Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain?

Following the withdrawal of ephedrine from the dietary supplement marketplace sales of products containing Citrus aurantium (CA) (bitter orange) for weight loss are believed to have increased dramatically. CA contains a number of constituents speculated to lead to weight loss, of which the most frequently cited constituent is synephrine. Concerns have been raised about the safety of products containing synephrine. To develop an adequate basis for clinical and public health recommendations, it is necessary to understand the nature of the synephrine alkaloids in CA. There are six possible isomers of synephrine (para, meta, ortho; and for each a d or l form). Some authors have stated that CA contains only p-synephrine, whereas other authors have stated that CA contains m-synephrine. This is an important distinction because the two molecules have different pharmacologic properties, which may differentially affect safety and efficacy. We are unable to identify published data that explicitly show whether CA contains p-synephrine, m-synephrine, or both. In this brief report, we show that at least one product purportedly containing synephrine alkaloids from CA contains both p-synephrine and m-synephrine. We believe this justifies further investigation into which synephrine alkaloids are present in CA and products purportedly containing synephrine alkaloids from CA and the relative quantities of each of the different isomers.

Association between obesity and a polymorphism in the beta(1)-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women.

INTRODUCTION: Genetic variants affecting adrenoceptors have been suggested to influence body fatness. A putative gain-of-function polymorphism in the beta(1)-adrenoceptor was recently discovered (Gly389Arg ADRB1). We examined the association between Gly389Arg ADRB1 and obesity status in a large cohort of well-characterized individuals. METHODS: First, a large cohort of 931 Caucasian women (55.0+/-12.2 y) were genotyped for Gly389Arg ADRBbeta1 and we examined the association of the Arg allele with body weight and BMI (Gly/Gly, n=54; Gly/Arg, n=360; Arg/Arg, n=517). To further examine phenotypes regulating energy balance and body fatness, we examined the contribution of the Arg allele to body composition (DEXA), fat distribution (CT scan), resting energy expenditure, energy and macronutrient intake, maximal oxygen capacity, and physical activity in a subsample of 214 women from the main cohort that had been carefully characterized (Gly/Gly, n=19; Gly/Arg, n=82; Arg/Arg, n=113). RESULTS: In the entire cohort (n=931), allele frequencies were 0.25 and 0.75 for the Gly and Arg alleles, respectively. In this cohort, we found that each Arg allele was associated with greater body weight of 2.91 kg (P=0.01) and BMI of 0.86 kg/m(2) (P=0.05). Accordingly, in the subsample of women, each Arg allele was associated with greater fat mass (3.71 kg; P=0.008). Other phenotypes were not significantly associated with the presence of the Arg allele. CONCLUSIONS: This is the first study to investigate the relationship between the Gly389Arg ADRB1 variant and obesity. We found that the Arg allele is associated with greater body weight and BMI in Caucasian women due to a greater fat mass.

Validation of the Arizona Activity Frequency Questionnaire using doubly labeled water.

PURPOSE: Physical activity questionnaires (PAQs) are considered the most cost-efficient method to estimate total energy expenditure (TEE) in epidemiological studies. However, relatively few PAQs have been validated using doubly labeled water (DLW) in women or in samples with diverse ethnic backgrounds. This study was conducted to validate the Arizona Activity Frequency Questionnaire (AAFQ) for estimation of TEE and physical activity energy expenditure (PAEE) over 1 month using DLW as a reference method. METHODS: Thirty-five relatively sedentary women completed the AAFQ before participating in an 8-d DLW protocol to measure TEE. TEE and PAEE were estimated from the AAFQ by calculating resting metabolic rate (RMR) using the equation of Mifflin et al. (AAFQmif), by measuring RMR using indirect calorimetry (AAFQic), and using MET conversion (AAFQmet). A predictive equation for TEE was generated. RESULTS: The mean +/- SD for TEE and PAEE from DLW were 9847 +/- 2555 kJ x d(-1) and 5578 +/- 2084 kJ x d(-1), respectively. Formulas using RMR to calculate the TEE and PAEE from the AAFQ tended to underestimate TEE and PAEE, whereas those that included only weight tended to overestimate TEE and PAEE. On the basis of the Mifflin et al. equation, the AAFQ tends to underestimate PAEE by 13%. This underestimation may be explained by the low lean body mass of the sample population and by effectiveness of the METs/RMR ratio in the obese. The following predictive equation was calculated: TEE (kJ x d(-1)) = (86.0 * average total daily METs) + (2.23 * RMRmif) - 6726. When the predictive equation is used, TEE calculated from the AAFQ is highly correlated with DLW TEE (adjusted r(2) = 0.70, P < 0.001). CONCLUSION: The AAFQ is an effective tool for the prediction of TEE and PAEE in epidemiological studies.

Effects of race, cigarette smoking, and use of contraceptive medications on resting energy expenditure in young women.

The prevalence of obesity is higher in Black women than in White women (JAMA 1994;272:205-11; Arch Pediatr Adolesc Med 1995;149:1085-91). Although it has been shown that Black women have a lower resting energy expenditure (REE), factors affecting REE remain unclear. This 1996-1997 study in Cincinnati, Ohio, assessed racial differences in REE and their determinants in a biracial cohort of 152 healthy young women aged 18-21 years. Two indirect calorimetric measurements were obtained during two overnight hospital admissions 10-14 days apart. Body composition was measured by using dual-energy x-ray absorptiometry. Mean REE (adjusted for body composition, smoking, and contraceptive medication use) was significantly (p = 0.04) lower by 71 kcal/day in Black women (1,453 (standard error, 21) kcal/day) than in White women (1,524 (standard error, 19) kcal/day). Smoking was associated with a REE that was 68 kcal/day higher for both groups (p = 0.03). A trend (p = 0.07) toward increased REE (by 46 kcal/day) was found with contraceptive medication use. In conclusion, young Black women had a significantly lower REE than did White women. Cigarette smoking significantly increased REE. The apparent presence of a more parsimonious energy metabolism in Black women suggests that maintenance of energy homeostasis requires particular vigilance in this high-risk population.

Relationship between hormone replacement therapy use with body fat distribution and insulin sensitivity in obese postmenopausal women.

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.

Recovery of (13)CO(2) from infused [1-(13)C]leucine and [1,2-(13)C(2)]leucine in healthy humans.

Carbon (C) in the 1-position of leucine is released as CO(2) with the decarboxylation of alpha-ketoisocaproate (KIC). Carbon in the 2-position of leucine undergoes several additional metabolic steps before entering the tricarboxylic acid (TCA) cycle in the 1-position of acetyl-CoA, where it can be released as CO(2) or be incorporated into other compounds. This study examined the metabolic fate of C in the 2-position of leucine. We infused 11 healthy subjects with [1-(13)C]leucine and [1,2-(13)C(2)]leucine for 3.5--4 h to measure leucine kinetics and the oxidation of the tracers from enrichments of (13)C in blood and expired CO(2). The fraction of leucine infused that was oxidized (f(ox)) was used to define the degree of recovery of the (13)C label(s) for each tracer. As expected, leucine appearance (means +/- SE) did not differ between tracers ((13)C(1): 92.1 +/- 3.1 vs. (13)C(2): 89.2 +/- 3.2 micromol x kg(-1) x h(-1)) when calculated using plasma leucine enrichments as an index of intracellular enrichment. A small (3%) but significant (P = 0.048) difference between tracers was found when KIC was used to calculate leucine appearance ((13)C(1): 118.0 +/- 4.1 vs. (13)C(2): 114.4 +/- 4.5 micromol x kg(-1) x h(-1)). The value of f(ox) was 14 +/- 1% for [1,2-(13)C(2)]leucine and was lower than the f(ox) for [1-(13)C]leucine (19 +/- 1%). From the f(ox) data, we calculated that the recovery of the 2-(13)C label in breath CO(2) was 58 +/- 6% relative to the 1-(13)C label. These findings show that, although a majority of the 2-(13)C label of leucine is recovered in breath CO(2), a significant percentage (approximately 42%) is retained in the body, presumably by transfer to other compounds, via TCA exchange reactions.

Previous exposure to hormone replacement therapy and confounders in metabolic studies.

OBJECTIVE: The quantity of intra-abdominal fat is highly associated with the development of diabetes mellitus. We sought to determine whether recent hormone replacement therapy (HRT) use modifies central fat and insulin sensitivity in postmenopausal women compared with women who had never used HRT. DESIGN: We measured intra-abdominal fat, subcutaneous abdominal fat, and sagittal diameter at the L4-L5 vertebral disc space using computed tomography imaging. Total body fat and fat-free mass were measured using dual energy x-ray absorptiometry. Insulin sensitivity was assessed using the euglycemic hyperinsulinemic clamp technique in 42 nonobese postmenopausal women, age 51 +/- 4 years (12 recent HRT users plus 30 never-users). All women who were taking HRT discontinued it for 2 months before the study. RESULTS: After statistical adjustment for age, previous use of HRT was associated with decreased intra-abdominal fat (72 +/- 34 cm2) compared with no HRT use (96 +/- 33 cm2; p = 0.05). This difference remained significant after adjustment for time since menopause. When previous HRT users were compared with nonusers, there were no differences in subcutaneous abdominal fat, sagittal diameter, fat-free mass, total fat, insulin sensitivity, or body weight. CONCLUSIONS: Recent HRT use is associated with lower intra-abdominal fat in nonobese, early postmenopausal women. This finding suggests a carry-over effect of HRT on intra-abdominal fat. Recent HRT use does not seem to be associated with differences in glucose disposal.

Determinants of insulin-stimulated glucose disposal in middle-aged, premenopausal women.

Controversy exists regarding the relative importance of adiposity, physical fitness, and physical activity in the regulation of insulin-stimulated glucose disposal. To address this issue, we measured insulin-stimulated glucose disposal [mg. kg fat-free mass (FFM)(-1). min(-1); oxidative and nonoxidative components] in 45 nondiabetic, nonobese, premenopausal women (mean +/- SD; 47 +/- 3 yr) by use of hyperinsulinemic euglycemic clamp (40 mU. m(-2). min(-1)) and [6,6-2H2]glucose dilution techniques. We also measured body composition, abdominal fat distribution, thigh muscle fat content, maximal oxygen consumption (VO2 max), and physical activity energy expenditure ((2)H(2)(18)O kinetics) as possible correlates of glucose disposal. VO2 max was the strongest correlate of glucose disposal (r = 0.63, P < 0.01), whereas whole body and abdominal adiposity showed modest associations (range of r values from -0.32 to -0.46, P < 0.05 to P < 0.01). A similar pattern of correlations was observed for nonoxidative glucose disposal. None of the variables measured correlated with oxidative glucose disposal. The relationship of VO2 max to glucose disposal persisted after statistical control for FFM, percent body fat, and intra-abdominal fat (r = 0.40, P < 0.01). In contrast, correlations of total and regional adiposity measures to insulin sensitivity were no longer significant after statistical adjustment for VO2 max. VO2 max was the only variable to enter stepwise regression models as a significant predictor of total and nonoxidative glucose disposal. Our results highlight the importance of VO2 max as a determinant of glucose disposal and suggest that it may be a stronger determinant of variation in glucose disposal than total and regional adiposity in nonobese, nondiabetic, premenopausal women.

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.

What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women?

Although obesity is often associated with insulin resistance and a cluster of metabolic disturbances, the existence of a subgroup of healthy but obese individuals has been postulated. It is unclear why some obese individuals fail to show traditional risk factors associated with the insulin resistance syndrome despite having a very high accumulation of body fat. To address this issue, we identified and studied a subgroup of metabolically normal but obese (MNO) postmenopausal women to gain insight into potential physiological factors that may protect them against the development of obesity-related comorbidities. We carefully examined the metabolic characteristics of 43 obese, sedentary postmenopausal women (mean +/- SD, 58.0 +/- 6.0 yr). Subjects were classified as MNO or as metabolically abnormal obese (MAO) based on an accepted cut-point for insulin sensitivity (measured by the hyperinsulinemic/euglycemic clamp technique). Thereafter, we determined 1) body composition (fat mass and lean body mass), 2) body fat distribution (abdominal visceral and sc adipose tissue areas, midthigh sc adipose tissue and muscle attenuation), 3) plasma lipid-lipoprotein levels, 4) plasma glucose and insulin concentrations, 5) resting blood pressure, 6) peak oxygen consumption, 7) physical activity energy expenditure, and 8) age-related onset of obesity with a questionnaire as potential modulators of differences in the risk profile. We identified 17 MNO subjects who displayed high insulin sensitivity (11.2 +/- 2.6 mg/min.kg lean body mass) and 26 MAO subjects with lower insulin sensitivity (5.7 +/- 1.1 mg/min.kg lean body mass). Despite comparable total body fatness between groups (45.2 +/- 5.3% vs. 44.8 +/- 6.6%; P: = NS), MNO individuals had 49% less visceral adipose tissue than MAO subjects (141 +/- 53 vs. 211 +/- 85 cm(2); P: < 0.01). No difference was noted between groups for abdominal sc adipose tissue (453 +/- 126 vs. 442 +/- 144 cm(2); P: = NS), total fat mass (38.1 +/- 10.6 vs. 40.0 +/- 11.8 kg), muscle attenuation (42.2 +/- 2.6 vs. 43.6 +/- 4.8 Houndsfield units), and physical activity energy expenditure (1060 +/- 323 vs. 1045 +/- 331 Cal/day). MNO subjects had lower fasting plasma glucose and insulin concentrations and lower insulin levels during the oral glucose tolerance test (P: values ranging between 0.01-0.001). No difference was observed between groups for 2-h glucose levels and glucose area during the oral glucose tolerance test. MNO subjects showed lower plasma triglycerides and higher high density lipoprotein cholesterol concentrations than MAO individuals (P: < 0.01 in both cases). Results from the questionnaire indicated that 48% of the MNO women presented an early onset of obesity (<20 yr old) compared with 29% of the MAO subjects (P: = 0.09). Stepwise regression analysis showed that visceral adipose tissue and the age-related onset of obesity explained 22% and 13%, respectively, of the variance observed in insulin sensitivity (total r(2) = 0.35; P: < 0.05 in both cases). Our results support the existence of a subgroup of obese but metabolically normal postmenopausal women who display high levels of insulin sensitivity despite having a high accumulation of body fat. This metabolically normal profile is associated with a lower accumulation of visceral adipose tissue and an earlier age-related onset of obesity.

Effects of estradiol and progesterone on body composition, protein synthesis, and lipoprotein lipase in rats.

Prior studies suggest that estradiol and progesterone regulate body composition in growing female rats. Because these studies did not consider the confounding effect of changes in food intake, it remains unclear whether ovarian hormones regulate body composition independently of their effects on food intake. We utilized a pair-feeding paradigm to examine the effects of these hormones on body composition. In addition, skeletal muscle protein fractional synthesis rate and adipose tissue lipoprotein lipase activity were measured to examine pathways of substrate deposition into fat and fat-free tissue. Female Sprague-Dawley rats [pubertal: 7-8 wk old; 190 +/- 0.5 (SE) g] were separated into four groups: 1) sham-operated (S; n = 8), 2) ovariectomized plus placebo (OVX; n = 8), 3) ovariectomized plus estradiol (OVX+E; n = 8), and 4) ovariectomized plus progesterone (OVX+P; n = 8). All ovariectomized groups were pair-fed to the S group. Body composition was measured using total body electrical conductivity. The relative increase in fat-free mass was greater (P < 0.01) in the OVX group (31 +/- 2%) than in the S (17 +/- 2%), OVX+E (18 +/- 2%), and OVX+P (22 +/- 2%) groups. The fractional synthetic rates of gastrocnemius muscle protein paralleled changes in fat-free mass: OVX had a higher (P < 0.05) synthesis rate (21 +/- 3%/day) than S (12 +/- 2%/day), OVX+E (11 +/- 2%/day), and OVX+P (8 +/- 1%/day) groups. Body fat increased in the S group (31 +/- 7%; P < 0.01), whereas the OVX groups lost fat (OVX: -10 +/- 7%; OVX+E: -15 +/- 7%; OVX+P: -13 +/- 7%). No differences in lipoprotein lipase were found. Our results suggest that estradiol and progesterone may regulate the growth of fat and fat-free tissues in female rats. Moreover, ovarian hormones may influence skeletal muscle growth through their effects on skeletal muscle protein synthesis.

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.

Caloric restriction mimetics: physical activity and body composition changes.

As the only paradigm that has consistently increased life span and inhibited the onset and/or progression of disease, dietary restriction has multiple effects on a variety of organ systems. In this brief review, the goal of the panel was to attempt to understand the role of changes in physical activity and body composition as possible modulators of the life span in experimental animals and humans. We focus on whether changes in exercise behavior and body composition produce similar changes as those found in dietary restriction and whether these changes can be used to either replace or enhance the beneficial effects of dietary restriction. The complexity of the two stimuli is emphasized in our report, with suggestions offered on how to better interpret existing research. Our panel briefly examines evidence in experimental animals and humans about the specific contributions of each of these factors to altering life span and age-related pathologies. We also discuss additional animal studies and/or human intervention studies that could be performed to clarify these issues. Finally, we provide suggested avenues for future research in this area of changes in physical activity and body composition as dietary restriction mimetics.

Assessment of physical function and exercise tolerance in older adults: reproducibility and comparability of five measures.

This study examined the reproducibility and comparability of five measures of function and exercise tolerance. The test battery and questionnaire on function and physical activity were administered twice, 7-10 days apart to 38 men and 12 women aged 54-80 years at the Baltimore Veterans Affairs Medical Center. Tests included fast pace 4 and 20-meter walks, 6-minute and graded treadmill walks, and a seated step test. All tests demonstrated good reproducibility with Pearson and intraclass correlation coefficients ranging from 0.84 to 0.98, and percent differences on retest ranging from 4 to 11%. Although correlations between different tests were all significant (range 0.34-0.89), comparison of performance ranks and linear regression analyses indicated that the short fast walks and seated step test may not be suitable substitutes for treadmill or long self-paced corridor walks. Only 28% had the same quintile performance ranking on the step test as on the treadmill walk, and 36% had rankings 2 or more points apart. The fast 20m walk shows the most promise as a low-level alternative to the 6-minute walk; performances had a correlation of 0.73, 82% of ranks were within one point, and 20m speed explained 42% of the variance in distance covered. More development is needed for comprehensive assessment of exercise tolerance in older adults; the 6-minute walk did not adequately discriminate fitness level in persons who walk regularly, and the treadmill posed problems for those with walking difficulty.

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.