Abstract: Objective: To determine the effect of orlistat, a new lipase inhibitor, on long-term weight loss, to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment, and to assess the effects of orlistat on obesity-related risk factors. Research Methods and Procedures: This was a 2-year, multicenter, randomized, double-blind, placebo-controlled study. Obese patients (body mass index 28 to 43 kg/m2) were randomized to placebo or orlistat (60 or 120 mg) three times a day, combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain. Changes in body weight, lipid profile, glycemic control, blood pressure, quality of life, safety, and tolerability were measured. Results: Orlistat-treated patients lost significantly more weight (p < 0.001) than placebo-treated patients after Year 1 (6.6%, 8.6%, and 9.7% for the placebo, and orlistat 60 mg and 120 mg groups, respectively). During the second year, orlistat therapy produced less weight regain than placebo (p = 0.005 for orlistat 60 mg; p < 0.001 for orlistat 120 mg). Several obesity-related risk factors improved significantly more with orlistat treatment than with placebo. Orlistat was generally well tolerated and only 6% of orlistat-treated patients withdrew because of adverse events. Orlistat leads to predictable gastrointestinal effects related to its mode of action, which were generally mild, transient, and self-limiting and usually occurred early during treatment. Discussion: Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.

Abstract: Several large epidemiological studies have shown an association between body mass index and blood pressure in normal weight and overweight patients. Weight gain in adult life especially seems to be an important risk factor for the development of hypertension. Weight loss has been recommended for the obese hypertensive patient and has been shown to be the most effective nonpharmacological treatment approach. However, long-term results of weight loss programs are disappointing with people often regaining most of the weight initially lost. In recent years, a modest weight loss, defined as a weight loss of 5% to 10% of baseline weight, has received increasing attention as a new treatment strategy for overweight and obese patients. A more gradual and moderate weight loss is more likely to be maintained over a longer period of time. Several studies have confirmed the blood pressure-lowering effect of a modest weight loss in both hypertensive and nonhypertensive patients. A modest weight loss can normalize blood pressure levels even without reaching ideal weight. In patients taking antihypertensive medication, a modest weight loss has been shown to lower or even discontinue the need for antihypertensive medication. In patients with high normal blood pressure, a modest weight loss can prevent the onset of frank hypertension. The blood pressure-lowering effect of weight loss is most likely a result of an improvement in insulin sensitivity and a decrease in sympathetic nervous system activity and occurs independent of salt restriction. In conclusion, a modest weight loss that can be maintained over a longer period of time is a valuable treatment goal in hypertensive patients.

Abstract: Objective: This study sought to examine at what body mass index (BMI) body image discrepancy (BD) was reported in a community sample of 389 white, Hispanic, and black women. In addition, we assessed the trajectory of the BMI–BD relationship as BMI increases by ethnic group. Research Methods and Procedures: All participants were assessed on height and weight and completed the Figure Rating Scale. Results: We found no difference in the proportion of women in each ethnic group reporting BD. However, white women experienced BD at a lower BMI level (BMI = 24.6), and below the criterion for overweight (BMI = 25). In contrast, black and Hispanic women did not report BD until they were overweight (BMIs of 29.2 and 28.5, respectively). Compared with black and white women, Hispanic women registered increases in BD at smaller increases in BMI. Discussion: These findings could have unhealthful implications for weight control behavior. The results encourage a closer look at ethnicity and BD, and their relationship to obesity and weight control.

Abstract: NAGY, TIM R., AND ANNE-LAURE CLAIR. Precision and accuracy of dual-energy X-ray absorptiometry for determining in vivo body composition of mice. Obes Res. 2000;8:392‐398. Objective: To evaluate the precision and accuracy of dualenergy X-ray absorptiometry (DXA) for the measurement of total-bone mineral density (TBMD), total-body bone mineral (TBBM), fat mass (FM), and bone-free lean tissue mass (LTM) in mice. Research Methods and Procedures: Twenty-five male C57BL/6J mice (6 to 11 weeks old; 19 to 29 g) were anesthetized and scanned three times (with repositioning between scans) using a peripheral densitometer (Lunar PIXImus). Gravimetric and chemical extraction techniques (Soxhlet) were used as the criterion method for the determination of body composition; ash content was determined by burning at 600°C for 8 hours. Results: The mean intraindividual coefficients of variation (CV) for the repeated DXA analyses were: TBMD, 0.84%; TBBM, 1.60%; FM, 2.20%; and LTM, 0.86%. Accuracy was determined by comparing the DXA-derived data from the first scan with the chemical carcass analysis data. DXA accurately measured bone ash content (p 5 0.942), underestimated LTM (0.59 6 0.05g, p , 0.001), and overestimated FM (2.19 6 0.06g, p , 0.001). Thus, DXA estimated 100% of bone ash content, 97% of carcass LTM, and 209% of carcass FM. DXA-derived values were then used to predict chemical values of FM and LTM. Chemically extracted FM was best predicted by DXA FM and DXA LTM [FM 52 0.50 1 1.09(DXA FM) 2 0.11(DXA LTM), model r 2 5 0.86, root mean square error (RMSE) 5 0.233 g] and chemically determined LTM by DXA LTM [LTM5 20.14 1 1.04(DXA LTM), r 2 5 0.99, RMSE 5 0.238 g]. Discussion: These data show that the precision of DXA for measuring TBMD, TBBM, FM, and LTM in mice ranges from a low of 0.84% to a high of 2.20% (CV). DXA accurately measured bone ash content but overestimated carcass FM and underestimated LTM. However, because of the close relationship between DXA-derived data and chemical carcass analysis for FM and LTM, prediction equations can be derived to more accurately predict body composition.

Abstract: Objective: Abdominal obesity has a key role in the pathogenesis of prevalent and serious diseases and has been shown to be associated with an altered hypothalamic-pituitary-adrenal (HPA) axis function, which is regulated by endocrine feedback mediated via hippocampal glucocorticoid receptors (GR). Research Methods and Procedures: We examined the HPA axis function by repeated salivary samples for the assessment of cortisol, as well as other endocrine, anthropometric, metabolic, and circulatory variables in middle-aged Swedish men (n = 284). With the restriction enzyme BclI, variants of the GR gene (GRL) locus were identified and two alleles with fragment lengths of 4.5 and 2.3 kilobases (kb) were detected. Results: The observed frequencies were 40.1% for the 2.3- and 2.3-kb, 46.2% for the 4.5- and 2.3-kb, and 13.7% for the 4.5- and 4.5-kb genotypes. The larger allele (4.5 and 4.5 kb) was associated with elevated body mass index (BMI; p < 0.001), waist-to-hip circumference ratio (p = 0.015), abdominal sagittal diameter (p = 0.002), leptin (p < 0.001), and systolic blood pressure (borderline, p = 0.058). The 4.5- and 4.5-kb allele was associated with leptin after adjustment for BMI. Moreover, salivary cortisol values, particularly after stimulation by a standardized lunch (p = 0.040 to 0.086), were elevated in the men with the larger allele. Discussion: These results indicate that there is an association between a deficient GR function, defined as a poor feedback regulation of the HPA axis activity, and a polymorphic restriction site at the GR gene locus. An abnormal control of HPA axis function due to genetic alterations may contribute to the pathogenesis of abdominal obesity.

Abstract: AL-BARAZANJI, KAMAL A., JONATHAN R. S. ARCH, ROBIN E. BUCKINGHAM, AND MOHAMMAD TADAYYON. Central exendin-4 infusion reduces body weight without altering plasma leptin in (fa/fa) Zucker rats. Obes Res. 2000;8:317‐323. Objective: To investigate whether chronic administration of the long-acting glucagon-like peptide-1 receptor agonist exendin-4 can elicit sustained reductions in food intake and body weight and whether its actions require an intact leptin system. Research Methods and Procedures: Male lean and obese Zucker (fa/fa) rats were infused intracerebroventricularly with exendin-4 using osmotic minipumps for 8 days. Results: Exendin-4 reduced body weight in both lean and obese Zucker rats, maximum suppression being reached on Day 5 in obese (8%) and Day 7 in lean (16%) rats. However, epididymal white adipose tissue weight was not reduced, and only in lean rats was there a reduction in plasma leptin concentration. Food intake was maximally suppressed (by 81%) on Day 3 in obese rats but was reduced by only 18% on Day 8. Similarly, in lean rats food intake was maximally reduced (by 93%) on Day 4 of treatment and by 45% on Day 8. Brown adipose tissue temperature was reduced from Days 2 to 4. Plasma corticosterone was elevated by 76% in lean but by only 28% in obese rats. Discussion: Chronic exendin-4 treatment reduced body weight in both obese and lean Zucker rats by reducing food intake: metabolic rate was apparently suppressed. These effects did not require an intact leptin system. Neither does the absence of an intact leptin system sensitize animals to exendin-4. Partial tolerance to the anorectic effect of exendin-4 in lean rats may have been due to elevated plasma corticosterone and depressed plasma leptin levels, but other counter-regulatory mechanisms seem to play a role in obese Zucker rats.

Abstract: Objective: Mis-reporting dietary intake is a substantial barrier to understanding the role of dietary behavior in disease. Work with adults indicates that heavier individuals under-report dietary intake and that under-reporting may be macronutrient-specific. Whether weight status and macronutrient intake influence the accuracy of dietary reports among children, however, is less clear. This research evaluated children's dietary reporting accuracy as a function of their relative weight, body composition, and macronutrient intake. Research Methods and Procedures: Participants included 146 4- to 11-year-old children. Reported energy intake was determined by interviewing children in the presence of parents, using three multiple pass, 24-hour recalls. Children were classified as having had an under-reported, accurately reported, or over-reported dietary intake relative to total energy expenditure, as measured by doubly labeled water. Reporting accuracy was examined as a function of children's body weight, body composition (using dual energy x-ray absorptiometry), and macronutrient intake. Results: Average reported intake was, on average, 14% greater than children's estimated expenditure (p < 0.01). Reporting accuracy varied as a function of children's relative weight and body composition; under-reporting tended to occur among heavier children, having the highest body fat content (p < 0.0001) and relative weight (p < 0.0001). Discussion: These findings suggest that weight status influences the accuracy of dietary reports made by children and their parents. More research is needed to address possible psychological and social factors that introduce bias in reporting children's dietary data.

Abstract: CAMPBELL, KAREN, HELEN ENGEL, ANNATIMPERIO, CATHERINE COOPER, AND DAVIDCRAWFORD. Obesity management: Australian generalpractitioners’ attitudes and practices. Obes Res. 2000;8:459–466.Objectives: To document general practitioners’ (GPs) atti-tudes and practices regarding the prevention and manage-ment of overweight and obesity.Research Methods and Procedures: A cross-sectional sur-vey of a randomly selected sample of 1500 Australian GPswas conducted, of which 752 questionnaires were returned.The measures included views on weight management, def-initions of success, views regarding the usefulness of drugs,approaches to and strategies recommended for weight man-agement, and problems and frustrations in managing over-weight and obesity.Results: GPs view weight management as important andfeel they have an important role to play. Although theyconsider themselves to be well prepared to treat overweightpatients, they believe that they have limited efficacy inweight management and find it professionally unrewarding.GPs view the assessment of a patient’s dietary and physicalactivity habits and the provision of dietary and physicalactivity advice as very important. The approaches leastlikely to be considered important and/or least likely to bepracticed were those that would support the patient inachieving and maintaining lifestyle change.Discussion: There remains considerable opportunity to im-prove the practice of GPs in their management of over-weight and obesity. Although education is fundamental, it isimportant to acknowledge the constraints of the GPs’ exist-ing working environment.Key words: general practitioners, health professionals,management, prevention

Abstract: Objective: Adipose angiotensinogen has been suggested as a stimulator of adipose tissue growth and development. Therefore, the association of subcutaneous adipose angiotensinogen gene expression with human obesity was studied. Research Methods and Procedures: The study group consisted of 17 men, undergoing either gastric banding for obesity or elective laparoscopic cholecystectomy (7 obese, 10 non-obese men; body mass index 22 to 51 kg/m2; age 26 to 68 years). Subcutaneous adipose angiotensinogen mRNA and 18S ribosomal RNA (reference gene) levels were measured using competitive quantitative reverse transcriptase-polymerase chain reaction. Results: Adipose angiotensinogen mRNA expression was about two times increased in obesity. The levels of 18S rRNA did not differ between the two groups. Body weight correlated independently and positively with adipose angiotensinogen mRNA expression after adjusting for differences in age and height. Discussion: Adipose angiotensinogen gene expression is elevated in obesity in men.

Abstract: Objective: Despite several studies indicating that social gradients are predictive of cardiovascular mortality, the pathogenetic mechanisms remain incompletely understood. Research Methods and Procedures: A population sample of 51-year-old men (N = 284) was divided into a socioeconomic gradient with manual laborers, civil servants, and university graduates. Anthropometric measurements were registered. Cortisol concentrations were measured in saliva, collected repeatedly during an ordinary working day, and a low-dose dexamethasone suppression test was performed. Results: Lower socioeconomic status was associated with visceral obesity and higher cortisol values in relation to perceived stress. However, total cortisol secretion over the day of study was not elevated. The regulation of cortisol secretion showed less plasticity and dexamethasone inhibition was less efficient in the men in the lower socioeconomic status group than in those with a higher socioeconomic status. These are known consequences of long term stress. Longer duration in low socioeconomic conditions seemed to worsen these phenomena. Discussion: It was concluded that a low socioeconomic status is associated with perturbed cortisol secretion, which is elevated in relation to perceived stress. When the hypothalamic-pituitary-adrenal axis is subjected to prolonged increases in cortisol elicited by chronic stress, the regulation of cortisol secretion is affected, indicating neuroendocrine dysregulations. These observations may provide a means for understanding the association of socioeconomic impairments with visceral obesity and the social inequality in risk for prevalent and serious diseases.

Abstract: Objective: To determine the prevalence of sleep apnea in morbidly obese patients and its relationship with cardiac arrhythmias. Research Methods and Procedures: Fifty-two consecutive morbidly obese (body mass index ≥ 40 kg/m2) outpatients from the Obesity Clinic of the National Institute of Nutrition Salvador Zubiran underwent two nights of polysomnography with standard laboratory techniques. Electrocardiographic polysomnography signals (Lead II) were evaluated by two experienced cardiologists, and sleep complaints were measured with a standard sleep questionnaire (Sleep Disorders Questionnaire). In order to make comparisons between groups with different severities of sleep-disordered breathing, we classified the patients in four groups using the apnea-hypopnea index (AHI): Group 1, AHI 5 < 15 (n = 10); Group 2, AHI 15 < 30 (n = 10); Group 3, AHI 30 < 65 (n = 14); Group 4, AHI ≥ 65 (n = 17). Results: A wide range of sleep-disordered breathing, ranging from AHI of 2.5 to 128.9 was found. Ninety-eight percent of the sample (n = 51) had an AHI ≥ 5 (mean = 51 ± 37), and 33% had severe sleep apnea with AHI ≥ 65 with a mean nocturnal desaturation time of <65% over 135 minutes. Electrocardiographic abnormalities were present in 31% of the patients. Cardiac rhythm alterations showed an association with the level of sleep-disordered breathing and oxygen desaturation. Discussion: We conclude that there is a high prevalence of sleep apnea in morbidly obese patients and that the risk for cardiac arrhythmias increases in this population in the presence of a severe sleep apnea (AHI ≥ 65) with severe oxygen desaturation (Sao2 ≤ 65%).

Abstract: Objective: To examine associations of hypertension with obesity and fat distribution among African American and white men and women. Research Methods and Procedures: The analysis sample included 15,063 African American and white men and women between the ages of 45 and 64 years who were participants in the 1987 through 1989 examination of the Atherosclerosis Risk in Communities Study (ARIC). Odds ratios and adjusted prevalences of hypertension were calculated across sexspecific quintiles of body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and waist-to-height ratio (waist/height) and adjusted for age, research center, smoking, education, physical activity, alcohol consumption, hormone replacement therapy, and menopausal status. Results: The prevalence of hypertension was higher among African Americans than whites. In the lowest quintile of BMI, 41% of African American women and 43% of African American men had hypertension compared with 14% of white women and 19% of white men. Elevated BMI, WHR, waist circumference, and waist/height were associated with increased odds of hypertension in African American and white men and women. In women, but not in men, there were significant interactions between ethnicity and the anthropometric variables studied here. The direction of the interaction indicated larger odds ratios for hypertension with increasing levels of anthropometric indices in white compared with African American women. Discussion: Obesity and abdominal fat preponderance were associated with increased prevalence of hypertension in African American and white men and women. Associations were similar among African American and white men, but obesity and fat patterning were less strongly associated with hypertension in African American than in white women.

Abstract: PICARD, FREDERIC, YVES DESHAIES, JOSEE LALONDE, PIERRE SAMSON, AND DENIS RICHARD. Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes Res. 2000;8:656 - 663. Objective: This study examined the effects of topiramate (TPM), a novel neurotherapeutic agent reported to reduce body weight in humans, on the components of energy bal- ance in female Zucker rats. Research Methods and Procedures: A2 3 3 factorial experiment was performed in which two cohorts of Zucker rats differing in their phenotype (phenotype: lean, Fa/?; obese, fa/fa) were each divided into three groups defined by the dose of TPM administered (dose: TPM 0, vehicle; TPM 15, 15 mg/kg; TPM 60, 60 mg/kg). Results: The reduction in body weight gain induced by TPM in both lean and obese rats reflected a decrease in total body energy gain, which was more evident in obese than in lean rats. Whereas TPM administration did not influence the intake of digestible energy in lean rats, it induced a reduc- tion in food intake in obese animals. In lean, but not in obese rats, apparent energy expenditure (as calculated by the difference between energy intake and energy gain) was higher in rats treated with TPM than in animals adminis- tered the vehicle. The low dose of TPM decreased fat gain (with emphasis on subcutaneous fat) without affecting pro- tein gain, whereas the high dose of the drug induced a reduction in both fat and protein gains. The effects of TPM on muscle and fat depot weights were representative of the global effects of TPM on whole body fat and protein gains. The calculated energetic efficiency (energy gain/energy in- take) was decreased in both lean and obese rats after TPM treatment. TPM dose independently reduced hyperinsulin- emia of obese rats, but it did not alter insulinemia of lean animals. Discussion: The present results provide sound evidence for the ability of TPM to reduce fat and energy gains through reducing energetic efficiency in both lean and obese Zucker rats.

Abstract: Objective: To investigate possible differences, between generally and abdominally obese men, in activity and regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Research Methods and Procedures: Fifty non-diabetic, middle-aged men were selected to obtain two groups with similar body mass index (BMI) but different waist/hip circumference ratio (WHR). Measurements were performed of the activity of the HPA axis and the sympathetic nervous system, as well as metabolic and endocrine variables. Results: Men with a high WHR, in comparisons with men with a low WHR, had higher insulin, glucose, and triglyceride values in the basal state and higher glucose and insulin after an oral glucose tolerance test. Men with high WHR had elevated diurnal adrenocorticotropic hormone (ACTH) values but similar cortisol values, except lower cortisol values in the morning. Diurnal growth hormone concentrations showed reduced peak size. Stimulation of the HPA axis with corticotropin-releasing hormone (CRH) and laboratory stress showed no difference in ACTH values between groups, but cortisol values were lower in men with high WHR. In comparison with men with a low WHR, men with a high WHR had elevated pulse pressure and heart rate in the basal state and after challenges by CRH and laboratory stress. They also had increased urinary excretion of catecholamine metabolites. Discussion: These results suggest a mild dysregulation of the HPA axis, occurring with elevated WHR independent of the BMI. The results also indicate a central activation of the sympathetic nervous system, such as in the early phases of hypertension, correlating with insulin resistance.

Abstract: Objective: This study assessed whether adding orlistat to sibutramine would induce further weight loss in patients who previously had lost weight while taking sibutramine alone. Research Methods and Procedures: Patients were 34 women with a mean age of 44.1 ± 10.4 years, weight of 89.4 ± 13.8 kg, and body mass index (BMI) of 33.9 ± 4.9 kg/m2 who had lost an average of 11.6 ± 9.2% of initial weight during the prior 1 year of treatment by sibutramine combined with lifestyle modification. Patients were randomly assigned, in double-blind fashion, to sibutramine plus orlistat or sibutramine plus placebo. In addition to medication, participants were provided five brief lifestyle modification visits during the 16-week continuation trial. Results: Mean body weight did not change significantly in either treatment condition during the 16 weeks. The addition of orlistat to sibutramine did not induce further weight loss as compared with treatment by sibutramine alone (mean changes = +0.1 ± 4.1 kg vs. +0.5 ± 2.1 kg, respectively). Discussion: These results must be interpreted with caution because of the study's small sample size. The findings, however, suggest that the combination of sibutramine and orlistat is unlikely to have additive effects that will yield mean losses ≥15% of initial weight, as desired by many obese individuals.

Abstract: The apparent obesity epidemic in the industrialized world is not explained completely by increased food intake or decreased energy expenditure. Once obesity develops in genetically predisposed individuals, their obese body weight is avidly defended against chronic caloric restriction. In animals genetically predisposed toward obesity, there are multiple abnormalities of neural function that prime them to become obese when dietary caloric density and quantity are raised. Once obesity is fully developed, these abnormalities largely disappear. This suggests that obesity might be the normal state for such individuals. Formation of new neural circuits involved in energy homeostasis might underlie the near permanence of the obese body weight. Such neural plasticity can occur during both nervous system development and in adult life. Maternal diabetes, obesity, and undernutrition have all been associated with obesity in the offspring of such mothers, especially in genetically predisposed individuals. Altered brain neural circuitry and function often accompanies such obesity. This enhanced obesity may then be passed on to subsequent generations in a feed-forward, upward spiral of increasing body weight across generations. Such findings suggest a form of “metabolic imprinting” upon genetically predisposed neural circuits involved in energy homeostasis. Centrally acting drugs used for obesity treatment lower the defended body weight and alter the function of neural pathways involved in energy homeostasis. But they generally have no permanent effect on body weight or neural function. Thus, early identification of obesity-prone mothers, infants, and adults and treatment of early obesity may be the only way to prevent the formation of permanent neural connections that promote and perpetuate obesity in genetically predisposed individuals.

Abstract: Objective: To examine the concept of the “good enough” body size acceptability across a wide range of ages and weight status. Research Methods and Procedures: Subjects were 303 children, 427 adolescents, 261 young adults, and 326 middle-age adults who selected acceptable body sizes from an array of drawings representing their own age and gender. They also selected body sizes representing their own actual and ideal size. Results: A large majority (87%) of subjects considered their own body size socially acceptable. This finding applied to both genders in all age groups and to underweight, normal weight, and overweight subjects. Even among obese subjects, 48% considered their own body size socially acceptable. For the large percentage of subjects who reported a discrepancy between their actual and ideal body sizes, most considered their own body size acceptable. This finding also applied to both genders in all age groups and to underweight, normal weight, and overweight subjects. Discussion: Most male and female subjects across a wide range of ages and status considered their own body size to be within the range of socially acceptable body sizes even though, for many, it did not match their ideal. The implications of expanding body size research to include the conceptual framework of body size acceptability is discussed in terms of contributing to a paradigm of positive psychology.

Abstract: KU, CHING-YI, BARBARA A. GOWER, GARY R. HUNTER, AND MICHAEL I. GORAN. Racial differences in insulin secretion and sensitivity in prepubertal children: Role of physical fitness and physical activity. Obes Res. 2000;8:506 ‐515. Objective: To investigate in prepubertal children whether physical fitness and/or physical activity are: 1) associated with insulin secretion and sensitivity and 2) account for racial differences in insulin secretion and sensitivity. Research Methods and Procedures: Subjects included 34 African American and 34 white nondiabetic children aged 5 to 11 years. Data were divided into two sets according to the availability of VO2max and physical activity data. Body composition was measured by dual-energy X-ray absorptiometry. Subcutaneous abdominal adipose tissue and intraabdominal adipose tissue were examined by computed tomography. Insulin sensitivity (SI) and acute insulin response (AIR) were determined by a frequently sampled intravenous glucose tolerance test. An all-out, progressive treadmill exercise test was used for measuring VO2max. Physical activity data were collected by questionnaire. Results: African American children had lower SI and higher AIR than white children, after adjusting for total body fat mass. African Americans reported higher levels of physical activity (hours/wk) than whites, but had a lower VO2max .I n multiple linear regression analysis, hours/wk of activity and hours/wk of vigorous activity, but not moderate activity, were independently related to SI and AIR after adjusting for race, total body fat mass or fat distribution, and total lean tissue mass. VO 2max was not related to AIR, and was inversely related to S I , after adjusting for body composition. Race remained significantly associated with both S I and AIR, even after adjusting for body composition, fat distribution, and hours/wk of activity or hours/wk of vigorous activity. Discussion: In summary, overall physical activity and, especially, vigorous activity were associated with insulin secretion and sensitivity. However, neither physical activity nor VO 2max explained the racial difference in insulin secre tion (higher in African Americans) and sensitivity (lower in African Americans). Thus, racial (African American to white) differences in aspects of insulin action seem to be due to factors other than body composition, fat distribution, cardiovascular fitness, and amount of physical activity.

Abstract: Objective: 1. To estimate the prevalence of pre-obesity and obesity in a 1992 to 1993 national survey of the Mexican urban adult population. 2. To compare our findings with other national surveys and with data for Mexican Americans. Research Methods and Procedures: The national representative sample of the Mexican urban adult population included 8462 women and 5929 men aged 20 to 69 years from 417 towns of >2500 people. Body mass index (BMI), calculated from measured weight and height, was classified using the World Health Organization categories of underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5 to 24.9 kg/m2), pre-obesity (PreOB = BMI 25 to 29.9 kg/m2) and obesity (OB = BMI 30+ kg/m2). Estimates for Mexican Americans were calculated from U.S. survey data. Results: Overall, 38% of the Mexican urban adult population were classified as pre-obese and 21% as obese. Men had a higher prevalence of pre-obesity than women did at all ages, but women had higher values of obesity. Both pre-obesity and obesity increased with age up to the age range brackets of 40 to 49 or 50 to 59 years for both men and women. Both pre-obesity and obesity prevalence estimates were remarkably similar to data for Mexican Americans from 1982 through 1984. Comparison with other large surveys showed that countries differed more in the prevalence of obesity than of pre-obesity, leading to differences in the PreOB/OB ratio, and that countries also differed in the gender ratio (female/male) for both pre-obesity and obesity. Discussion: Pre-obesity and obesity were high in our population and increased with age. Our approach of characterizing large surveys by PreOB/OB and gender ratios appeared promising.

Abstract: Objective: Hypothalamic neuropeptide CART (cocaineamphetamine-regulated transcript) is a leptin-dependent endogenous satiety factor in the rat, and single central injections of recombinant CART(42–89) lowers food intake in rats and mice. To assess the potential role of CART as a long-term regulator of food intake, we investigated the effects of continuous infusion of recombinant CART(42–89) on food consumption and body weight. Research Methods and Procedures: Two doses of CART(42–89) were tested: 12 or 4.8 μg/d. Adult male, both lean (+/?) and Zucker (fa/fa) obese, rats were equipped with intracerebroventricular cannulae in the right lateral ventricle. The cannulae were connected to subcutaneously placed osmotic mini-pumps. Pumps were filled with either CART(42–89) or vehicle (50 mM phosphate-buffered saline, pH 7.4). The pumps delivered a continuous infusion of CART(42–89) or vehicle, and food intake and body weight were followed for 10 days (12 μg/d) or 7 days (4.8 μg/d). Animals given the low dose had the pump removed on Day 7, and from half of the group, trunk blood was collected after decapitation, whereas the other half of the group had their mini-pumps removed and were followed for another 7 days before being decapitated. Results: Animals receiving the high doses displayed overt motor disturbances, whereas the low dose was devoid of such behavioral side effects. Both doses significantly lowered food intake with maximal effect on days 3 to 5 of the infusion period. The high dose of CART decreased body weight of normal animals to 85% of initial weight at days 3 to 5, whereas the weight of Zucker (fa/fa) obese rats dropped to 95% of the initial weight. In animals receiving 4.8 μg/d, moderate effects on body weight were seen between days 4 and 6 of the treatment period, but soon after termination of the treatment animals regained lost weight. To assess the biological activity of the contents of the osmotic mini-pumps, the pumps were removed from the subcutaneous implantation site, and 5 μL of their contents were injected intracerebroventricularly to naive animals kept on a restricted feeding schedule. The content of pumps from animals receiving 4.8 μg/d of CART(42–89) potently inhibited food intake, confirming full biological activity despite being kept for 7 days at body temperature. Discussion: Due to obvious effects on motor behavior, it is impossible with certainty to conclude that the observed effects on feeding and body weight are primary interference with satiety centers or secondary to effects on locomotor pathways. Also, the present experiments suggest that hypothalamic appetite-regulating neurons are subject to pharmacological desensitization upon prolonged exposure to CART peptide. The underlying mechanism of such desensitization is as yet unknown.

Abstract: Objective: Clinical research has shown an increased prevalence of obesity in children with asthma. This study was designed to assess the relationship between asthma and pediatric body mass index (BMI) in a national database and to examine factors that may modify this relationship. Design: The cross-sectional relationship between asthma and pediatric BMI and obesity (BMI ≥ 85th percentile) was studied. Variables that may influence the relationship between asthma and pediatric BMI, such as race/ethnicity and television watching were included in the model for the total sample. A smaller sample of 3009 white and African American youth were studied in regression models including maternal BMI. Study Population: A nationally representative crosssectional sample of 5154 children and adolescents of 6 to 16 years of age from the Third National Health And Nutrition Examination Survey. Results: In the full sample, asthma and television watching were related to BMI, accounting for 3% of the variance in BMI. When maternal BMI was included in the nonHispanic sample, television watching, maternal BMI, and the interaction of maternal BMI and asthma were related to youth BMI, accounting for 15% of the variance. The standardized BMI z-score for those youth without asthma and no maternal obesity was 0.06, which increased to 0.33 if the youth had asthma, to 0.70 if the youth did not have asthma but the mother was obese, and to 1.71 if the youth had asthma and the mother was obese. Asthma, television watching, and maternal BMI were independent predictors of youth obesity. Conclusions: BMI and prevalence of obesity is higher in youth with asthma. Pediatric BMI, but not obesity, is also related to the interaction of asthma and maternal BMI in white and African American youth. Comorbidity of asthma and obesity may complicate treatment of either condition, and prevention of obesity should be encouraged for asthmatic children.

Abstract: Objective: To better understand risk factors for the development of obesity in early childhood, we examined the association between children's adiposity and their parents' eating behavior and body mass index (BMI). Research Methods and Procedures: Parents of 85 white children 36 months of age (49 boys and 36 girls) completed the Three-Factor Eating Questionnaire measuring three dimensions of parent eating behavior: disinhibited eating, cognitive restraint of eating, and susceptibility to hunger. Parent BMI (kg/m2) was calculated using self-reported height and weight. The children's percentage body fat was assessed by dual energy X-ray absorptiometry analysis. Results: Twenty-six percent of parents were obese (BMI ≥ 30 kg/m2). Both maternal and paternal BMI were associated with higher scores for disinhibition (r = 0.69 and r = 0.68, p < 0.001), and maternal BMI was also associated with higher scores for hunger (r = 0.51, p < 0.001). There were no significant relationships between children's percentage body fat and parent eating scores, and the correlation between children's percentage body fat and parent BMI was significant only between mothers and daughters (r = 0.35, p = 0.04). Obese parents were no more likely to have a child who was fatter (upper quintile of percentage body fat for gender). Discussion: Among 36 month-old white children, parent eating behavior was related to parent BMI, but not to children's adiposity. There was only a weak relationship between parent BMI and child adiposity. Despite the aggregation of adiposity within families due to shared genes and environments, children may not express differences in susceptibility to obesity by 3 years of age.

Abstract: Objective: We have reported that glucose utilization regulates leptin expression and secretion from isolated rat adipocytes. In this study, we employed two antidiabetic agents that act to increase glucose uptake by peripheral tissues, metformin and vanadium, as pharmacological tools to examine the effects of altering glucose utilization on leptin secretion in primary cultures of rat adipocytes. Research Methods and Procedures: Isolated adipocytes (100 μL of packed cells per well) were anchored in a defined matrix of basement membrane components (Matrigel) with media containing 5.5 mM glucose and incubated for 96 hours with metformin or vanadium. Leptin secretion, glucose utilization, and lactate production were assessed. Results: Metformin (0.5 and 1.0 mM) increased glucose uptake in the presence of 0.16 nM insulin by 37 ± 10% (p < 0.005) and 62 ± 8% (p < 0.0001) over insulin alone, respectively. Metformin from 0.5 to 5.0 mM increased lactate production by 105 ± 43% (p < 0.025) to 202 ± 52% (p < 0.0025) and at 1.0 and 5.0 mM increased the proportional rate of glucose conversion to lactate by 78 ± 18% (p < 0.005) and 166 ± 41% (p < 0.0025), respectively. At concentrations less than 0.5 mM, metformin did not affect leptin secretion, but at 0.5 mM, the only concentration that significantly increased glucose utilization without increasing glucose conversion to lactate, leptin secretion was modestly stimulated (by 20 ± 9%; p < 0.05). Concentrations from 1.0 to 25 mM inhibited leptin secretion by 25 ± 8% (p < 0.005) to 89 ± 4% (p < 0.0001). Across metformin doses, leptin secretion was inversely related to the percentage of glucose taken up and released as lactate (r = −0.74; p < 0.0001). Vanadium (5 to 20 μM) increased glucose uptake from 20 ± 7% (p < 0.01) to 34 ± 13% (p < 0.02) and increased lactate production at 5 μM by 17 ± 8% (p < 0.025) and 10 μM by 61 ± 20% (p < 0.02) but did not alter the conversion of glucose to lactate. Vanadium (5 to 50 μM) inhibited leptin secretion by 33 ± 6% (p < 0.0025) to 61 ± 8% (p < 0.0001). Discussion: Both metformin and vanadium increase glucose uptake and inhibit leptin secretion from cultured adipocytes. The inhibition of leptin secretion by metformin is related to an increase in the metabolism of glucose to lactate. The inhibition by vanadium most likely involves direct effects on cellular phosphatases. We hypothesize that the effect of glucose utilization to stimulate leptin production involves the metabolism of glucose to a fate other than anaerobic lactate production, possibly oxidation or lipogenesis.

Abstract: Objective: A low resting metabolic rate for a given body size and composition, a low rate of fat oxidation, low levels of physical activity, and low plasma leptin concentrations are all risk factors for body weight gain. The aim of the present investigation was to compare resting metabolic rate (RMR), respiratory quotient (RQ), levels of physical activity, and plasma leptin concentrations in eight post-obese adults (2 males and 6 females; 48.9 ± 12.2 years; body mass index [BMI]: 24.5 ± 1.0 kg/m2; body fat 33 ± 5%; mean ± SD) who lost 27.1 ± 21.3 kg (16 to 79 kg) and had maintained this weight loss for ≥2 months (2 to 9 months) to eight age- and BMI-matched control never-obese subjects (1 male and 7 females; 49.1 ± 5.2 years; BMI 24.4 ± 1.0 kg/m2; body fat 33 ± 7%). Research Methods and Procedures: Following 3 days of weight maintenance diet (50% carbohydrate and 30% fat), RMR and RQ were measured after a 10-hour fast using indirect calorimetry and plasma leptin concentrations were measured using radioimmunoassay. Levels of physical activity were estimated using an accelerometer over a 48-hour period in free living conditions. Results: After adjustment for fat mass and fat-free mass, post-obese subjects had, compared with controls, similar levels of physical activity (4185 ± 205 vs. 4295 ± 204 counts) and similar RMR (1383 ± 268 vs. 1430 ± 104 kcal/day) but higher RQ (0.86 ± 0.04 vs. 0.81 ± 0.03, p < 0.05). Leptin concentration correlated positively with percent body fat (r = 0.57, p < 0.05) and, after adjusting for fat mass and fat-free mass, was lower in post-obese than in control subjects (4.5 ± 2.1 vs. 11.6 ± 7.9 ng/mL, p < 0.05). Discussion: The low fat oxidation and low plasma leptin concentrations observed in post-obese individuals may, in part, explain their propensity to relapse.

Abstract: Objective: To evaluate the safety and efficacy of sibutramine 15 mg by mouth once per day in obese patients over a period of 6 months. Research Methods and Procedures: A monocenter, double-blind, placebo controlled, parallel, prospective clinical trial was carried out. Sixty-nine male and female obese patients (body mass index [BMI] > 30 kg/m2) aged 16 to 65 years entered the trial. Results: 22 of 35 patients in the sibutramine group and 9 of 34 patients in the placebo group completed the trial. The high dropout rate in the sibutramine group was due to adverse events in 3 cases, lack of efficacy (as judged by patients) in 7, loss to follow-up in 2, and an orthopedic device being worn in 1; in the placebo group the dropouts were ascribed to lack of efficacy (as judged by patients) in 17 cases and to loss to follow-up in 8 cases. Using the method of last observation carried forward, the weight loss in the sibutramine group was 10.27 kg (95% confidence intervals [95% CI] 7.66; 13.07) and 1.26 kg (95% CI 0.3; 2.23) in the placebo group. The BMI loss was 4.17 kg/m2 (95% CI 3.11; 5.22) in the sibutramine group and 0.53 kg/m2 (95% CI 0.13; 0.92) in the placebo group. The waist circumference reduction was 12.51 cm (95% CI 9.25; 15.77) in the sibutramine group and 3.26 cm (95% CI 1.38; 5.14) in the control group (p < 0.05 by paired Student's t test for all the intragroup comparisons). Twenty-three sibutramine patients had 34 adverse events, the most frequent adverse events in the sibutramine group were upper respiratory tract infections (n = 6) and constipation (n = 6); 16 placebo patients had 21 adverse events. Three sibutramine patients withdrew their informed consent when they had adverse events. Discussion: The results show that sibutramine induces significant loss of body weight and waist circumference. Cardiovascular function was not significantly affected by sibutramine. Sibutramine was well tolerated by most of the patients.

Abstract: Objective: Studies on weight change and mortality have yielded inconclusive results. This 10-year prospective study was undertaken to improve understanding of factors affecting weight change. Research Methods and Procedures: The subjects were 1143 men, aged 36 to 88 years (mean, 53.3 years) at entry. A questionnaire was filled in at entry and at the end of the follow-up with queries on weight, height, weight at the age of 20, physician-diagnosed diseases, smoking, alcohol use, dietary habits, leisure physical activity, occupation, present occupational activity, living conditions (living alone or cohabiting), and former athletic status. Further information on morbidity was obtained from selected national registers. Factors predicting weight change during the study were identified by stepwise linear multiple regression analysis. Results: The mean 10-year weight change was 0.8 (range, −29 to +24) kg. Age at entry (β-coefficient, −0.17, SE 0.02), weight at entry (β, −0.03, SE 0.01), diabetes at entry (β, −3.55, SE 1.02), diabetes diagnosed after entry (β, −3.94, SE 0.96), malignant cancer (β, −1.60, SE 0.70), being a smoker (β, −1.59, SE 0.48), and increased physical activity (β, −1.27, SE 0.54) were significantly (p < 0.05) associated with weight loss in the final model. The model explained 13% of the variance of weight change. Discussion: The results emphasize the complexity of weight change. Some factors associated with weight change are apparently negatively, and some positively, associated with health. This could explain the equivocal findings on weight change and mortality in the literature.

Abstract: OBJECTIVE Elevated levels of tumor necrosis factor-alpha (TNF-alpha) protein and mRNA have been reported in adipose tissue from obese humans and rodents. However, TNF-alpha has catabolic and antiadipogenic effects on adipocytes. Addressing this paradox, we tested the hypothesis that paracrine levels of TNF-alpha, alone or together with insulin-like growth factor-I (IGF-I), support preadipocyte development. RESEARCH METHODS AND PROCEDURES Cultured stromal-vascular cells from rat inguinal fat depots were exposed to serum-free media containing insulin and 0.2 nM TNF-alpha, 2.0 nM TNF-alpha, or 0.2 nM TNF-alpha + 1.0 nM IGF-I at different times during 7 days of culture. RESULTS TNF-alpha inhibited adipocyte differentiation as indicated by a reduction in both immunocytochemical reactivity for the preadipocyte-specific antigen (AD3; early differentiation marker) and glycerol-3-phosphate dehydrogenase activity (late differentiation marker). Early exposure (Days 1 through 3 of culture) to 0.2 nM TNF-alpha did not have a long term effect on inhibiting differentiation. Continuous exposure to 0.2 nM TNF-alpha from Days 1 through 7 of culture resulted in a 75% increase in cell number from control. There was a synergistic effect of 0.2 nM TNF-alpha + 1 nM IGF-I on increasing cell number by Day 7 of culture to levels greater than those observed with either treatment applied alone. DISCUSSION These data suggest that paracrine levels (0.2 nM) of TNF-alpha alone or in combination with IGF-I may support adipose tissue development by increasing the total number of stromal-vascular and/or uncommitted cells within the tissue. These cells may then be recruited to become preadipocytes or may alternatively serve as infrastructure to support adipose tissue growth.

Abstract: Objective: Epidemiological studies suggest that high birth weight might be associated with an increased risk of obesity later in life. Programming of metabolic, endocrine, and/or autonomic pathways during intrauterine development has been proposed to explain this association. Research Methods and Procedures: To determine the relationship between birth weight and body composition and energy metabolism later in life, we measured fat mass and fat-free mass (hydrodensitometry or double-energy X-ray absorptiometry), 24-hour energy expenditure, sleeping metabolic rate, and 24-hour respiratory quotient (respiratory chamber) in 272 adult nondiabetic Pima Indians (161 males/111 females, age 25 ± 5 years, mean ± SD). In these subjects, birth weight varied over a wide range (2000 to 5000 g). Individuals known to be offspring of diabetic pregnancies were excluded. In 44 of the 272 subjects, muscle sympathetic nerve activity was assessed by microneurography. Results: Birth weight was positively correlated with adult height (r = 0.20, p < 0.001) and fat-free mass (r = 0.21, p < 0.001), but not with fat mass (r = 0.01, not significant). Sleeping metabolic rate, adjusted for age, sex, fat-free mass, and fat mass, was negatively related to birth weight (r = −0.13, p < 0.05), whereas adjusted 24-hour energy expenditure (r = 0.07, not significant) and 24-hour respiratory quotient (r = −0.09, not significant) were not. There was no relationship between birth weight and muscle sympathetic nerve activity (r = 0.12, not significant, n = 44). Discussion: In Pima Indians who are not offspring of diabetic pregnancies, high birth weight is associated with increased height and lean body mass, but not with increased adiposity later in life. Although high birth weight may be associated with relatively low resting energy expenditure, it is not associated with major abnormalities in 24-hour energy metabolism or with low muscle sympathetic nerve activity later in life.

Abstract: Objective: The regulation of body weight and body composition involves input from genes and the environment. This interaction is demonstrated by the different susceptibility of Osborne-Mendel (OM) and S5B/P1 rat strains to obesity when offered a high-fat diet. In animals and humans, diet-induced obesity has been characterized by hyperleptinemia, which has been interpreted as evidence for leptin resistance. This investigation determined if altered expression of leptin receptors (ObR) in the hypothalamus could potentially contribute to altered sensitivity to diet-induced obesity between OM and S5B/Pl rats. Research Methods and Procedures: OM and S5B/Pl rats were fed high-fat (HF) or low-fat (LF) diets for 14 days. Ribonuclease protection assays and Western blotting were used to assay the levels of mRNA and protein, respectively, for short (ObR-S) and long (ObR-L) forms of the leptin receptor in the hypothalamus. Results: The mRNA encoding ObR-L, the predominant signaling form of the receptor, was higher in OM rats than in S5B/P1 rats (p < 0.01) both on HF and LF diets. No changes in ObR-L mRNA expression were observed in OM rats with diet, but, S5B/P1 rats showed a slight increase in the ObR-L on the LF diet. On the contrary, there were no changes in ObR-S mRNA expression due to diet or strain. Western blots showed that both the short and long forms of the receptor were increased on the LF diet, but there were no strain differences. OM and S5B/Pl rats had comparable leptin levels after maintenance on a LF diet (6.20 ± 0.63 and 4.81 ± 0.82 ng/mL, respectively). Serum leptin levels in OM rats were increased by the HF diet and were elevated 2-fold over those of their S5B/Pl counterparts. Discussion: These results suggest that a decrease in the levels of both the long form and short form of the receptor may contribute to the leptin resistance seen in HF-fed rats. These effects appear to be post-transcriptional, because equivalent changes were not observed in the expression of ObR-L and ObR-S mRNAs. They may be related to the increase in circulating leptin levels, suggesting that high serum leptin levels contribute to increased leptin resistance and subsequently lead to obesity. We conclude that down-regulation of receptor protein levels is associated with hypothalamic leptin resistance of HF-fed rats.