Search

Background and objectives Lower total energy expenditure (TEE) and resting metabolic rate (RMR) are associated with greater weight gain in Native American adults. Whether these effects exist in childhood is unclear. We hypothesized that lower energy expenditure measured in childhood would predict greater relative change in body mass index (BMI) during adolescence. Methods Measurements of height, weight, body composition, RMR and TEE were completed in 181 Native American children at exams done at age 5 and 10 years, with 126 children having biennial follow-up assessments of weight and height after age 10 years until age 20 years. TEE and RMR were adjusted for age, sex, height, fat mass and fat free mass. BMI-change was assessed using population specific and Center for Disease Control (CDC) BMI z-scores and change in the relative difference to the 95th BMI-centile. Results Lower adjusted RMR at age 10 years was associated with greater increase in population-specific and CDC BMI z-scores, greater increase in the relative difference to the 95th BMI-centile and greater weight gain (all r ≤ −0.22, p ≤ 0.01). However, no association was found with adjusted RMR at age 5 years and with adjusted TEE and physical activity level assessed at age 5 or 10 years. Conclusions Lower adjusted RMR at age 10 years predicted greater change in adolescent BMI z-score indicating that the effects of relatively low metabolic rate on future weight gain in this population may begin in late childhood.

Aims High saturated fatty acid (SFA) diets blunt peripheral insulin action. GLP-1 receptor agonists suppress postprandial lipids and endothelial dysfunction, which may counter SFA-induced insulin resistance. This study tested whether liraglutide suppresses postprandial elevations in lipids and thus protects against high SFA-diet induced insulin resistance. Materials and methods In a randomized placebo-controlled cross-over study, 32 subjects with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and following a 24-hr SFA-enriched diet after each treatment. Plasma glucose, insulin, triglycerides and non-esterified fatty acids (NEFA) were measured over the initial 8 hours (breakfast and lunch) on the SFA diet. A subset of participants had ex vivo measurements of insulin-mediated vasodilation of adipose tissue arterioles and glucose metabolism regulatory proteins in skeletal muscle. Results Liraglutide reduced plasma glucose, triglycerides and NEFA concentrations during the SFA-diet (by 50, 25 and 9% respectively), and the SFA-diet increased plasma glucose during the IST (by 36%) (all p

Increased consumption of high-fat diets is associated with the development of insulin resistance and type 2 diabetes. Current models to study the mechanisms of high-fat diet-induced IR in humans are limited by their long duration or low efficacy. In the present study we developed and characterized an acute dietary model of saturated fatty acid-enriched diet induced insulin resistance.High caloric diets enriched with saturated fatty acids (SFA) or carbohydrates (CARB) were evaluated in subjects with normal and impaired glucose tolerance (NGT or IGT). Both diets were compared to a standard eucaloric American Heart Association (AHA) control diet in a series of crossover studies. Whole body insulin resistance was estimated as steady state plasma glucose (SSPG) concentrations during the last 30min of a 3-h insulin suppression test.SSPG was increased after a 24-h SFA diet (by 83±74% vs. control, n=38) in the entire cohort, which was comprised of participants with NGT (92±82%, n=22) or IGT (65±55%, n=16) (all p0.001). SSPG was also increased after a single SFA breakfast (55±32%, p=0.008, n=7). The increase in SSPG was less pronounced after an overnight fast following a daylong SFA diet (24±31%, p=0.04, n=10), and further attenuated 24h after returning to the control diet (19±35%, p=0.09, n=11). SSPG was not increased after a 24-h CARB diet (26±50%, p=0.11, n=12).A short-term SFA-enriched diet induced whole body insulin resistance in both NGT and IGT subjects. Insulin resistance persisted overnight after the last SFA meal and was attenuated by one day of a healthy diet. This model offers opportunities for identifying early mechanisms and potential treatments of dietary saturated fat induced insulin resistance.

We have previously shown that a higher 24-h respiratory quotient (24-h RQ) predicts greater ad-libitum food intake and that nighttime eaters (NE) ingested more calories during an in-patient food intake study and gained more weight over time. We investigated whether 24-h RQ was higher in individuals who exhibited nighttime eating behavior. Healthy nondiabetic Pima Indians (PI; n = 97, 54 male/43 female) and whites (W; n = 32, 22 male/10 female) were admitted to our Clinical Research Unit. After 3 days of a weight maintaining diet, 24-h energy expenditure (24-h EE), 24-h RQ, rates of carbohydrate (CHOX) and lipid oxidation (LIPOX), and spontaneous physical activity (SPA) were measured in a metabolic chamber whereas volunteers were in energy balance and unable to consume excess calories. Individuals subsequently ate ad libitum from a computerized vending machine for 3 days with amount and timing of food intake recorded. Fifty-five individuals (36%; 39 PI, 16 W) were NE, who ate between 11 PM and 5 AM on at least one of the 3 days on the vending machines. There were no differences in BMI or percentage body fat between NE and non-NE. After adjusting for age, sex, race, fat-free mass, fat mass, and energy balance, NE had a higher 24-h RQ (P = 0.01), higher CHOX (P = 0.009), and lower LIPOX (P = 0.03) and higher 24-h SPA (P = 0.04) compared to non-NE. There were no differences in adjusted 24-h EE or sleep RQ between the groups. Individuals with nighttime eating behavior have higher 24-h RQ, higher CHOX and lower LIPOX, a phenotype associated with increased food intake and weight gain.

Background: Accurate assessment of energy intake is difficult but critical for the evaluation of eating behavior and intervention effects. Consequently, methods to assess ad libitum energy intake under controlled conditions have been developed. Objective: Our objective was to evaluate the reproducibility of ad libitum energy intake with the use of a computerized vending machine system. Design: Twelve individuals (mean ± SD: 36 ± 8 y old; 41 ± 8% body fat) consumed a weight-maintaining diet for 3 d; subsequently, they self-selected all food with the use of a computerized vending machine system for an additional 3 d. Mean daily energy intake was calculated from the actual weight of foods consumed and expressed as a percentage of weight-maintenance energy needs (%WMEN). Subjects repeated the study multiple times during 2 y. The within-person reproducibility of energy intake was determined through the calculation of the intraclass correlation coefficients (ICCs) between visits. Results: Daily energy intake for all subjects was 5020 ± 1753 kcal during visit 1 and 4855 ± 1615 kcal during visit 2. There were no significant associations between energy intake and body weight, body mass index, or percentage body fat while subjects used the vending machines, which indicates that intake was not driven by body size or need. Despite overconsumption (%WMEN = 181 ± 57%), the reproducibility of intake between visits, whether expressed as daily energy intake (ICC = 0.90), %WMEN (ICC = 0.86), weight of food consumed (ICC = 0.87), or fat intake (g/d; ICC = 0.87), was highly significant (P < 0.0001). Conclusion: Although ad libitum energy intake exceeded %WMEN, the within-person reliability of this intake across multiple visits was high, which makes this a reproducible method for the measurement of ad libitum intake in subjects who reside in a research unit. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00342732","term_id":"NCT00342732"}}NCT00342732.

The antiglycemic effects of vinegar have been known for more than a century and have been demonstrated in animal as well as human studies. Although the exact mechanism of vinegar action is not known, several possibilities have been proposed including suppression of disaccharidase activity, delayed gastric emptying, enhanced glucose uptake in the periphery and conversion to glycogen, and increased satiety. We hypothesized that by suppressing endogenous insulin secretion, we could estimate the glucose absorption rate from an oral carbohydrate load and determine the effects of vinegar ingestion on this rate. To do so, 5 subjects had 4 studies at 1-week intervals, randomly receiving placebo twice (60 mL water) and vinegar twice (20 mL apple cider vinegar, 40 mL water), followed 2 minutes later by a meal of mashed potatoes (0.75 g carbohydrate per kilogram body weight) that was consumed over 20 minutes. At the beginning of the meal, an oral octreotide/insulin suppression test (25-microg bolus octreotide; 180 minute infusion 5 mU/m(2) body surface area per minute regular human insulin, and 0.5 microg/min octreotide) was begun. Blood samples for insulin and glucose were drawn at 20-minute intervals. The oral octreotide/insulin suppression test suppressed endogenous insulin secretion for the first 100 minutes of the study. During this time, the rate of rise of glucose was modestly but significantly (P = .01) greater after vinegar ingestion compared to placebo, suggesting that vinegar does not act to decrease glycemia by interference with enteral carbohydrate absorption.

Offspring of women with diabetes during pregnancy are at increased risk of accelerated weight gain and diabetes, effects partly mediated by the in utero environment. Whether differences in energy intake can explain this increased risk is unknown. We compared diet composition, eating patterns, and physiological responses to a mixed meal in 63 nondiabetic children whose mothers developed diabetes either before (offspring of diabetic mothers, ODMs, n = 31, age 9.2 +/- 1.7 years, mean +/- s.d.) or after (offspring of prediabetic mothers, OPDMs, n = 32, 9.6 +/- 1.3 years) the pregnancy. After consuming a standardized diet for 3 days, participants ate ad libitum from a computer-operated vending machine stocked with foods they had rated favorably on a food preferences questionnaire. Mothers and children always ate together. A subset of 35 children underwent a meal test with blood draws to measure insulin and glucose. Children's energy intake was associated with age, sex, and percent body fat, and strongly with mother's energy intake (r = 0.57, P < 0.0001). After adjustment for these variables, there were no differences between ODM and OPDM in energy intake or diet composition. The insulin area under the curve (AUC) following the meal test was significantly correlated with total energy intake but not after adjustment for the above covariates. Differences in energy intake were not observed between ODM and OPDM. Mother's energy intake was a significant predictor of children's energy intake. These findings indicate that in this subset of children in a controlled in-patient setting, maternal influence may outweigh intrauterine effects on energy intake.

Aging diminishes hormone secretion and target cell responsiveness, possibly due to loss of cell membrane fluidity or alteration of membrane phospholipids affecting signal transduction. We investigated whether a high omega-3 polyunsaturated fatty acid diet would improve endocrine function in 6 men and 6 women aged over 60 years. Subjects first ate an isocaloric control diet for 6 weeks, followed by an 8-week experimental diet, which included 720 g of fatty fish weekly plus 15 ml of sardine oil daily. In the last week, we measured RBC membrane fatty acids on each diet, performed pituitary, adrenal, hepatic, and Leydig cell endocrine provocative testing, and assayed selected cytokines. We also assessed insulin sensitivity utilizing octreotide insulin suppression testing and assessed free fatty acid (FFA) responses to isoproteronol. Insulin sensitivity increased significantly after 8 weeks on the omega-3 diet and FFA responses trended lower. Serum C-reactive protein was significantly reduced and a trend towards lower IL-6 was noted. No differences were found in other metabolic parameters, adiponectin levels, or hormone responses. We conclude that, in older people, high omega-3 consumption increases insulin sensitivity, may reduce FFA mobilization by catecholamines, and reduces inflammatory markers, but did not alter endocrine responsiveness after 8 weeks.

Background: We previously found that obese men have less activation in the left dorsolateral prefrontal cortex (LDLPFC) in response to a meal than do lean men, which indicates an association between this altered neuronal response and the pathophysiology of obesity. Objectives: The objectives of the study were to extend this finding in obese women and to investigate activity in this region in women with a history of severe obesity who have successfully lost weight (ie, formerly obese women, sometimes called postobese women). Design: We reanalyzed previously collected data to compare post-meal (after receiving a liquid meal) with premeal (after a 36-h fast) regional cerebral blood flow, a marker of neuronal activity, by using 15 O-water positron emission tomography in 10 lean [26 ± 6% body fat (BF)], 9 obese (39 ± 3%BF) and 8 formerly obese (28 ± 4%BF) right-handed women. Data were analyzed by using a 2-level, random-effect analysis of variance. Results: The regional cerebral blood flow in the LDLPFC differed in response to the meal across the 3 groups (P < 0.001, uncorrected for multiple comparisons). Post hoc group comparisons showed that obese women had significantly less activation in this area than did lean and formerly obese women. No significant difference between formerly obese and lean women was found. Conclusions: These results extend our previous findings, indicating that obese women have less activation in the LDLPFC in response to a meal than do lean or formerly obese women. Neuronal activity in this region did not differ significantly between the latter 2 groups. Longitudinal studies are needed to determine whether these differences in neuronal activity change with or predict weight change.

Glucose exerts a dual action in the regulation of energy balance, consisting of inhibition of energy intake and stimulation of energy expenditure. Whether blood glucose affects long-term regulation of body weight in humans remains to be established. We sought to test the hypothesis that the post-challenge glucose response is a predictor of weight change.We performed a prospective analysis of the impact of glucose response to an oral glucose tolerance test (OGTT) and a mixed-meal test (MT) on subsequent changes in body weight (BW) on 253 Pima Indians (166 men and 87 women) with normal glucose regulation at baseline and follow-up (follow-up: 7 +/- 4 years). Main outcome measures included BW change (total, percent, and annual), plasma glucose and insulin concentrations during OGTT and MT [total and incremental areas under the curve (AUCs)], resting metabolic rate (RMR; indirect calorimetry), and insulin action (euglycemic-hyperinsulinemic clamp).Total and incremental glucose AUCs during the OGTT (but not the MT) were negatively associated with BW change (total, percent, and annual), both before and after adjusting for sex, age, initial BW, follow-up time, insulin action, RMR, fasting plasma glucose and insulin concentrations, and insulin response. Total and incremental glucose AUCs during the OGTT were independent determinants of final BW with age, initial BW, follow-up time, fasting plasma insulin concentrations, and RMR.Higher post-challenge glucose response protects against BW gain in subjects with normal glucose regulation. We propose that this action may be because of the effect of glucose on food intake and/or thermogenesis.

The diabetic intrauterine environment is a known risk factor for the development of diabetes in the offspring.We compared anthropometric and metabolic characteristics of 41 nondiabetic children whose mothers developed diabetes either before (ODM, n = 19, 9.3 +/- 1.1 yr) or after (OPDM, n = 22, 9.5 +/- 1.3 yr) the pregnancy of interest. Maternal diabetes status was established from OGTT results before, during, and after the pregnancy of interest.After consuming a standardized diet for 2 d, a mixed-meal breakfast was given after an overnight fast. Fasting concentrations and responses of plasma glucose and insulin were evaluated using linear regression analyses to assess potential independent determinants of plasma insulin concentration at each time point.After adjustment for age and sex, there were no differences between ODM and OPDM children for maternal age at diagnosis, height, weight, body mass index, BMI z score, or percent body fat (dual energy x-ray absorptiometry). After adjusting for age, sex, percent body fat, and the corresponding glucose level at each time point, ODM had a lower plasma insulin level at the 15-min time point during the meal test than OPDM (P = 0.01).A lower initial insulin response to a standard mixed-meal challenge can be detected in nondiabetic ODM compared with OPDM children as early as 9 yr of age. This response may be another indicator for an attenuated early insulin response and explain the increased risk for diabetes in these children.

To investigate whether dietary restraint, a landmark of successful dieting, is associated with specific patterns of brain responses to the sensory experience of food and meal consumption.Cross-sectional study of the brain's response to the sensory experience of food and meal consumption in nine successful dieters (age: 38+/-7 years, body fat (%): 28+/-3) and 20 non-dieters (age: 31+/-9 years, body fat (%): 33+/-9), all women.Changes in brain activity in response to the sensory experience of food and meal consumption were assessed by using positron emission tomography and (15)O water as a radiotracer. Body fatness was assessed by dual X-ray absorptiometry. Subjective ratings of hunger and fullness were measured by visual analogue scale. Dietary restraint, disinhibition and hunger were assessed by the Three Factor Eating Questionnaire.Successful dieters had a significantly higher level of dietary restraint compared to non-dieters. In response to meal consumption, successful dieters had a greater activation in the dorsal prefrontal cortex (DPFC), dorsal striatum and anterior cerebellar lobe as compared to non-dieters. In response to the same stimulation, the orbitofrontal cortex (OFC) was significantly more activated in non-dieters as compared to successful dieters. Dietary restraint was positively correlated with the response in the DPFC and negatively with the response in the OFC. The responses in the DPFC and OFC were negatively intercorrelated.Cortical areas involved in controlling inappropriate behavioral responses, such as the DPFC, are particularly activated in successful dieters in response to meal consumption. The association between the degree of dietary restraint and the coordinated neural changes in the DPFC and OFC raises the possibility that cognitive control of food intake is achieved by modulating neural circuits controlling food reward.

BACKGROUND: Estimating changes in weight from changes in energy balance is important for predicting the effect of obesity prevention interventions. OBJECTIVE: The objective was to develop and validate an equation for predicting the mean weight of a population of children in response to a change in total energy intake (TEI) or total energy expenditure (TEE). DESIGN: In 963 children with a mean (+/-SD) age of 8.1 +/- 2.8 y (range: 4-18 y) and weight of 31.5 +/- 17.6 kg, TEE was measured by using doubly labeled water. Log weight (dependent variable) and log TEE (independent variable) were analyzed in a linear regression model with height, age, and sex as covariates. It was assumed that points of dynamic balance, called "settling points," occur for populations wherein energy is in balance (TEE = TEI), weight is stable (ignoring growth), and energy flux (EnFlux) equals TEE. RESULTS: TEE (or EnFlux) explained 74% of the variance in weight. The unstandardized regression coefficient was 0.45 (95% CI: 0.38, 0.51; R(2) = 0.86) after including covariates. Conversion into proportional changes (time(1) to time(2)) gave the equation (weight(2)/weight(1)) = (EnFlux(2)/EnFlux(1))(0.45). In 3 longitudinal studies (n = 212; mean follow-up of 3.4 y), the equation predicted the mean follow-up measured weight to within 0.5%. CONCLUSIONS: The relation of EnFlux with weight was positive, which implied that a high TEI (rather than low physical activity and low TEE) was the main determinant of high body weight. Two populations of children with a 10% difference in mean EnFlux would have a 4.5% difference in mean weight.

Objective Dietary calcium intake, especially from dairy products, may have a protective effect against obesity. This study aimed to determine if calcium intake is associated with body weight and adiposity in Pima Indians, an obesity-prone population. Research Methods and Procedures Subjects were 65 Pima Indian adults (35 men/30 women, age 33±8 years [mean±standard deviation]) participating in a study of eating behavior and 78 Pima Indian children (36 boys/42 girls, age 10.4±0.3 years) participating in a study of childhood obesity. Height and weight were measured, and body composition was determined by dual-energy x-ray absorptiometry. Food intake in adults was assessed using the Block 1998 Food Questionnaire; food intake in children was assessed using a 24-hour recall with parental assistance. Results In adults, mean energy intake was 3,163±1,037 kcal/day, mean percentage of energy from fat was 41%±7%, and calcium intake was 914±333 mg/day. In children, mean energy intake was 1,988±733 kcal/day, mean percentage of energy from fat was 36%±9%, and calcium intake was 637±352 mg/day, half the recommended daily intake for this age group. There were no significant associations between calcium intake and body weight ( r =0.05, P =.71; r =0.04, P =.73), body fat ( r =0.16, P =.19; r =0.12, P =.42), or body mass index ( r =0.01, P =.97; r =0.04, P =.77) in either adults or children, respectively. Discussion One explanation for the lack of association between reported calcium intake and body size in Pima Indians may be that the high-fat, high-energy diet consumed by the population overwhelmed the "anti-obesigenic" effect of calcium. Conclusions We were unable to find an association between calcium intake and body size or adiposity in Pima Indian adults and children. Although the essentiality of calcium to bone health is well established, the role of calcium and dairy product intake in obesity and weight management remains uncertain.

Given the increasing rates of both childhood obesity and type 2 diabetes (T2DM), we investigated whether maternal diabetes status during pregnancy is a determinant of risk factors associated with T2DM or cardiovascular disease in offspring during childhood.Forty-two Pima Indians, aged 7-11 yr, were identified retrospectively from maternal oral glucose tolerance tests as offspring of a diabetic pregnancy (22 ODM, eight males, 14 females) or offspring born before the mother developed diabetes (20 PRE, 12 males, eight females). SETTING/MAIN OUTCOME MEASURES: Weight, height, body mass index, percent body fat, blood pressure, and fasting concentrations of glucose, insulin, hemoglobin A1c (HbA1c), total cholesterol, triglycerides, and high-density lipoprotein-cholesterol were measured while staying in an in-patient clinical research unit and compared in cross-sectional analyses.After adjustment for age and gender, ODM had significantly higher concentrations of HbA1c (ODM = 5.7 +/- 0.4, PRE = 5.0 +/- 0.4%, P = 0.002), higher systolic (SBP) blood pressure (ODM = 118 +/- 13, PRE = 107 +/- 10 mm Hg; P = 0.02), and lower concentrations of high-density lipoprotein (ODM = 41 +/- 9, PRE = 48 +/- 6 mg/dl, P = 0.03) than PRE. Maternal diabetes status during pregnancy persisted as a significant determinant of SBP (beta = 7.50, P = 0.03) and HbA1c (beta = 0.43, P = 0.002), independent of age, gender, and percent body fat.Intrauterine exposure to diabetes is a significant determinant of higher SBP and HbA1c during childhood, independent of adiposity and a genetic predisposition to T2DM. These data suggest that in utero exposure to diabetes confers an additional independent risk for the development of T2DM and/or cardiovascular disease later in life.

Background: Taste preferences for highly palatable foods rich in sugar and fat may underlie the current epidemic of obesity. Objective: This study aimed to determine whether the hedonic response to sweet and creamy solutions differs between whites and Pima Indians and whether a preference for these tastes predicts weight gain. Design: One hundred twenty-three Pima Indian and 64 white volunteers taste tested solutions of nonfat milk (0.1% fat), whole milk (3.5% fat), half and half(11.3% fat), and cream (37.5% fat) containing 0%, 5%, 10%, or 20% sugar by weight. Solutions were rated for perceived sweetness, creaminess, and pleasantness (hedonic response) on a 100-mm visual analogue scale. Follow-up body weight was measured in 75 Pima Indians 5.5 ± 3.0 y (x ± SD) after baseline taste testing. Results: The Pima Indians had a significantly (P = 0.006) lower hedonic response than did the whites (repeated-measures analysis of variance). Neither body size (P = 0.56) nor adiposity (P = 0.86) was a significant predictor of the hedonic response. There was a positive correlation (r = 0.28, P = 0.01) between the maximal hedonic response at baseline and subsequent weight gain in the Pima Indians. Conclusion: Although the Pima Indians liked sweet and creamy solutions less than the whites did, a heightened hedonic response for these solutions among the Pima Indians was associated with weight gain.

OBJECTIVE—To determine whether measures of physical activity are related to an insulin sensitivity index ([ISI] 104/fasting insulin × glucose) independent of weight or adiposity in children. RESEARCH DESIGN AND METHODS—We conducted a longitudinal study of 90 Pima Indian children (39 boys and 51 girls) at 5 and 10 years of age measuring adiposity (dual-energy X-ray absorptiometry), physical activity behavior (questionnaire: number of activities per week [ACT], average hours per week [TIME]), and energy expenditure (doubly labeled water: physical activity level [PAL]). RESULTS—In cross-sectional analyses, ACT was correlated with ISI at 5 years of age (r = 0.24, P = 0.02) and at 10 years of age (r = 0.21, P = 0.05), but these relationships were not independent of weight or adiposity. PAL was correlated with ISI at 10 years of age (r = 0.39, P = 0.03) but was not independent of weight or adiposity. Longitudinally, ISI decreased from 5 to 10 years of age, and increases in weight and adiposity were associated with decreases in ISI (r = −0.51 and −0.41, respectively; both P < 0.0001). ACT decreased from 5 to 10 years of age, but children who had smaller decreases in ACT had smaller decreases in ISI, independent of increases in weight or adiposity (partial r = 0.22, P = 0.04 adjusted for either weight or adiposity). CONCLUSIONS—These data suggest that early establishment and maintenance of an active lifestyle can have a beneficial effect on ISI that is partially independent of changes in weight or adiposity. This is particularly relevant considering the current epidemics of both obesity and type 2 diabetes in children.

Ghrelin, a recently discovered GH secretagogue with orexigenic effects, is proposed to be a regulator of energy balance. To test whether fasting plasma ghrelin concentrations predict future gain in body weight or adiposity, we measured weight, height, body mass index (BMI), percentage of body fat (by dual energy x-ray absorptiometry), and fasting plasma concentrations of ghrelin, insulin, and glucose in 10-yr-old Pima Indians (n = 40; 13 males and 27 females) and subsequent weight, height, and BMI 1.7 +/- 0.6 yr later. At baseline, the fasting plasma ghrelin concentration was negatively associated with height (r = -0.52; P = 0.0006), weight, (r = -0.37; P = 0.02), percentage of body fat (r = -0.33, P = 0.04), and fasting plasma insulin concentration (r = -0.41; P = 0.01). In multiple regression models adjusting for gender and fasting plasma insulin, the fasting plasma ghrelin concentration was an independent determinant of height (beta = -13.9; P = 0.02), but not weight or BMI. Prospectively, the baseline fasting plasma ghrelin concentration was not an independent determinant of the relative rate of increase in weight, height, or adiposity. In conclusion, the fasting plasma ghrelin concentration was lower in taller and fatter Pima Indian children, but did not independently predict baseline weight, adiposity, or future growth rates. These data do not support a direct relationship between the fasting plasma ghrelin concentration and subsequent relative changes in height or weight in growing children.

Prader-Willi syndrome (PWS) is a genetic disorder occurring in 1 of 10,000 –16,000 live births and is characterized by excessive appetite with progressive massive obesity as well as short stature and mental retardation. Most patients have GH deficiency and hypogonadotropic hypogonadism. The causes of the hyperphagia and abnormal GH secretion are unknown. To determine whether ghrelin, a novel GH secretagogue with orexigenic properties, is elevated in PWS, we measured fasting plasma ghrelin concentration; body composition (dualenergy x-ray absorptiometry); and subjective ratings of hunger (visual analog scale) in seven subjects (6 males and 1 female; age, 26 7 yr; body fat, 39 11%, mean SD) with PWS (diagnosis confirmed by genetic test) and 30 healthy subjects (reference population, 15 males and 15 females; age, 32 7 yr; body fat, 36 11%) fasted overnight. All subjects were weight stable for at least 6 months before admission to the study. The mean plasma ghrelin concentration was higher in PWS than in the reference population (307 164 vs. 109 24 fmol/ml; P < 0.001), and this difference remained significant after adjustment for percentage body fat (P < 0.001). Plasma ghrelin was also higher (P 0.0004) in PWS than in five healthy subjects fasted for 36 h. A positive correlation was found between plasma ghrelin and subjective ratings of hunger (r 0.71; P 0.008). Furthermore, in subjects with PWS, the concentration of the hormone was not different before and after ingestion of 2 ml and a satiating amount of the same liquid meal (ghrelin concentrations: 307 164 vs. 306 205 vs. 260 134 fmol/ml, respectively; ANOVA for repeated measures, P 0.56). This is the first evidence that ghrelin, a novel orexigenic hormone, is elevated in subjects with PWS. Our finding suggests that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS. (J Clin Endocrinol Metab 87: 5461–5464, 2002)

Objective. To assess the effect of energy expenditure, including resting metabolic rate (RMR), total energy expenditure (TEE), and activity energy expenditure (AEE), as well as substrate oxidation (respiratory quotient [RQ]), on the development of obesity in a large cohort of Native American children with a high propensity for obesity. Methods. During the summer months of 1992 to 1995 and again 5 years later, 138 (65 boys and 73 girls) 5-year-old Pima Indian children were studied. At baseline and follow-up, height and weight were measured; body composition was assessed with the use of 18O dilution; RMR and RQ were assessed with the use of indirect calorimetry; TEE was measured with the use of the doubly-labeled water method; and AEE was calculated (TEE − [RMR + 0.1 × TEE]). In addition, an activity questionnaire was used to assess participation in sporting activities as well as television viewing during the previous year. Linear regression models were used to assess the effects of the baseline variables on the development of obesity. Results. Pima Indian children were markedly overweight at both 5 and 10 years of age. Cross-sectionally, percentage of body fat and body weight at 5 and 10 years of age were negatively correlated with sports participation and positively correlated with television viewing. Most important, there was a marked change in the correlation between body size and activity between 5 and 10 years of age: at age 5 years, weight was positively correlated with AEE and PAL, but at age 10 years, the correlation with AEE was lost and that with PAL was negative. However, prospectively, none of the variables measured at baseline was a predictor of percentage of body fat at age 10 years after adjustment for percentage of body fat at age 5 years. Conclusions. At age 5 years, obesity is associated with decreased participation in sports and increased television viewing but not with a decreased PAL. At age 10 years, obesity is associated with decreased participation in sports, increased television viewing, and a decreased PAL, suggesting that a decrease in PAL in free-living conditions seems to follow, not precede, the development of obesity.

A polymorphism in FABP2 that results in an alanine-to-threonine substitution at amino acid 54 of the intestinal fatty acid-binding protein (IFABP) is associated with insulin resistance in Pima Indians. In vitro, the threonine form (Thr54) has a higher binding affinity for long-chain fatty acids than does the alanine form (Ala54). We tested whether this polymorphism affected metabolic responses to dietary fat, in vivo. Eighteen healthy Pima Indians, half homozygous for the Thr54 form of IFABP and half homozygous for the Ala54 form, were studied. The groups were matched for sex, age, and body mass index. Plasma triglyceride, nonesterified fatty acid (NEFA), glucose, and insulin responses were measured after a mixed meal (35% of daily energy requirements, 50 g of fat) and after a high fat challenge (1362 kcal, 129 g of fat). NEFA concentrations were ∼15% higher after the mixed meal and peaked earlier and were ∼20% higher at 7 h in response to the high fat test meal in Thr54 homozygotes compared with Ala54 homozygotes. Insulin responses to the test meals tended to be higher in Thr54 homozygotes, but glucose and triglyceride responses were not different. The results of this study suggest that the Thr54 form of IFABP is associated with higher and prolonged NEFA responses to dietary fat in vivo. Higher NEFA concentrations may contribute to insulin resistance and hyperinsulinemia in individuals with this allele.—Pratley, R. E., L. Baier, D. A. Pan, A. D. Salbe, L. Storlien, E. Ravussin, and C. Bogardus. Effects of an Ala54Thr polymorphism in the intestinal fatty acid-binding protein on responses to dietary fat in humans. J. Lipid Res. 2000. 41: 2002–2008.

Knowledge of how the brain contributes to the regulation of food intake in humans is limited. We used positron emission tomography and measures of regional cerebral blood flow (rCBF) (a marker of neuronal activity) to describe the functional anatomy of satiation (i.e., the response to a liquid meal) in the context of extreme hunger (36-h fast) in 11 obese (BMI > or =35 kg/m2, age 27+/-5 years, weight 115+/-11 kg, 38+/-7% body fat; mean +/- SD) and 11 lean (BMI < or =25 kg/m2, age 35+/-8 years, weight 73+/-9 kg, 19+/-6% body fat) men. As in lean men, satiation in obese men produced significant increases in rCBF in the vicinity of the ventromedial and dorsolateral prefrontal cortex and significant decreases in rCBF in the vicinity of the limbic/paralimbic areas (i.e., hippocampal formation, temporal pole), striatum (i.e., caudate, putamen), precuneus, and cerebellum. However, rCBF increases in the prefrontal cortex were significantly greater in obese men than in lean men (P < 0.005). rCBF decreases in limbic/paralimbic areas, temporal and occipital cortex, and cerebellum were also significantly greater in obese men than in lean men (P < 0.005), whereas rCBF decreases in the hypothalamus and thalamus were attenuated in obese men compared with lean men (P < 0.05). This study raises the possibility that the brain responses to a meal in the prefrontal areas (which may be involved in the inhibition of inappropriate response tendencies) and limbic/paralimbic areas (commonly associated with the regulation of emotion) may be different in obese and lean men. Additional studies are required to investigate how these differential responses are related to the pathophysiology of obesity.

Relatively low rates of energy expenditure and fat oxidation predict body weight gain. Weight gain, in turn, is associated with increases in energy expenditure and fat oxidation that may oppose further weight change. In response to experimental weight gain induced by overfeeding, increases in energy expenditure and fat oxidation are overcompensatory, i.e. greater than predicted for the change in body composition. To determine whether such metabolic adaptation occurs in response to spontaneous long term weight change, we conducted a longitudinal study in which 24-h energy expenditure (24-EE) and 24-h respiratory quotient (24-RQ; i.e. fat to carbohydrate oxidation) were repeatedly measured in 102 Pima Indians at baseline and after a mean follow-up of 3.6 +/- 2.7 yr, during which changes in body weight varied widely (-21 to +28 kg). We found that changes in 24-EE and 24-RQ in response to weight change were related to the amount of weight change, even after adjustment for body composition (partial r = 0.23 and -0.30, respectively; both P < 0.05). For a 15-kg weight gain, the increases in 24-EE (+244 Cal/day) and 24-h fat oxidation (+152 Cal/day) were 33 and 53 Cal/day greater than predicted from the cross-sectional relationship between both measures and body weight. Changes in 24-EE and 24-RQ varied substantially among individuals. Thus, on the average, spontaneous long term weight changes are accompanied by small metabolic adaptations in both energy expenditure and fat oxidation. The metabolic responses to weight changes are highly variable among individuals, however.

Weight loss is common among patients with Huntington's disease (HD), although the mechanisms contributing to this phenomenon are not known. We measured 24-hour sedentary energy expenditure (24-hour EE) and sleeping metabolic rate (SMR) in a human respiratory chamber in 17 patients with mild to moderate HD and 17 control subjects matched for age, sex, and body mass index. Total energy expenditure was measured during 7 days in free-living conditions, using the doubly labeled water technique. Body weight, fat mass, and fat-free mass (measured by dual-energy x-ray absorptiometry) were similar in patients with HD and control subjects. Twenty-four-hour EE was 14% higher in HD patients than controls in absolute terms (2,038+/-98 vs 1,784+/-68 kcal/24 hours) and after adjustment for age, sex, fat mass, and fat-free mass (1,998+/-45 vs. 1,824+/-45 kcal/24 hours). In contrast, SMR and total energy expenditure were similar in patients and controls both in absolute terms (1,314+/-38 vs 1,316+/-42 and 2,402+/-102 vs. 2,373+/-98 kcal/24 hours, respectively) and after adjustment. Spontaneous physical activity measured by radar in the chamber and the ratio of 24-hour EE to SMR were significantly higher in HD patients than controls (11.4+/-1.4 vs 6.1+/-0.6% and 1.54+/-0.05 vs 1.36+/-0.03, respectively). In the group as a whole, 24-hour EE/SMR correlated with spontaneous physical activity. Among HD patients, both 24-hour EE/SMR and spontaneous physical activity correlated with the severity of chorea, but SMR and total energy expenditure did not. There were no differences in reported energy intake during 7 days in patients with HD compared with controls. The results of this study indicate that sedentary energy expenditure is higher in patients with HD than in controls in proportion to the severity of the movement disorder. Total free-living energy expenditure is not higher, however, because patients with HD appear to engage in less voluntary physical activity.

The central role of the hypothalamus in the origination and/or processing of feeding-related stimuli may be modulated by the activity of other functional areas of the brain including the insular cortex (involved in enteroceptive monitoring) and the prefrontal cortex (involved in the inhibition of inappropriate response tendencies). Regional cerebral blood flow (rCBF), a marker of neuronal activity, was measured in 11 healthy, normal-weight men by using positron emission tomography in a state of hunger (after 36-h fast) and a state of satiation (after a liquid meal). Hunger was associated with significantly increased rCBF in the vicinity of the hypothalamus and insular cortex and in additional paralimbic and limbic areas (orbitofrontal cortex, anterior cingulate cortex, and parahippocampal and hippocampal formation), thalamus, caudate, precuneus, putamen, and cerebellum. Satiation was associated with increased rCBF in the vicinity of the ventromedial prefrontal cortex, dorsolateral prefrontal cortex, and inferior parietal lobule. Changes in plasma insulin concentrations in response to the meal were negatively correlated with changes in rCBF in the insular and orbitofrontal cortex. Changes in plasma free fatty acid concentrations in response to the meal were negatively correlated with changes in rCBF in the anterior cingulate and positively correlated with changes in rCBF in the dorsolateral prefrontal cortex. In conclusion, these findings raise the possibility that several regions of the brain participate in the regulation of hunger and satiation and that insulin and free fatty acids may be metabolic modulators of postprandial brain neuronal events. Although exploratory, the present study provides a foundation for investigating the human brain regions and cognitive operations that respond to nutritional stimuli.

Almost one-quarter of U.S. children are now obese, a dramatic increase of over 20% in the past decade. It is intriguing that the increase in prevalence has been occurring while overall fat consumption has been declining. Body mass and composition are influenced by genetic factors, but the actual heritability of juvenile obesity is not known. A low physical activity (PA) is characteristic of obese children and adolescents, and it may be one cause of juvenile obesity. There is little evidence, however, that overall energy expenditure is low among the obese. There is a strong association between the prevalence of obesity and the extent of TV viewing. Enhanced PA can reduce body fat and blood pressure and improve lipoprotein profile in obese individuals. Its effect on body composition, however, is slower than with low-calorie diets. The three main dietary approaches are: protein sparing modified fast, balanced hypocaloric diets, and comprehensive behavioral lifestyle programs. To achieve long-standing control of overweight, one should combine changes in eating and activity patterns, using behavior modification techniques. However, the onus is also on society to reduce incentives for a sedentary lifestyle and over-consumption of food. To address the key issues related to childhood weight management, the American College of Sports Medicine convened a Scientific Roundtable in Indianapolis.

The usefulness of serum insulin-like growth factor 1 (IGF 1 ) determinations as an estimate of nutritional status in HIV-infected individuals is unclear. Serum IGF 1 levels were correlated with measurements of total body potassium (TBK), a measure of body cell mass, and changes in TBK in 32 subjects including 18 AIDS patients, 4 HIV seronegative and 5 seropositive asymptomatic homosexual male controls, and 5 HIV seronegative heterosexual controls. Longitudinal follow-up of body composition including measurements of TBK, body fat content, serum IGF 1 , and albumin concentrations was determined in the AIDS group and in demonstrated subgroups of AIDS patients with progressive depletion, stable body composition, and those undergoing repletion. IGF 1 levels correlated with serum albumin levels (r=0.66, p 1 levels were lower in the AIDS groups than in the control groups (p 1 levels may be a convenient way to predict the course of nutritional status in an HIV-infected individual.

As the battle of the bulge seems headed toward becomingthe “culture war of the new century,” with state legislaturesdiscussing and/or passing bills to ban “junk food” fromschools and trial lawyers gearing up to file lawsuits againstthe food industry, much as they did against the tobaccoindustry (1,2), it is very likely that the scientific communitywill come under increasing pressure to answer the questionof why we eat so much.Rare forms of obesity caused by defects of the energyhomeostasis regulatory mechanisms operating in the sub-conscious brain have been described in animals and humans(3). However, eating is as much a means of achievingenergy balance as it is a form of pleasure and reward. Thismakes the drive to eat one of the most powerful urges ofanimal and human behavior.

Malnutrition is an important consequence of infection with the human immunodeficiency virus (HIV); involuntary weight loss greater than 10% is one criterion that the Centers for Disease Control and Prevention uses for the diagnosis of acquired immunodeficiency syndrome (AIDS). This study was designed to determine whether nutrition intervention in a group of adult, HIV-positive outpatients affected weight maintenance.We undertook a retrospective review of 175 patient charts from the AIDS Reproductive Health Clinic and the Center for Special Studies at The New York Hospital. Forty-nine charts were excluded because the patient expressed a desire to reduce weight, discontinued medical care, or died. Seven charts were eliminated because of missing data. In the remaining patients (n = 119), weights were recorded for the initial clinic contact and for a follow-up visit at least 6 months later. Nutrition intervention completed by a registered dietitian was indicated on 42 patient charts (intervention group); intervention included dietary assessment, intake analysis, appropriate counselling, follow-up, and provision of supplements as needed. The remaining 77 charts did not indicate nutrition intervention; this group was called the nonintervention group. Differences between the intervention and nonintervention groups were analyzed using the two-tailed Fisher exact test and the Mann-Whitney nonparametric test.Forty-two subjects (35% of the total) recieved nutrition intervention, including all of those with gastrointestinal problems (n = 10) and wasting (n = 11). Individuals in the intervention group gained a significant (P.02) 1.2 +/- 11.4 lb (mean +/- standard deviation; median = +3 lb) compared with those in the nonintervention group who lost a mean of 3.5 +/- 12.8 lb (median = -4 lb). Twenty-six subjects (63%) in the intervention group maintained or gained weight compared with 32 subjects (42%), in the nonintervention group.The results of this study suggest that nutrition intervention in HIV-infected persons can improve nutritional status and may lead to an enhanced ability to fight infection.

Depressed serum somatomedin C levels have been suggested by others as an early indicator of selenium (Se) toxicity. In both human and animal studies, somatomedin C levels were lower in Se supplemented as compared to control subjects. The present study examined Se and somatomedin C levels in 44 adult long-term residents of seleniferous areas in South Dakota. Serum Se (SSe) and whole blood Se (WBSe) levels were analyzed by GC/MS. Toenail Se (TSe) was measured by neutron activation analysis. Somatomedin C was analyzed by RIA assay. Subjects were divided into 3 groups based on the following criteria: group I, SSe 240, WBSe >400 ng/ml. Data were pooled across gender (20 males, 24 females). Somatomedin C levels were not different despite greater than 50% differences in SSe, WBSe, and TSe levels among the groups. In these subjects, somatomedin C was not a sensitive index of elevated Se exposure.

Because selenium (Se) compounds may have anticarcinogenic properties, noninvasive techniques to monitor Se status are needed. Hair and nails have been suggested, but earlier work by us showed that their Se content is a function of the amount ingested, chemical form, methionine intake, and growth rate. Here we report that the Se in hair and nails can also be influenced by the concurrent intake of certain toxic elements. Male weanling rats were fed diets containing 2.0 ppm Se as Na 2 SeO 4 for 4 weeks. Elements were added to the water of 5 groups of rats as follows: none, 10 ppm As as sodium arsenite, 10 ppm Hg as mercuric chloride, 10 ppm Tl as thallium acetate, and 10 ppm Cd as cadmium chloride. Control rats received diets containing 0.1 ppm Se as Na 2 SeO 4 and distilled water. Hair and nail Se levels were significantly decreased by administration of As, and As decreased red cell, plasma, and kidney Se contents as well. In contrast, Hg decreased hair and nail, but increased plasma, liver, muscle, bone, colon, and kidney Se contents. Tl decreased hair but increased liver and kidney Se content. Cd had no effect on hair or nail Se content but decreased red cell Se levels. Toxic elements have tissue-specific effects on body pools of Se that are not well-reflected in changes of hair and nail Se contents.

Background: Ghrelin has a short-term orexigenic effect but may also be a marker of food intake over time. We previously found an inverse association between ghrelin concentrations and food intake. Objectives: The objectives were to determine whether the fasting plasma ghrelin concentration is related to food intake and whether the previous day’s intake predicts the suppression of ghrelin. Design: Sixty-nine nondiabetic adults (40 men) aged 33 6 9 y were studied as inpatients at a Clinical Research Center. After 6 d of consuming a maintenance diet, the subjects self-selected their food from our vending machine system for 3 d. Total plasma ghrelin concentrations were measured every morning during the vending machine period. Results: The fasting ghrelin concentration was negatively correlated with body mass index (r ¼ 20.31, P ¼ 0.016) and weight (r ¼ 20.26, P ¼ 0.044). Mean morning ghrelin concentrations remained constant (149 6 59, 152 6 60, 148 6 61, and 145 6 59 pg/mL on days 1, 2, 3, and 4, respectively) even though the subjects overate while using the vending machines (160 6 42% of weightmaintenance needs). No associations were found between daily ghrelin concentrations and subsequent food intake on any day (day 1: r ¼ 20.04, P ¼ 0.76; day 2: r ¼ 20.01, P ¼ 0.95; day 3: r ¼ 20.11, P ¼ 0.38). Suppression of total ghrelin concentrations was not associated with the previous day’s intake or with subsequent food intake. Conclusion: Morning plasma ghrelin concentrations do not affect acute increases in food intake. This trial was registered at clinicaltrials.gov as NCT00342732. Am J Clin Nutr 2009;89:801–6.

Background: Nighttime food intake has rarely been studied in inpatient settings and only one study observed a relation between self-reported nighttime eating and weight gain. Objective: We investigated the prevalence of nighttime eating and its effect on weight change. Design:HealthynondiabeticPimaIndians(n117;67M,50F)and whites(n43;29M,13F)wereadmittedtoaclinicalresearchunit. After consuming a standardized diet for 3 d, participants ate ad libitum from a computer-operated vending machine that recorded the time of food selection. Energy intake was calculated as mean kcal/d. Follow-up weight was available for 94 volunteers. Results: Fifty-five subjects (36%) were nighttime eaters (NEs; persons who ate between 2300 and 0500 on 1 of the 3 d). Prevalence was similar among whites and Pima Indians (37% and 35%, respectively). There were no significant differences in body mass index or percentage body fat between NEs and non-NEs. NEs consumed morecaloriesperday(4758)thandidnon-NEs(4244;P0.02),but the percentage of calories from macronutrients did not differ. NEs consumed 15% (690 kcal) of their daily energy during nighttime episodes. After control for baseline weight and follow-up time (x SD:3.41.8y),NEs(n29)gainedmoreweight(6.2kg)thandid non-NEs (n 65; 1.7 kg; P 0.03). Conclusions: Nighttime eating was common, and it predicted weight gain. It remains to be determined whether this behavior indicates abnormal sleep patterns leading to nighttime wakefulness and food intake in those prone to weight gain. Am J Clin Nutr 2008;88:900–5.

Although the inhibitory effect of caloric restriction on tumorigenesis is substantial and well known, the pertinent mechanisms remain to be determined. We recently suggested that the risk of cancer may be directly related to the total number of dividing cells within an affected organ. This study evaluates the effects of early caloric restriction on the cellular growth of the colon. The experiment began one day postpartum and ended six weeks later with the killing of all animals. It consisted of two consecutive periods: a) three weeks of suckling and b) three weeks postweaning. Animals whose food was restricted only during the suckling period showed normal colons when killed at six weeks. Caloric restriction (40%) for three weeks postweaning resulted in colons of lower weight with fewer cells (less total DNA) and reduced total DNA synthesis [( 3H]thymidine uptake, dpm/colon) when compared with animals fed ad libitum postweaning. Conversely, only rats fed ad libitum from birth through the first three weeks after weaning demonstrated an increase (21%) in the rate of DNA synthesis (dpm/mg DNA) compared with other animals. In addition, the colonic crypts showed no differences in the number of cells or the number of dividing cells, as determined by autoradiography. By contrast, the total number of crypts (and/or the number of mucosal cells between crypts) are reduced, and hence the total number of colonic mucosal cells dividing at any given time are similarly decreased. The reduced number of dividing cells in the colons of these animals (i.e., those restricted postweaning) could explain previous data suggesting that they are resistant to the induction of colon cancer.

Objective: To explore the potential role of the endogenous peptide YY (PYY) in the long-term regulation of body weight and energy homeostasis. Research Methods and Procedures: Fasting and postprandial plasma PYY concentrations were measured after an overnight fast and 30 to 180 minutes after a standardized meal in 29 (21 men/8 women) non-diabetic subjects, 16 of whom had a follow-up visit 10.8 ± 1.4 months later. Ratings of hunger and satiety were collected using visual analog scales. Resting metabolic rate (RMR) (15-hour RMR) and respiratory quotient (RQ) were assessed using a respiratory chamber. Results: Fasting PYY concentrations were negatively correlated with various markers of adiposity and negatively associated with 15-hour RMR (r = −0.46, p = 0.01). Postprandial changes in PYY (area under the curve) were positively associated with postprandial changes in ratings of satiety (r = 0.47, p = 0.01). The maximal PYY concentrations achieved after the meal (peak PYY) were negatively associated with 24-hour RQ (r = −0.41, p = 0.03). Prospectively, the peak PYY concentrations were negatively associated with changes in body weight (r = −0.58, p = 0.01). Discussion: Our data indicate that the endogenous PYY may be involved in the long-term regulation of body weight. It seems that this long-term effect was not exclusively driven by the modulation of food intake but also by the control of energy expenditure and lipid metabolism.

The possible role of adiponectin, a protein uniquely produced by the adipose tissue and significantly reduced in obesity and other insulin-resistant states, in the regulation of energy expenditure (EE) is still poorly understood.The objective of the study was to investigate the relationship between total fasting plasma adiponectin concentrations and the various components of EE measured in a metabolic chamber in Pima Indians and to test whether body fat distribution may have a role in this association.This was a cross-sectional study.The study was an inpatient clinical research unit.Sixty nondiabetic Pima Indians (45 males and 15 females), aged 18-45 yr, spanning a wide range of adiposity (body mass index 19.6-46.2 kg/m(2)) participated in the study.Total fasting plasma adiponectin concentrations, EE (24-h respiratory chamber), insulin sensitivity (euglycemic-hyperisulinemic clamp), body composition (dual-energy x-ray absorptiometry), and body fat distribution (waist to thigh ratio) were the main outcome measures.Total fasting plasma adiponectin concentrations are negatively associated with sleep EE adjusted for sex, age, fat-free mass, and fat mass. This correlation is still significant, although attenuated, after inclusion of insulin-stimulated glucose disposal among the regressors and further attenuated when adjusted also for waist to thigh ratio.The decrease in total fasting plasma adiponectin concentrations that accompanies fat accumulation may be a mechanism to prevent further weight gain by decreasing insulin sensitivity and increasing energy expenditure.

Context: Elevated activities of serum enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and -glutamyltransferase (GGT), have been associated with obesity and insulin resistance (IR). ALT is an independent predictor of type 2 diabetes mellitus (T2DM) in adult Pima Indians, and GGT predicts T2DM in other adult populations. Objective: Our aim was to establish whether independent relationships exist between either adiposity or IR and hepatic enzymes in a group of Pima Indian children. Subjects and Methods: In a cross-sectional study, 44 children (22 males and 22 females; 7–11 yr old) were measured for weight (WT), height, percent body fat, and serum activities of ALT, AST, and GGT. Body mass index (kilograms per meter squared) was calculated. IR was calculated from fasting plasma concentrations of glucose and insulin using the homeostasis model assessment (HOMA-IR). Results: Hepatic enzymes were positively associated with obesity measures, fasting insulin, and HOMA-IR. GGT was additionally associated with serum lipids and white blood cell count. GGT, but not AST or ALT, was a significant determinant of HOMA-IR independently of age, sex, and WT, body mass index, or percent body fat. The model that accounted for the largest portion of the variance in HOMA-IR included WT ( 0.004; P 0.008) and GGT ( 0.20; P 0.004; total R 2 0.62; P 0.0001). Conclusion:Significantrelationshipsbetweenadiposityandhepatic enzyme activities exist during childhood in Pima Indians. Whether serum GGT activity predicts the development of T2DM in these children remains to be determined in follow-up studies. (J Clin Endocrinol Metab 91: 1419–1422, 2006)

Ghrelin is a novel GH secretagogue with orexigenic effects. We hypothesized that high fasting plasma ghrelin concentrations (FxGhr) might predict high ad libitum food intake. FxGhr were measured in 30 normoglycemic subjects: 15 Pima Indians (8 male/7 female; age, 32 +/- 7 yr; body weight, 87 +/- 21 kg; mean +/-sd) and 15 Caucasians (12 male/3 female, 36 +/- 8 yr, 94 +/- 26 kg) in energy balance for 3 d before testing. Subjects then self-selected their food ad libitum for the following 3 d. Mean daily energy intake (DEI) was calculated from the weight of foods consumed and expressed as a percent of weight maintenance energy needs. FxGhr were twice as high in Caucasians as in Pima Indians (103 +/- 53 vs. 52 +/- 18 fmol/ml, P0.001) and remained higher after adjustment for age, gender, and body weight (P0.0001). Neither DEI, nor percent of weight maintenance energy needs, nor percent of calories from fat differed between the races. In both groups, FxGhr were negatively correlated with DEI (r = -0.61, P = 0.01; r = -0.54, P = 0.04, respectively). These negative relationships were not explained by interindividual differences in age, gender, or body weight. This unexpected finding that low FxGhr predict ad libitum food intake suggests that the role of endogenous ghrelin in the regulation of energy homeostasis remains uncertain.

The sensory experience of food is a primary reinforcer of eating and overeating plays a major role in the development of human obesity. However, whether the sensory experience of a forthcoming meal and the associated physiological phenomena (cephalic phase response, expectation of reward), which prepare the organism for the ingestion of food play a role in the regulation of energy intake and contribute to the development of obesity remains largely unresolved. We used positron emission tomography (PET) and 15O-water to measure changes in regional cerebral blood flow (rCBF) and to assess the brain's response to the oral administration of 2 ml of a liquid meal (Ensure Plus, 1.5 kcal/ml) after a 36-h fast and shortly before consuming the same meal. Twenty-one obese (BMI35 kg/m2, 10M/11F, age 28 +/- 6 years, body fat 40 +/- 6%) and 20 lean individuals (BMI25 kg/m2, 10M/10F, age 33 +/- 9 years, body fat 21 +/- 7%) were studied. Compared to lean individuals, obese individuals had higher fasting plasma glucose (83.3 +/- 6.2 vs. 75.5 +/- 9.6 mg/dl; P = 0.0003) and insulin concentrations (6.1 +/- 3.5 vs. 2.5 +/- 1.7 microU/ml; P0.0001) and were characterized by a higher score of dietary disinhibition (i.e., the susceptibility of eating behavior to emotional factors and sensory cues, 5.7 +/- 3.6 vs. 3.5 +/- 2.7; P = 0.01) assessed by the Three Factor Eating Questionnaire. In response to the sensory experience of food, differences in rCBF were observed in several regions of the brain, including greater increases in the middle-dorsal insula and midbrain, and greater decreases in the posterior cingulate, temporal, and orbitofrontal cortices in obese compared to lean individuals (P0.05, after small volume correction). In a multiple regression model, percentage of body fat (P = 0.04), glycemia (P = 0.01), and disinhibition (P = 0.07) were independent correlates of the neural response to the sensory experience of the meal in the middle-dorsal insular cortex (R2 = 0.45). We conclude that obesity is associated with an abnormal brain response to the sensory aspects of a liquid meal after a prolonged fast especially in areas of the primary gustatory cortex. This is only partially explained by the elevated glycemia and high level of disinhibition which characterize individuals with increased adiposity. These results provide a new perspective on the understanding of the neuroanatomical correlates of abnormal eating behavior and their relationship with obesity in humans.

Objective. To assess the effects of body weight, body composition, parental obesity, and metabolic variables on the development of obesity in a large cohort of 5-year-old Native American children with a high propensity for obesity. Methods. During the summer months of 1992 to 1995 and again 5 years later, 138 (65 boys and 73 girls) 5-year-old Pima Indian children were studied. Height; weight; body composition; parental obesity; and fasting plasma insulin, glucose, and leptin concentrations were determined at baseline and follow-up. Linear regression models were used to assess the effect of the baseline variables on the development of obesity. Results. At both 5 and 10 years of age, Pima Indian children were heavier and fatter than an age- and gender-matched reference population. All anthropometric and metabolic variables tracked strongly from 5 to 10 years of age (r ≥ 0.70). The most significant determinant of percentage of body fat at 10 years of age was percentage of body fat at 5 years of age (R2 = 0.53). The combined effect of high maternal body mass index, elevated fasting plasma leptin concentrations, and low fasting plasma insulin concentrations at baseline explained an additional 4% of the total variance in adiposity at follow-up. Conclusions. Although parental obesity and metabolic variables such as insulinemia and leptinemia at baseline account for a small percentage of the variance in adiposity at follow-up, early childhood obesity is the dominant predictor of obesity 5 years later. These results suggest that strategies to prevent childhood obesity must be initiated at a very early age.

We used positron emission tomographic scanning of the brain and measures of regional cerebral blood flow to investigate the response of 44 right-handed people to the oral administration of 2 ml of a liquid formula meal after a 36 h fast (and shortly before the administration of a satiating amount of the same meal). Several areas of the left hemisphere were significantly more activated than the contralateral, including the frontal operculum, ventral insula, and piriform cortex. In contrast with reports of right-hemisphere dominance in chemosensory perception in non-hungry individuals, our study reveals a preferential activation of the left hemisphere when people who are very hungry are briefly exposed to the chemical and physical properties of a liquid meal. This raises the possibility that the physiological context in which perception takes place (i.e. extreme vs moderate vs no hunger) may importantly affect the brain representation of chemosensory stimuli.

The hypothalamus has a major role in the control of food intake. However, neurotracing studies have shown that the hypothalamus receives input from several other regions of the brain that are likely to modulate its activity. Of particular interest to the understanding of human eating behavior is the possible involvement of the cortex. Using positron emission tomography (PET), we generated functional brain maps of the neuroanatomical correlates of hunger (after a 36-h fast) and satiation (after oral administration of a liquid formula meal) in lean and obese subjects. Results in lean individuals indicate that the neuroanatomical correlates of hunger form a complex network of brain regions including the hypothalamus, thalamus, and several limbic/paralimbic areas such as the insula, hippocampal/parahippocampal formation, and the orbitofrontal cortex. Satiation was associated with preferentially increased neuronal activity in the prefrontal cortex. Our studies also indicate that the brain responses to hunger/satiation in the hypothalamus, limbic/paralimbic areas (commonly associated with the regulation of emotion), and prefrontal cortex (thought to be involved in the inhibition of inappropriate response tendencies) might be different in obese and lean individuals. In conclusion, neuroimaging of the human brain is proving to be an important tool for understanding the complexity of brain involvement in the regulation of eating behavior. PET studies might help to unravel the neuropathophysiology underlying human obesity.

Background: Sex differences in eating behavior are well documented, but it is not known whether these differences have neuroanatomical correlates. Recent neuroimaging studies have provided functional maps of the human cerebral areas activated in response to hunger and satiation. Objective: The objective of this study was to assess whether the brain's response to a meal is sex-specific. Design: Using positron emission tomography, we measured regional cerebral blood flow, a marker of neuronal activity, to investigate the functional neuroanatomy of hunger (36-h fast) and satiation (in response to a liquid meal) in 22 women and 22 men. Results: We observed extensive similarities, as well as some differences, between the sexes. In response to hunger, the men tended to have greater activation in the frontotemporal and paralimbic areas than did the women (P < 0.005). In response to satiation, the women tended to have greater activation in the occipital and parietal sensory association areas and in the dorso-lateral prefrontal cortex than did the men (P < 0.005); in contrast, the men tended to have greater activation in the ventrome-dial prefrontal cortex than did the women (P < 0.005). Conclusions: Despite extensive similarities in the brain responses to hunger and satiation between the men and women, our study showed sex-specific brain responses to a meal that indicate possible differences between men and women in the cognitive and emotional processing of hunger and satiation. This study provides a foundation for investigating the brain regions and cognitive processes that distinguish normal and abnormal eating behavior in men and women.

Objective. To determine the period of childhood in which weight relative to height increases in Pima Indian children and young adults in comparison with the general US population. Methods. Heights and weights of children in the Pima Indian population were derived from either clinical examinations conducted by the Department of Public Health Nursing (from 1–48 months of age), or from examinations in the National Institutes of Health longitudinal survey of health in the Pima population (for birth and ages 5–20 years), and compared with standards for the US population recently published by the National Center for Health Statistics. Results. Weight relative to height (weight-for-length in children aged Conclusion. Excessive weight gain occurs early in the Pima population with changes relative to reference values most marked in the first 6 months of life and between 2 and 11 years. Interventions toward primary prevention of obesity may need to be targeted at children rather than adults in this population.

Objective: To investigate the response of the brains of women to the ingestion of a meal. Research Methods and Procedures: We used measures of regional cerebral blood flow (rCBF), a marker of neuronal activity, by positron emission tomography to describe the functional anatomy of satiation, i.e., the response to a liquid meal in the context of extreme hunger (36-hour fast) in 10 lean (BMI ≤ 25 kg/m2; 32 ± 10 years old, 61 ± 7 kg; mean ± SD) and 12 obese (BMI ≥ 35 kg/m2; 30 ± 7 years old, 110 ± 14 kg) women. Results: In lean and obese women, satiation produced significant increases in rCBF in the vicinity of the prefrontal cortex (p < 0.005). Satiation also produced significant decreases in rCBF in several regions including the thalamus, insular cortex, parahippocampal gyrus, temporal cortex, and cerebellum (in lean and obese women), and hypothalamus, cingulate, nucleus accumbens, and amygdala (in obese women only; all p < 0.005). Compared with lean women, obese women had significantly greater increases in rCBF in the ventral prefrontal cortex and had significantly greater decreases in the paralimbic areas and in areas of the frontal and temporal cortex. Discussion: This study indicates that satiation elicits differential brain responses in obese and lean women. It also lends additional support to the hypothesis that the paralimbic areas participate in a central orexigenic network modulated by the prefrontal cortex through feedback loops.

Vagally-mediated hyperinsulinemia is a common abnormality in various rodent models of genetic and hypothalamic obesity that have a high propensity for type 2 diabetes. We hypothesized that Pima Indians, a population with a high prevalence of hyperinsulinemia, obesity, and type 2 diabetes also have an increased parasympathetic drive to the pancreas. To test this, we measured plasma concentrations of insulin and pancreatic polypeptide (PP), a surrogate marker of pancreatic vagal tone, in lean and obese Pima Indian and Caucasian children (n = 43, 26P/17C, 7 +/- 1 y) and adults (n = 92, 61P/31C, 31 +/- 5 y). Pima Indian children had approximately 2-fold higher fasting insulin and 57% higher fasting PP concentrations than age- and sex-matched Caucasian children (P.05). Although there was no difference in fasting PP concentration between Pima Indian and Caucasian adults, in response to a mixed meal, Pima Indians had a 51% higher early (30 minutes) PP concentration and 2-fold higher early insulin concentration than Caucasians (P.05). PP concentrations at 60 minutes and 120 minutes after the meal were also markedly higher in both lean and obese Pima Indians compared with lean and obese Caucasians. These results suggest that Pima Indians may have an increased parasympathetic drive to the pancreas, which could lead to a primary hypersecretion of insulin and contribute to their high propensity for obesity and diabetes, as is the case in various rodent models of obesity.