Phenotypic characteristics associated with insulin resistance in metabolically obese but normal-weight young women.

Metabolically obese, normal-weight (MONW) individuals are a hypothesized subgroup of the general population. These normal-weight individuals potentially display a cluster of obesity-related features, although this has not been systematically tested in young women. We hypothesized that MONW young women would display higher levels of total and visceral fat and lower levels of physical activity than normal women. In a cohort of 71 healthy nonobese women (21-35 years old), we identified MONW women based on cut points for insulin sensitivity (normal = glucose disposal >8 mg x min(-1) x kg(-1) of fat-free mass [FFM], n = 58; impaired = glucose disposal <8 ml x min(-1) x kg(-1) of FFM, n = 13). Thereafter, we measured body composition (dual energy X-ray absorptiometry) and body fat distribution (computed tomography), cardiorespiratory fitness (VO2max on a treadmill), physical activity energy expenditure (doubly labeled water and indirect calorimetry), glucose tolerance (oral glucose tolerance test), serum lipid profile, and dietary intake. We found a higher body fat percentage (32 +/- 6 vs. 27 +/- 6%, P = 0.01) and higher subcutaneous (213 +/- 61 vs. 160 +/- 78 cm2, P = 0.03) and visceral (44 +/- 16 vs. 35 +/- 14 cm2, P < 0.05) abdominal adiposity in the MONW group versus the normal group. The MONW group showed a lower physical activity energy expenditure (2.66 +/- 0.92 vs. 4.39 +/- 1.50 MJ/day, P = 0.01), but no difference in cardiorespiratory fitness was noted between groups. In conclusion, despite a normal body weight, a subset of young, apparently healthy women displayed a cluster of risky phenotypic characteristics that, if left untreated, may eventually predispose them to type 2 diabetes and cardiovascular disease.

Daily energy expenditure is related to plasma leptin concentrations in older African-American women but not men.

Recent research suggests that leptin may control body weight by regulating energy expenditure and energy intake in mice. To explore the possible role of leptin in the regulation of energy expenditure in humans, we used doubly-labeled water methodology to determine whether fasting plasma leptin concentrations were related to total daily energy expenditure (TEE) and its components, resting energy expenditure (REE) and physical activity energy expenditure (PAEE), in free-living older African-American men (n = 21) and women (n = 25). Plasma leptin concentrations were higher in women than men, even after the adjustment for differences in fat mass (28 +/- 3 ng/ml for women vs. 17 +/- 3 ng/ml for men; P < 0.01). The logarithm of plasma leptin concentrations correlated with fat mass in both women (r = 0.80) and men (r = 0.78) (P < 0.0001). After statistical adjustment for sex differences in fat-free mass and fat mass, women had lower TEE (22%) and REE (15%) (P < 0.01) and a trend (P = 0.08) toward lower PAEE, compared with men. After controlling for the effects of fat-free mass on energy expenditure, plasma leptin concentrations were related to REE (r = 0.68, P < 0.001) and tended to be related to TEE (r = 0.37, P = 0.07) in African-American women but not men (r = 0.18 and -0.03, respectively). Plasma leptin concentrations were not related to PAEE in either men or women. These results suggest that leptin may contribute to the regulation of TEE in older African-American women through its effects on resting energy metabolism, but the role of leptin in the regulation of energy expenditure is less apparent in older African-American men.

Obesity-related phenotypes and the beta3-adrenoceptor gene variant in postmenopausal women.

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.

Identification of an interactive effect of beta3- and alpha2b-adrenoceptor gene polymorphisms on fat mass in Caucasian women.

Several adrenoceptor subtypes are expressed in adipocytes, which together exert their influence on adipocyte metabolism. Therefore, we specifically examined the interactive effect of Trp64Arg (beta3) and Glu12/Glu9 (alpha2b) adrenoceptor (AR) polymorphisms on energy metabolism and body composition in healthy women with a wide range of body habitus. We genotyped 909 unrelated women (age 55 +/- 12 [mean +/- SD] years, range 19-87; body weight 88 +/- 22 kg, range 40-167; and BMI 33 +/- 8 kg/m2, range 16-64) for Trp64Arg beta3AR and Glu12/Glu9 alpha2bAR variants. We examined the independent effect of the Glu12/Glu9 alpha2bAR variant on body composition and energy balance, in a large cohort of Caucasian women (n = 909). A second goal was to examine the interaction effect of Glu12/Glu9 alpha2bAR and Trp64Arg beta3AR on the same phenotypes. The obesity-related phenotypes studied were as follows: body weight, BMI, fat mass, visceral fat, fat-free mass, resting metabolic rate (RMR), VO2max, leisure time physical activity, and daily energy intake. Body composition and body fat distribution were measured by dual-energy X-ray absorptiometry and radiographic imagery, VO2max by a treadmill test to exhaustion, and RMR by indirect calorimetry. An analysis of covariance indicated that in the entire cohort, there was no significant difference between Glu12/Glu9 alpha2bAR carriers and control subjects for any of the obesity-related phenotypes that were examined. However, we observed a significant interaction effect of the Trp64Arg and Glu12/Glu9 variants on fat mass (P = 0.009) and percent fat (P = 0.016). Age, height, body weight, BMI, fat-free mass, visceral fat, energy expenditure, respiratory quotient, physical fitness, and energy intake were not different among groups. Collectively, these findings support an interaction effect of the two adrenoceptor variants on body fatness in Caucasian women, although the physiological mechanism by which they exert this effect remains to be determined.

Impaired capacity to lose visceral adipose tissue during weight reduction in obese postmenopausal women with the Trp64Arg beta3-adrenoceptor gene variant.

Controversy exists regarding the association between the Trp64Arg variant of the beta3-adrenoceptor gene and visceral obesity. The cross-sectional nature of most studies, the modest effect of the variant, and sex or ethnic differences between groups have contributed to discrepancies among investigations. To overcome these confounding factors, we examined the effect of the Trp64Arg variant on total and visceral adipose tissue loss, insulin sensitivity, and cardiovascular disease risk factors in response to weight reduction in obese older women. A total of 24 women (age 57 +/- 4 years), including 1 Trp64Arg homozygote, 10 Trp64Arg heterozygotes, and 13 normal homozygotes, were admitted to a weight reduction program of 13 +/- 3 months, with weight and nutritional intake stabilization established before testing. Total and regional adiposity were measured with dual-energy X-ray absorptiometry and computed tomography, insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp technique, and a blood lipid profile was obtained. No baseline differences were noted in adiposity measurements, glucose disposal, and lipid profiles among carriers and noncarriers of the variant allele. In response to weight loss, carriers and noncarriers of the Trp64Arg allele had similar reductions in body weight (-16.4 +/- 5.0 vs. -14.1 +/- 6.2 kg, NS) and body fat (-10.0 +/- 5.2 vs. -11.5 +/- 3.9 kg, NS). However, loss of visceral adipose tissue was 43% lower in carriers of the Trp64Arg allele compared with noncarriers (-46 +/- 27 vs. -81 +/- 51 cm2, P = 0.05). Furthermore, there was less improvement in the total cholesterol-to-HDL cholesterol ratio (-0.18 +/- 0.54 vs. -0.72 +/- 0.56, P = 0.04) in carriers compared with noncarriers of the allele. Although glucose disposal improved in both groups, there was no difference in the magnitude of improvement between carriers and noncarriers of the variant allele. In conclusion, older obese women carrying the Trp64Arg beta3-adrenoceptor gene variant have an impaired capacity to lose visceral adipose tissue in response to prolonged caloric restriction. Despite these genetic differences in loss of intraabdominal adipose tissue, improvement in glucose disposal was similar between groups.

Physiological predictors of increasing total and central adiposity in aging men and women.

BACKGROUND: Increasing levels of total and central body fat with advancing age contribute to the development of cardiovascular and metabolic disease. We examined gender-related differences and physiological predictors of the rate of increase in total and central body fat in men and women. METHODS: We studied 427 healthy men (age range, 17 to 90 years) and 293 women (age range, 18 to 88 years). We measured body fatness by hydrostatic weighing, central adiposity from the waist circumference, peak volume of oxygen utilization (VO2) from a treadmill test, leisure time physical activity (LTA) from a questionnaire, resting metabolic rate and respiratory quotient from indirect calorimetry, and energy intake from 3-day food diaries. RESULTS: Fat mass increased with age, and the rate was greater in women (r = .61; slope = 0.25 kg/y; P < .01) than in men (r = .43; slope = 0.16 kg/y; P < .01). Increasing fat mass in men and women was most strongly associated with declines in peak VO2 and LTA. Controlling for these variables reduced the increase in fat mass from 17% to 3% per decade in men and from 26% to 5% per decade in women. The increase in waist circumference with age was also greater in women (r = .53; slope = 0.28 cm/y) than in men (r = .39; slope = 0.18 cm/y; P < .01). Increasing waist circumference with age in men and women was most strongly associated with declines in LTA and peak VO2, respectively. Control for these variables reduced the age-related increase in waist circumference from 2% to 1% per decade in men and from 4% to 1% per decade in women. We observed no independent contribution of resting metabolic rate, respiratory quotient, menopause status, energy, or macronutrient intake to the age-related increase in fat mass and waist circumference. CONCLUSIONS: Our findings suggest that (1) the age-related increase in fat mass and waist circumference is greater in women than in men and (2) the physiological characteristics that reflect a decline in physical activity-related energy expenditure, rather than resting energy expenditure, are important predictors of the increases in total and central fatness. Lifestyle changes that increase the level of physical activity may be advantageous in blunting age-related increases in total and central body fatness.

Sex hormone-binding globulin levels in middle-aged premenopausal women. Associations with visceral obesity and metabolic profile.

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.

Effect of menopausal status on insulin-stimulated glucose disposal: comparison of middle-aged premenopausal and early postmenopausal women.

OBJECTIVE: Studies in animal models suggest that ovarian hormone deficiency is associated with the development of insulin resistance. In women, ovarian hormone levels are dramatically reduced after the menopause transition. However, the effect of the menopause transition on insulin sensitivity is unclear. Thus, we examined the effect of menopausal status on insulin sensitivity. RESEARCH DESIGN AND METHODS: Insulin-stimulated glucose disposal was measured in 43 middle-aged premenopausal women (47 +/- 3 years of age) during the luteal phase of the menstrual cycle and 40 early postmenopausal women (51 +/- 4 years; time since menopause, 21 +/- 13 months) using the hyperinsulinemic-euglycemic clamp technique. Body composition was measured by dual-energy X-ray absorptiometry and abdominal fat distribution by computed tomography RESULTS: No difference in fat-free mass (FFM) was found between groups. Total body (P < 0.01), subcutaneous abdominal (P < 0.05), and intra-abdominal (P < 0.01) adiposity were greater in postmenopausal women compared with premenopausal women. No differences in insulin-stimulated glucose disposal were found between premenopausal and postmenopausal women on an absolute basis (pre, 436 +/- 130 vs. post, 446 +/- 120 mg/min), when expressed relative to FFM (pre, 10.7 +/- 3.0 vs. post, 11.5 +/- 3.6 mg x kg(-1) FFM x min(-1)) or when statistically adjusted for FFM (pre, 436 +/- 125 vs. post, 445 +/- 126 mg/min). CONCLUSIONS: These results suggest that menopausal status does not affect insulin sensitivity, as measured by the hyperinsulinemic-euglycemic clamp technique.

Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women.

OBJECTIVE: We examined the hypothesis that an age-related increase in the compartments of visceral fat would account, in part, for the deleterious changes in insulin sensitivity and blood lipid profile in nonobese women. RESEARCH DESIGN AND METHODS: We directly assessed visceral and subcutaneous abdominal adipose tissue areas (computed tomography), glucose disposal (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), blood-lipid profile, and aerobic fitness (VO2max) in 178 nonobese women categorized into four age groups: group 1, 28 +/- 4 years, n = 88; group 2, 46 +/- 2 years, n = 38; group 3, 53 +/- 2 years, n = 31; and group 4. 67 +/- 6 years, n = 21. RESULTS: Visceral abdominal adipose tissue area increased with age (2.36 cm2 per year, P < 0.0001). We noted an age-related increase in total cholesterol (P < 0.0003), triglycerides (P < 0.0009), LDL cholesterol (P < 0.027), and the ratio of total cholesterol to HDL cholesterol (P < 0.042). However, age-related changes in insulin sensitivity exhibited a different age-related pattern. That is, insulin sensitivity, expressed on an absolute basis or indexed per kilogram of fat-free mass, was lowest in group 4 but was not significantly different among groups 1, 2, and 3. After statistical control for visceral fat, lower insulin sensitivity persisted in group 4, although differences were diminished relative to other groups. However, the effect of visceral fat on age-related changes in the blood-lipid profile was stronger. That is, differences in visceral and deep subcutaneous adipose tissue area abolished age-related differences in total cholesterol, triglycerides, and LDL cholesterol. No independent effects of VO2max or leisure-time physical activity on age-related changes in insulin sensitivity or on the blood-lipid profile were noted. CONCLUSIONS: We conclude that 1) visceral fat shows an increase with advancing age, whereas a decrease in insulin sensitivity was noted only in older women; 2) age-related differences in visceral fat explain only a modest part of the decline in insulin sensitivity in nonobese women; and 3) unfavorable changes in plasma lipids were strongly associated with the age-related increase in visceral abdominal adipose tissue.

Influence of physical activity on insulin-like growth factor-I in healthy younger and older men.

To examine the hypothesis that a lower level of physical activity influences the age-related decline in insulin-like growth factor-I (IGF-I), we measured serum concentrations in healthy nonobese younger and older men, characterized for maximal aerobic capacity (VO2 max) and energy expended in leisure time physical activity. To examine the independent influence of physical activity on IGF-I relative to other lifestyle variables, we also determined fat-free weight, percent body fat, body fat distribution (waist to hip and waist to thigh ratios), and habitual caloric intake in our population. IGF-I was 33% lower (P less than 0.01) in older men than in younger men, inversely related to percent body fat (r = -0.55) and indices of upper body fat distribution (waist to hip ratio, r = -0.45; waist to thigh ratio, r = -0.47), and positively related to VO2 max (r = 0.64) and leisure time physical activity (r = 0.45; P less than 0.01). IGF-I was not related to fat-free weight or daily caloric intake. After controlling for the effects of age by multiple regression analysis, VO2 max (r = 0.29) and leisure time physical activity (r = 0.24) were the sole factors independently related to IGF-I (P less than 0.05). Our results suggest that multiple factors contribute to the age-related decline in IGF-I. Lower levels of IGF-I in aging men are related at least in part to diminished physical activity.

Hormonal and physiological correlates of energy expenditure and substrate oxidation in middle-aged, premenopausal women.

An understanding of the hormonal and physiological correlates of energy expenditure and substrate oxidation in middle-aged women will increase our knowledge of factors that promote changes in energy balance and adiposity. We measured resting and postprandial energy expenditure and substrate oxidation in 59 middle-aged, premenopausal women (mean+/-sD age, 47+/-2 yr) to examine the hormonal and physiological correlates of energy and substrate metabolism. Energy expenditure and substrate oxidation were measured at rest using indirect calorimetry and urinary nitrogen excretion and for 180 min after the ingestion of a liquid meal (10 kcal/kg fat-free mass; 410+/-44 Cal). Fasting hormone levels were measured by RIA, glucose tolerance was determined by a 75-g oral glucose tolerance test, body composition was measured by dual energy x-ray absorptiometry, and peak aerobic capacity was determined by a treadmill test. Using stepwise regression analysis, we found that resting energy expenditure was predicted by fat-free mass and serum leptin concentration (r2 = 66%; P < 0.01), fat oxidation was predicted by resting energy expenditure (r2 = 17%; P < 0.01), and carbohydrate oxidation was predicted by serum leptin and appendicular skeletal muscle mass (r2 = 21%;P < 0.01). Novariables were related to postprandial energy expenditure or substrate oxidation. We conclude that in middle-aged, premenopausal women, variation in resting energy expenditure and substrate oxidation is primarily explained by fat-free mass and serum leptin levels. Thus, changes in metabolically active tissue mass or leptin concentration may partially contribute to changes in resting energy expenditure or substrate oxidation in middle-aged women.

Sodium-potassium pump activity contributes to the age-related decline in resting metabolic rate.

We examined the hypothesis that a decline in Na-K pump activity contributes to the lower resting metabolic rate (RMR) in older males, independent of the loss of fat-free mass. Plasma and erythrocyte Na and K concentrations were measured using flame photometry. Changes in these concentrations after incubation with and without ouabain were used to calculate erythrocyte Na-K pump rate and rate constant in 27 younger (28 +/- 7 yr) and 25 older (67 +/- 6 yr) men. Older men showed an 18% lower erythrocyte Na-K pump rate constant (0.32 +/- 0.09 vs. 0.39 +/- 0.10 h-1; P < 0.01), a 12% lower RMR (1.10 +/- 0.14 vs. 1.25 +/- 0.14 kcal/min; P < 0.01) and an 8% lower level of fat-free mass (61.7 +/- 5.8 vs. 67.4 +/- 8.1 kg; P < 0.01) relative to younger men. A lower RMR persisted in older men (1.14 +/- 0.12 kcal/min) compared to younger men (1.21 +/- 0.12 kcal/min; P < 0.05) after control for the effect of fat-free mass. No differences in RMR were found, however, between older (1.17 +/- 0.13 kcal/min) and younger men (1.20 +/- 0.13 kcal/min) after controlling for both fat-free mass and the erythrocyte Na-K pump rate constant. A positive relation was noted between RMR and the erythrocyte Na-K pump rate constant, after removing the effects of fat-free mass (partial r = 0.30; P < 0.05). Our results support the conclusions that: 1) the in vivo activity of the Na-K pump is related to RMR, and 2) the age-related reduction in Na-K pump activity is a partial contributor to the decline in RMR in older men.

Are aerobically fit older individuals more physically active in their free-living time? A doubly labeled water approach.

There is considerable controversy regarding factors regulating free-living physical activity energy expenditure (PAEE) in older individuals. This component is highly variable, is difficult to accurately assess, and reflects both volitional and nonvolitional activities. We examined the association between maximal aerobic fitness (peak VO2) and free-living PAEE in older individuals. One hundred and eighty healthy older patients (96 females and 84 males) between 45-90 yr of age were studied. Total energy expenditure was measured from doubly labeled water. PAEE was calculated as the difference between total energy expenditure, resting metabolic rate, and estimated thermic effect of a meal. Peak VO2 was assessed from an exercise test to volitional fatigue. Fat mass and fat-free mass were assessed from dual energy x-ray absorptiometry. After correction for age, fat mass, and fat-free mass, significant correlations were observed between peak VO2 and PAEE for older males (r = 0.42; P < 0.0001) and females (r = 0.24; P < 0.05), although significant variation among volunteers was noted. When subjects were subdivided by tertiles based on their peak VO2 (liters per min), males with the highest peak VO2 showed greater free-living PAEE than individuals with low peak VO2 (P < 0.01). Similar results were observed in females (P < 0.05). Our results suggest a positive association between higher levels of peak VO2 and greater free-living PAEE in older individuals. This relationship is stronger in older men than in women. These additional energy-dissipating properties during their free-living time may serve to preserve leanness and buffer fat gain with age.

Racial differences in plasma leptin concentrations in obese postmenopausal women.

Leptin may play an important role in the regulation of body weight by influencing energy intake and expenditure. Differences in body composition, resting energy expenditure (REE), and physical activity between African-American and Caucasian women could be reflective of racial differences in plasma leptin concentrations. Thus, we examined racial differences in leptin levels and the relationships of leptin to body composition and resting metabolism in obese postmenopausal African-American (n = 28) and Caucasian (n = 29) women matched for level of body fat. African-American and Caucasian women were similar in age (64.1 +/- 1.3 vs. 63.2 +/- 1.0 yr), body weight (84.7 +/- 3.3 vs. 80.4 +/- 1.3 kg), adipose tissue mass (39.7 +/- 2.8 vs. 38.0 +/- 1.0 kg), waist to hip ratio (0.81 +/- 0.02 vs. 0.81 +/- 0.01), and maximal aerobic capacity (1.5 +/- 0.05 vs. 1.6 +/- 0.05 L/min). African-American women had greater lean tissue mass than Caucasian women (41.8 +/- 1.1 vs. 39.3 +/- 0.6 kg; P = 0.05). The leptin concentration was 20% lower in African-American than Caucasian women (36.0 +/- 4.8 vs. 45.8 +/- 3.5; P < 0.05), whereas REE values were similar. Leptin correlated strongly with percent body fat in African-American (r = 0.71; P < 0.0001) and Caucasian women (r = 0.61; P < 0.001) and with REE in African-American (r = 0.58; P < 0.001), but not Caucasian, women (r = 0.08). These findings suggest racial differences in plasma leptin levels and in leptin's role in the regulation of REE, which may play a role in the greater incidence of obesity in the African-American compared to the Caucasian population.

Visceral adipose tissue is an independent correlate of glucose disposal in older obese postmenopausal women.

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.

Effects of resistance training and endurance training on insulin sensitivity in nonobese, young women: a controlled randomized trial.

We examined the effects of a 6-month randomized program of endurance training (n = 14), resistance training (n = 17), or control conditions (n = 20) on insulin sensitivity in nonobese, younger women (18-35 yr). To examine the possible mechanism(s) related to alterations in insulin sensitivity, we measured body composition, regional adiposity, and skeletal muscle characteristics with computed tomography. We observed no changes in total body fat, sc abdominal adipose tissue, or visceral adipose tissue with endurance or resistance training. Insulin sensitivity, however, increased with endurance training (pre, 421 +/- 107; post, 490 +/- 133 mg/min; P < 0.05) and resistance training (pre, 382 +/- 87; post, 417 +/- 89 mg/min; P = 0.06). When the glucose disposal rate was expressed per kg fat-free mass (FFM), the improved insulin sensitivity persisted in endurance-trained (pre, 10.5 +/- 2.7; post, 12.1 +/- 3.3 mg/min x kg FFM; P < 0.05), but not in resistance-trained (pre, 9.7 +/- 1.9; post, 10.2 +/- 1.8 mg/min x kg FFM; P = NS) women. Muscle attenuation ratios increased (P < 0.05) in both endurance- and resistance-trained individuals, but this was not related to changes in insulin sensitivity. Moreover, the change in insulin sensitivity was not related to the increased maximum aerobic capacity in endurance-trained women (r = 0.24; P = NS). We suggest that both endurance and resistance training improve glucose disposal, although by different mechanisms, in young women. An increase in the amount of FFM from resistance training contributes to increased glucose disposal probably from a mass effect, without altering the intrinsic capacity of the muscle to respond to insulin. On the other hand, endurance training enhances glucose disposal independent of changes in FFM or maximum aerobic capacity, suggestive of an intrinsic change in the muscle to metabolize glucose. We conclude that enhanced glucose uptake after physical training in young women occurs with and without changes in FFM and body composition.

Energy requirements and physical activity of older free-living African-Americans: a doubly labeled water study.

We examined daily energy requirements and determinants of physical activity in older, free-living African-American women (n = 37; age, 64 +/- 8 yr) and men (n = 28; age, 64 +/- 7 yr). Total daily energy expenditure and its components [i.e. resting metabolic rate (RMR) and physical activity energy expenditure] were determined using doubly labeled water and indirect calorimetry. Body composition from dual energy x-ray absorptiometry, maximal oxygen consumption from a graded treadmill test, and leisure time physical activity from a structured interview were determined. Total daily energy expenditure adjusted for body composition was lower (P < 0.05) for women (2198 +/- 621 kcal/d) than for men (2633 +/- 669 kcal/d) due to a lower RMR (1431 +/- 240 vs. 1576 +/- 259 kcal/d; P = 0.07) and physical activity energy expenditure (548 +/- 559 vs. 794 +/- 603 kcal/d; P = 0.19), respectively. The physical activity level ratio (i.e. total daily energy expenditure/RMR) was not different from Food and Agriculture Organization/World Health Organization/United Nations University recommendations (i.e. 1.51) for women (1.51 +/- 0.25), but was higher for men (1.71 +/- 0.32). The strongest correlates with physical activity energy expenditure were age for women (r = -0.44; P < 0.01) and maximal oxygen consumption for men (r = 0.39; P < 0.05). These data show that daily energy requirements are significantly lower in African-American women compared to men, primarily due to lower levels of physical activity energy expenditure. Furthermore, lower levels of cardiovascular fitness in men and advancing age in women are associated with lower physical activity energy expenditure.

Respiratory fitness, free living physical activity, and cardiovascular disease risk in older individuals: a doubly labeled water study.

The objective of this study was to examine the importance of cardiorespiratory fitness vs. physical activity energy expenditure on selected cardiovascular disease risk factors in older individuals. One hundred and seventeen older individuals, 53 men (68 +/- 9 yr) and 63 women (67 +/- 7 yr), participated in the study. This cohort was divided into 4 groups: 1) high cardiorespiratory fitness and high physical activity, 2) high cardiorespiratory fitness and low physical activity, 3) low cardiorespiratory fitness and high physical activity, and 4) low cardiorespiratory fitness and low physical activity. Cardiorespiratory fitness (VO2max) was determined from a graded exercise test, physical activity energy expenditure was measured by doubly labeled water and indirect calorimetry, body composition was determined by dual energy x-ray absorptiometry, and dietary practices were determined by a 3-day recall. Cardiorespiratory fitness exerted greater effects on the cardiovascular disease risk profile than physical activity. That is, older individuals with higher levels of cardiorespiratory fitness, regardless of their physical activity levels, showed lower levels of fasting insulin (P < 0.01), triglycerides (P < 0.05), total cholesterol (P < 0.05), total to high density lipoprotein cholesterol ratio (P < 0.05), low density lipoprotein (P < 0.05), and lower waist circumference (P < 0.01). Moreover, individuals with a high cardiorespiratory fitness but low physical activity energy expenditure displayed a more favorable cardiovascular disease risk profile than individuals with low cardiorespiratory fitness and high physical activity energy expenditure. The results suggest that higher levels of cardiorespiratory fitness have greater cardioprotective effects than higher levels of free living physical activity in older individuals. Although these findings do not discount the health benefits of being physically active, it is possible that greater emphasis should be placed on aerobic exercise to increase cardiorespiratory fitness in the elderly.

Regulation of protein metabolism in middle-aged, premenopausal women: roles of adiposity and estradiol.

The age-related loss of fat-free mass (FFM) is accelerated in women during the middle-age years and continues at an increased rate throughout the postmenopausal period. Because protein is the primary structural component of fat-free tissue, changes in FFM are largely due to alterations in protein metabolism. Knowledge of the hormonal and physiological correlates of protein metabolism in middle-aged women, therefore, has important implications for understanding the mechanisms underlying changes in FFM. We measured leucine kinetics (expressed relative to FFM: micromol/kg FFM/h) in 46 middle-aged, premenopausal women (mean +/- SD, 47 +/- 3 yr) after an overnight fast (i.e. basal) and during euglycemic hyperinsulinemia (40 mU/m2/min) using a 5.5-h infusion of [1-13C]leucine. Additionally, we measured insulin-stimulated glucose disposal by euglycemic hyperinsulinemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution by computed tomography, and hormone levels by RIA as possible correlates of protein metabolism. Under basal conditions, stepwise regression analysis showed that leucine appearance (i.e. protein breakdown) was related to percent body fat and serum estradiol (r2 = 40%; P < 0.01), and leucine oxidation was related to serum estradiol and percent body fat (r2 = 26%; P < 0.05). Under euglycemic hyperinsulinemic conditions, no variables correlated with the percent change in leucine appearance. The percent change in leucine oxidation was related to intraabdominal adipose tissue area and glucose disposal rate (r2 = 48%; P < 0.01). Correlates and r2 values for nonoxidative leucine disposal (i.e. protein synthesis) under basal and euglycemic hyperinsulinemic conditions were similar to those observed for leucine appearance. From these results, we conclude that adiposity and/or serum estradiol may contribute to the regulation of protein metabolism and FFM in middle-aged, premenopausal women.

Trp64Arg variant of the beta3-adrenoceptor and insulin resistance in obese postmenopausal women.

There is controversy regarding the role of the Trp64Arg variant of the beta3-adrenergic receptor (beta3AR) gene in the pathogenesis of insulin resistance. The modest effect of the variant as well as differences in study design, gender, age, and genetic background may contribute to divergent results among investigations. Insulin sensitivity (euglycemic clamp and tracers) was measured in 13 obese women (57 +/- 6 yr old) heterozygous for the beta3AR variant and in 14 women (57 +/- 4 yr old) homozygous for the normal gene. Groups were matched for age, body composition, intraabdominal fat, sc abdominal fat, physical activity level, and aerobic capacity. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in beta3AR heterozygotes (241 +/- 135 mg/min) vs. normal homozygotes (379 +/- 172 mg/min). Basal endogenous glucose production was not different (P = 0.20) between heterozygotes (175 +/- 27 mg/min) and normal homozygotes (164 +/- 14 mg/min). Endogenous glucose production during hyperinsulinemia was also not different (P = 0.22) between heterozygotes (77 +/- 57 mg/min) and normal homozygotes (56 +/- 16 mg/min). Total glucose disposal adjusted for residual endogenous glucose production was lower (P = 0.049) for heterozygotes (320 +/- 111 mg/min) than for normal homozygotes (441 +/- 183 mg/min). Our results suggest that obese postmenopausal women who are heterozygous for the Trp64Arg variant in the beta3AR gene have greater insulin resistance than age-, body composition-, and physical activity-matched women homozygous for the normal gene.