Denis Prud'homme

Treatment of obesity : need to focus on high risk abdominally obese patients

Editorial by Little and Byrne It is generally accepted that obesity is a health hazard because of its association with numerous metabolic complications such as dyslipidaemia, type 2 diabetes, and cardiovascular diseases.1 On that basis, health agencies 2 3 have proposed that obesity should be defined on the basis of weight in kg expressed over height in m2, the so called body mass index,4 initially described by Quetelet in 1869 (table). Epidemiological studies have reported a progressive increase in the incidence of chronic diseases such as hypertension, diabetes, and coronary heart disease with increasing body mass index.1-3 However, despite this well documented evidence, physicians are, in their daily practice, perplexed by the remarkable heterogeneity found in their obese patients. For instance, some patients show a relatively “normal” profile of metabolic risk factors despite the presence of substantial excess body fat, whereas others who are only moderately overweight can nevertheless be characterised by a whole cluster of metabolic complications, increasing the risk of type 2 diabetes, coronary atherosclerosis, and cardiovascular disease. View this table: Classification of obesity based on body mass index (BMI)2 3 #### Summary points A simple measurement such as waist circumference can indicate accumulation of abdominal fat Viscerally obese men are characterised by an atherogenic plasma lipoprotein profile A triad of non-traditional markers for coronary heart disease found in viscerally obese middle aged men (hyperinsulinaemia, raised apolipoprotein B concentration, and small LDL particles) increases the risk of coronary heart disease 20-fold Four out of five middle aged men with a waist measurement ≥90 cm and triglyceride concentrations ≥2 mmol/l are characterised by this triad Even in the absence of hypercholesterolaemia, hyperglycaemia, or hypertension, obese patients could be at high risk of coronary heart disease if they have this “hypertriglyceridaemic waist” phenotype In this regard, epidemiological and metabolic studies …

Visceral Obesity in Men: Associations With Glucose Tolerance, Plasma Insulin, and Lipoprotein Levels

The relations of regional adipose tissue (AT) distribution measured by computed tomography (CT) to plasma insulin-glucose homeostasis and lipoprotein-lipid levels were studied in 58 obese and 29 lean control men. In the group of obese men, the visceral AT area measured by CT was positively correlated with fasting plasma triglyceride and insulin levels and with glucose and insulin areas under the curves measured during a 75-g oral glucose tolerance test. Visceral AT area was also negatively associated with plasma high-density lipoprotein (HDL) and HDL2 cholesterol levels. The relative accumulation of abdominal fat, estimated by the ratio of abdominal to femoral AT areas obtained by CT, was also a significant correlate of indices of carbohydrate metabolism and was the best univariate correlate of plasma lipoprotein levels. No significant associations were observed between the visceral AT area, the ratio of abdominal to femoral AT areas, and indices of carbohydrate and lipoprotein metabolism in the group of lean men. On the other hand, the subcutaneous abdominal AT area was a significant correlate of the glucose area under the curve in both groups of men, but this association was not independent from the percentage of total body fat. No relationship was observed between the femoral AT area and indices of carbohydrate metabolism in either lean or obese groups. In obese men, however, the femoral AT area was negatively correlated with plasma triglyceride concentration and positively correlated with plasma HDL and HDL2 cholesterol levels. Comparison between two subgroups of equally obese men showing either low or high levels of visceral AT and a group of lean men generally revealed that only obese men with high levels of visceral AT showed significant metabolic alterations compared with lean men. These results demonstrate that the amount of visceral AT and the ratio of abdominal to femoral AT measured by CT are important correlates of the alterations in carbohydrate and lipoprotein metabolism observed in obese men. In addition, our results suggest that obesity is required to observe significant associations between body fat distribution measured by CT and metabolic variables. Finally, we suggest that, in men, a high accumulation of femoral fat may be protective against the adverse effects of obesity, particularly abdominal obesity, on plasma lipoprotein levels.

The dense LDL phenotype : Association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men

OBJECTIVE To investigate the potential relationship between the cluster of metabolic abnormalities found in visceral obesity and the small dense LDL phenotype. RESEARCH DESIGN AND METHODS We have estimated LDL peak particle size by nondenaturing 2–16% gradient gel electrophoresis in a sample of 79 men. Glucose tolerance and fasting plasma insulin and lipoprotein levels were also measured. RESULTS The LDL particle score, calculated from migration, distances and relative band intensities and reflecting the proportion of small dense LDL particles, was positively correlated with plasma triglyceride (TG) (r = 0.60, P < 0.0001) and negatively correlated with HDL cholesterol (r = −0.56, P < 0.0001) levels. Although the LDL particle score was not associated with variations in plasma LDL cholesterol or LDL apolipoprotein (apo) B concentrations, it was significantly correlated with the LDL apo B–to–LDL cholesterol ratio (r = 0.60, P < 0.0001). Fasting plasma insulin and visceral adipose tissue (AT) areas measured by computed tomography were weakly but significantly correlated with the LDL particle score (r = 0.23 and 0.29, respectively, P < 0.05). LDL peak particle size showed similar but inverse correlations with anthropometric and metabolic variables. Subjects classified as having small dense LDL particles (by comparing subjects in the highest tertile versus those in the lowest tertile of the LDL particle score distribution) were characterized by increased plasma TG, reduced HDL cholesterol, higher fasting insulin levels, and elevated visceral AT accumulation. However, multiple regression analyses revealed that visceral AT accumulation was not an independent predictor of the dense LDL phenotype after inclusion of TG and HDL cholesterol levels and lipoprotein ratios in the model. CONCLUSIONS It thus appears that the high TG–low HDL cholesterol dyslipidemia frequently found in visceral obesity and in a hyperinsulinemic state is a strong correlate of the small dense LDL phenotype. Although associated with the dense LDL phenotype, visceral obesity and hyperinsulinemia were not independent predictors of an increased proportion of small dense LDL particles after controlling for TG and HDL cholesterol levels.

Gender Difference in Postprandial Lipemia Importance of Visceral Adipose Tissue Accumulation

Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and low HDL-cholesterol concentrations are common features of a plurimetabolic syndrome, which increases the risk of coronary artery disease. Although it has been proposed that the development of atherosclerosis through alterations in plasma lipid levels could be a postprandial phenomenon, most studies on gender differences in plasma lipoprotein-lipid concentrations have reported fasting levels. Therefore, the aim of our study was to examine the response of postprandial triglyceride-rich lipoproteins to a standardized meal in 63 men and 25 women. In addition to the measurement of fasting and postprandial plasma lipid levels, numerous physical and metabolic variables were assessed, including body composition by underwater weighing and body fat distribution by computed tomography. Although no gender difference was noted in total body fat mass, men were characterized by a preferential accumulation of abdominal adipose tissue as revealed by an increased waist circumference and a greater visceral adipose tissue accumulation (50% difference) compared with women (P<0.001). Men also showed a greater plasma triglyceride response (P<0.005) as well as increased postprandial insulin and free fatty acid levels compared with women (P<0.01). Visceral adipose tissue was significantly associated with the postprandial triglyceride response in both genders (men: r=0.49, P<0. 0001; women: r=0.43, P<0.05). Finally, when men and women were matched for visceral adipose tissue accumulation, the gender difference in postprandial plasma triglyceride response was eliminated. Thus results of the present study suggest that the well known gender difference in visceral adipose tissue accumulation is an important contributing factor involved in the exaggerated postprandial triglyceride-rich lipoprotein response noted in men compared with women.

Are gender differences in cardiovascular disease risk factors explained by the level of visceral adipose tissue

SummaryIt has been suggested that the lower prevalence of cardiovascular disease in women before menopause in comparison with men may be explained by differences in body fat distribution, plasma lipoprotein levels and indices of plasma glucose-insulin homeostasis. Thus, gender differences in visceral adipose tissue accumulation measured by computed tomography and metabolic variables were studied in 80 men and 69 pre-menopausal women, aged 23–50 years. Despite the fact that women had higher levels of total body fat (p<0.0001), they displayed lower areas of abdominal visceral adipose tissue (p<0.06) and a lower ratio of abdominal visceral to mid-thigh adipose tissue areas than men (p<0.0001). After adjustment for body fat mass, women generally displayed a more favourable risk profile than men which included higher plasma HDL2-cholesterol and lower plasma insulin, apolipoprotein B and triglyceride levels (p<0.01). Metabolic variables adjusted for body fat mass were then compared between genders after control for differences in abdominal visceral adipose tissue area. After such controls, variables related to plasma glucose-insulin homeostasis were no longer significantly different between men and women. Gender differences for plasma concentrations of triglyceride, apolipoprotein B and the ratio of HDL2-cholesterol/HDL3-cholesterol also disappeared, whereas plasma concentrations of HDL-cholesterol, HDL2-cholesterol as well as the ratio of HDL-cholesterol/total cholesterol remained significantly higher in women than in men (p<0.01). These results suggest that abdominal visceral adipose tissue is an important correlate of gender differences in cardiovascular disease risk. However, additional factors are likely to be involved in gender differences in plasma HDL-cholesterol levels.

Hyperleptinemia is more closely associated with adipose cell hypertrophy than with adipose tissue hyperplasia.

OBJECTIVES: To investigate the relationships of fat cell weight (FCW) as well as of estimated total adipose cell number to fasting plasma leptin concentration.DESIGN: Cross-sectional correlational study.SUBJECTS: A sample of 63 men (mean age±s.d.: 36±4 y) and 42 premenopausal women (35±5 y).MEASUREMENTS: Adipose tissue (AT) biopsies were obtained in order to determine FCW as well as estimated adipose cell number. Fasting plasma leptin and insulin concentrations as well as various fatness and body fat distribution variables (underwater weighing and computed tomography) were also measured.RESULTS: In both genders, mean FCW as well as the estimated adipose cell number were significantly correlated with body fatness and AT distribution variables (0.41≤r≤0.84). Larger abdominal (P<0.005) and femoral (P<0.0001) FCW were found in women than in men. This gender difference in adipose cell size was associated with increased leptin concentrations in women compared with men. In both genders, increased abdominal FCW was associated with higher plasma leptin concentrations (men: r=0.38, P<0.005 and women: r=0.55, P<0.0001). However, the association between femoral FCW and leptinemia was only significant in women (r=0.45, P<0.005). Contrary to women, plasma leptin concentrations were associated with estimated adipose cell number in men (r=0.59, P<0.0001). Multiple regression analyses revealed that gender (43.3%), mean FCW (16.2%) and the estimated adipose cell number (10.1%) were significant predictors of fasting leptinemia.CONCLUSIONS: Results of the present study indicate that in men and women, adipose cell hypertrophy is associated with increased plasma leptin concentrations. This finding provides further support to the observation that adipose tissue leptin secretion may be regulated, at least to a certain extent, by adipocyte size. Thus, the present study suggests that the higher plasma leptin concentrations found in women than in men could be partly explained by the well documented gender difference in adipose cell size and number.

Sensitivity of maximal aerobic power to training is genotype-dependent.

Ten pairs of monozygotic twins of both sexes were submitted to a 20-wk endurance-training program, four and five times per week, 40 min per session, at an average of 80% of the maximal heart rate reserve. Testing and training were performed on cycle ergometers. Maximal aerobic power (MAP in ml O2 X min-1 X kg-1) and ventilatory aerobic (VAT) and anaerobic (VANT) thresholds (ml O2 X min-1 X kg-1) were measured before and after the training program, as well as during the 7th and 14th week to adjust training to changes in maximal heart rate. Considering the 20 individuals as a group, training significantly (P less than or equal to 0.01) increased MAP (from 44 +/- 6 to 50 +/- 6), VAT (25 +/- 3 to 30 +/- 4), and VANT (36 +/- 5 to 42 +/- 6). Thus, MAP improved by 12% of the pre-test value, while mean changes in VAT and VANT reached 20% and 17%, respectively. There were, however, considerable interindividual differences in training gains as exemplified by a range of about 0% to 41% for MAP. Differences in the MAP response to training were not distributed randomly among the twin pairs. Thus, intraclass correlations computed with the amount of improvement in MAP (ml O2 X min-1 X kg-1) reached 0.74 (P less than 0.01) indicating that members of the same twin-pair yielded approximately the same response to training. The same coefficient reached 0.43 and 0.24 for VAT and VANT, respectively (P greater than 0.05). These results suggest that there are considerable individual differences in the adaptive capacity to short-term endurance training. Moreover, sensitivity of maximal aerobic power to such training is largely genotype-dependent.

Plasma leptin concentrations : gender differences and associations with metabolic risk factors for cardiovascular disease

Summary The cloning of the obese gene and the characterization of its protein product, leptin, has permitted the study of a new hormone potentially involved in the regulation of adipose tissue mass. The present study examined the gender differences in fasting plasma leptin concentration and its relationship to body fatness, adipose tissue distribution and the metabolic profile in samples of 91 men (mean age ± SD: 37.3 ± 4.8 years) and 48 women (38.5 ± 6.8 years). Plasma leptin concentrations were strongly associated with body fat mass measured by underwater weighing [men: r = 0.80, p < 0.0001; women: r = 0.85, p < 0.0001]. In both genders, plasma leptin levels were also strongly correlated with waist girth as well as cross-sectional areas of abdominal subcutaneous and visceral adipose tissue measured by computed tomography. Women had, on average, plasma leptin concentrations that were three times higher than men. Furthermore, this gender difference remained significant when comparing men and women matched for similar levels of body fat mass. The associations between plasma leptin and lipoprotein concentrations were dependent of adiposity. In both men and women, elevated fasting plasma leptin levels were associated with higher plasma insulin concentrations, but only in women was the association maintained after correction for fat mass. Thus, results of the present study show that women have higher plasma leptin levels compared to men, independent of the concomitant variation in total body fat mass. Furthermore, our results also suggest that, in women, the association between plasma leptin and insulin concentrations is independent of adiposity, a finding which provides further support to the observation that adipose tissue leptin secretion may be upregulated by insulin. [Diabetologia (1997) 40: 1178–1184]

Seven-year changes in body fat and visceral adipose tissue in women. Association with indexes of plasma glucose-insulin homeostasis.

OBJECTIVE To study the associations between changes in body fatness, visceral adipose tissue (AT), and indexes of plasma glucose-insulin homeostasis over a 7-year follow-up period. RESEARCH DESIGN AND METHODS A sample of 30 nondiabetic women aged 35.2 ± 5.6 (SD) years at baseline was studied. RESULTS Changes in visceral AT and in subcutaneous AT (measured by computed tomography) as well as changes in body fat mass (obtained by hydrostatic weighting) were significantly related to changes in fasting plasma insulin levels and in plasma insulin area measured after a 75-g oral glucose load (0.47 ≤ r ≤ 0.62; P < 0.01). Changes in visceral AT but not in body fat mass or in subcutaneous AT area were significantly associated with changes in plasma glucose area (r = 0.37; P < 0.05). When two subgroups of women with similar mean increases in body fat mass but with either small or large increases in visceral AT were compared, the subgroup with the largest gain in visceral AT showed the greatest deterioration in indexes of plasma glucose-insulin homeostasis. On the other hand, when two subgroups with similar mean increases in visceral AT but with different changes in body fat mass were compared, both subgroups showed similar changes in plasma glucose and insulin concentrations. CONCLUSIONS Results of this 7-year follow-up study in women suggest that changes in indexes of plasma glucose-insulin homeostasis are significantly associated with changes in visceral AT, even after control for changes in body fat mass.

Identifying metabolically healthy but obese individuals in sedentary postmenopausal women.

The purpose of this study was to compare different methods to identify metabolically healthy but obese (MHO) individuals in a cohort of obese postmenopausal women. We examined the anthropometric and metabolic characteristics of 113 obese (age: 57.3 ± 4.8 years; BMI: 34.2 ± 2.7 kg/m2), sedentary postmenopausal women. The following methods were used to identify MHO subjects: the hyperinsulinemic–euglycemic clamp (MHO: upper quartile of glucose disposal rates); the Matsuda index (MHO: upper quartile of the Matsuda index); the homeostasis model assessment (HOMA) index (MHO: lower quartile of the HOMA index); having 0–1 cardiometabolic abnormalities (systolic/diastolic blood pressure ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, glucose ≥5.6 mmol/l, HOMA >5.13, high‐sensitive C‐reactive protein (hsCRP) >0.1 mg/l, high‐density lipoprotein‐cholesterol (HDL‐C) <1.3 mmol/l); and meeting four out of five metabolic factors (HOMA ≤2.7, TG ≤1.7 mmol/l, HDL‐C ≥1.3 mmol/l, low‐density lipoprotein‐cholesterol ≤2.6 mmol/l, hsCRP ≤3.0 mg/l). Thereafter, we measured insulin sensitivity, body composition (dual‐energy X‐ray absorptiometry), body fat distribution (computed tomography scan), energy expenditure, plasma lipids, inflammation markers, resting blood pressure, and cardiorespiratory fitness. We found significant differences in body composition (i.e., peripheral fat mass, central lean body mass (LBM)) and metabolic risk factors (i.e., HDL‐C, hsCRP) between MHO and at risk individuals using the different methods to identify both groups. In addition, significant differences between MHO subjects using the different methods to identify MHO individuals were observed such as age, TG/HDL, hsCRP, and fasting insulin. However, independently of the methods used, we noted some recurrent characteristics that identify MHO subjects such as TG, apolipoprotein B, and ferritin. In conclusion, the present study shows variations in body composition and metabolic profile based on the methods studied to define the MHO phenotype. Therefore, an expert consensus may be needed to standardize the identification of MHO individuals.