Laval University, Québec, Canada. · Eur J Endocrinol. · Pubmed #17893259 links to  free full text

Abstract: 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.

Drolet R, Richard C, Sniderman AD, Mailloux J, Fortier M, Huot C, Rhéaume C, Tchernof A. · Molecular Endocrinology and Oncology Research Center, Laval University Medical Research Center and Laval University, Québec, PQ, Canada. · Int J Obes (Lond). · Pubmed #17726433 No free full text.

Abstract: OBJECTIVE: To examine the expression of selected transcription factors involved in adipogenesis and genes related to lipid metabolism in abdominal subcutaneous and omental fat tissue. RESEARCH DESIGN AND METHODS: We obtained subcutaneous and omental adipose tissue samples from 40 women undergoing abdominal hysterectomies (age: 47+/-5 years; BMI 27.9+/-5.3 kg/m(2)). We measured isolated adipocyte size and metabolism, and detailed measures of body fat accumulation and body fat distribution were obtained (dual-energy X-ray absorptiometry and computed tomography, respectively). RESULTS: Adipocyte size of both subcutaneous and omental fat were increased with higher body fat mass values, with similar regression slopes in each compartment. In contrast, with higher body fat mass values, fat accumulation was progressively higher in the subcutaneous than in the visceral fat compartment, suggesting hyperplasia in the subcutaneous fat compartment. Messenger RNA levels of CEBPalpha, PPARgamma2, SREBP1c and genes related to lipid metabolism (LPL, FABP4, DGAT1, DGAT2, PLIN and HSL) were significantly higher in subcutaneous than in omental fat tissue (P< or =0.001 for all). Only subcutaneous expression of these genes tracked with obesity levels as reflected by significant positive associations between subcutaneous fat CEBPalpha, SREBP1c and DGAT2 expression and total body fat mass (r=0.37, r=0.41, r=0.57, respectively, P< or =0,05), fat percentage (r=0.40, r=0.39, r=058, respectively, P< or =0,05) and subcutaneous adipose tissue area (r=0.36, r=0.38, r=0.58, respectively, P< or =0,05). Omental adipose tissue expression levels of these genes were not significantly related to adiposity measures. CONCLUSIONS: These results show that in obese women, hyperplasia is predominant in the subcutaneous fat depot, whereas fat cell hypertrophy is observed both in the omental and subcutaneous compartments.

Bouchard L, Tchernof A, Deshaies Y, Lebel S, Hould FS, Marceau P, Vohl MC. · Lipid Research Center, Nutraceuticals and Functional Foods Institute, and Department of Food Science and Nutrition, Laval University, Québec, Canada. · Clin Genet. · Pubmed #17718860 No free full text.

Abstract: We have recently characterized the transcriptome of the omental adipose tissue of non-diabetic, obese men with and without the metabolic syndrome (MS). The cysteine-rich protein 61 (CYR61) is one of the most differentially expressed genes between the groups and has been selected for a detailed molecular investigation. Direct sequencing of complete CYR61 gene revealed five polymorphisms with minor allele frequency >5% in the promoter region (rs 3753794, rs 3753793 and rs 2297140), intron 1 (rs 2297141) and intron 2 (IVS 2+50). Chi-square test and logistic regression were applied to test for association between CYR61 polymorphisms and the individual MS components in a cohort of 697 obese individuals. In men and women, rs 3753794 and rs 3753793 (r2 = 0.77) were associated plasma HDL-cholesterol levels (p = 0.016 and p = 0.008). Carriers of the A allele for rs 3753794 were more likely to have high plasma HDL-cholesterol levels (1.50-fold; p = 0.016), as compared with G/G homozygotes and the A/A homozygotes for rs 3753793 were more likely to exhibit low plasma HDL-cholesterol levels (1.56-fold; p = 0.008), as compared with C/C homozygotes. Furthermore, an association between IVS 2+50 polymorphism and HDL-cholesterol was found in women and in men analyzed separately (p = 0.002 and p = 0.038, respectively). These results suggest that CYR61 is a promising candidate gene for lipoprotein/lipid perturbations.

Bouchard L, Tchernof A, Deshaies Y, Marceau S, Lescelleur O, Biron S, Vohl MC. · Lipid Research Center, Laval University, Quebec, Canada. · Obes Surg. · Pubmed #17546847 No free full text.

Abstract: BACKGROUND: Few genes have been associated with the metabolic syndrome (MS), although its genetic component is well accepted. The aim of this study was to compare the adipose tissue gene expression profiles of obese men with and without the MS and to apply an integrative genomic approach to propose new candidate genes. METHODS: Affymetrix HG-U133 plus 2 arrays have been used for expression profiling of omental adipose tissue of non-diabetic obese men with (n=7) and without (n=7) the MS, as defined by the NCEP-ATPIII, that undergo a bariatric operation. RESULTS: Omentum expresses a total of 23 055 transcripts. Overall, 489 genes were differentially expressed between the two groups. A total of 80 differentially expressed genes were located within a previously identified region of linkage. In this subset of genes, zinc finger protein 36 (ZFP36) gene has been identified as the most promising genetic target for the MS-based mean fold expression differences and on biological plausibility. 2 out of 5 identified ZFP36 gene polymorphisms have been genotyped in a cohort of 698 obese subjects. The minor allele of these polymorphisms was associated with a lower body weight in women (rs251864; P< or =0.01) and glucose level in men (c.1564_1565delTT; P<0.05). The haplogenotype was associated with plasma LDL-cholesterol levels in men and women (P< or =0.02), and weight in women (P< or =0.05). The haplogenotype was also associated with omental adipose tissue ZFP36 mRNA levels (n=83 women; P=0.02), and explained 10.1% of its variance. CONCLUSION: These results suggest that converging genomics is helpful to prioritize MS-related candidate genes and that ZFP36 is a promising candidate gene for obesity-associated metabolic complications.

Boivin A, Brochu G, Marceau S, Marceau P, Hould FS, Tchernof A. · Molecular Endocrinology and Oncology Research Center, Laval University Medical Research Center and Laval University, Québec, Canada G1V 4G2. · Metabolism. · Pubmed #17379013 No free full text.

Abstract: We examined omental and subcutaneous adipose tissue adipocyte size, and lipolysis and lipoprotein lipase (LPL) activity in a sample of 33 men aged 22.6 to 61.2 years and with a body mass index ranging from 24.6 to 79.1 kg/m2. We tested the hypothesis that lipolysis rates would be higher in the omental fat depot than in subcutaneous adipose tissue and that this difference would persist across the spectrum of abdominal adiposity values. Omental and subcutaneous adipose tissue samples were obtained during surgery. Adipocytes were isolated by collagenase digestion. Adipocyte size and LPL activity as well as basal, isoproterenol-, forskolin-, and dibutyryl cyclic adenosine monophosphate-stimulated lipolysis were measured. Although adipocytes from both fat compartments were larger in obese subjects, no difference was observed in the size of omental vs subcutaneous fat cells. Lipoprotein lipase activity, expressed as a function of cell number, was significantly higher in omental than in subcutaneous fat tissue (P<.005). Basal lipolysis and lipolytic responses to isoproterenol, forskolin, or dibutyryl cyclic adenosine monophosphate, expressed either as a function of cell number or as a fold response over basal levels, were not significantly different in omental vs subcutaneous fat cells. When stratifying the sample in tertiles of waist circumference, adipocyte diameter was similar in the omental and subcutaneous depots for all adiposity values. Omental adipocyte size reached a plateau in the 2 upper tertiles of waist circumference, that is, from a waist circumference of 125 cm and above. Lipoprotein lipase activity was significantly higher in omental cells in the middle tertile of waist circumference (P=.05), and no regional difference was noted in lipolysis values across waist circumference tertiles. In conclusion, in normal-weight to morbidly obese men, although adipocyte size and lipolysis tended to increase with higher waist circumference, no difference was observed between the omental and subcutaneous fat depot.