Effect of liraglutide on dietary lipid-induced insulin resistance in humans.

AIMS: To test whether liraglutide suppresses postprandial elevations in lipids and thus protects against high saturated fatty acid (SFA) diet-induced insulin resistance. METHODS: In a randomized placebo-controlled crossover study, 32 participants with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and after a 24-hour 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 underwent 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 < .01 vs placebo). The SFA diet-induced impairment of vasodilation on placebo (-9.4% vs baseline; P < .01) was ameliorated by liraglutide (-4.8%; P = .1 vs baseline). In skeletal muscle, liraglutide abolished the SFA-induced increase in thioredoxin-interacting protein (TxNIP) expression (75% decrease; P < .01 vs placebo) and increased 5'AMP-activated protein kinase (AMPK) phosphorylation (50% vs -3%; P = .04 vs placebo). CONCLUSIONS: Liraglutide blunted the SFA-enriched diet-induced peripheral insulin resistance. This effect may be related to improved microvascular function and modulation of TxNIP and AMPK pathways in skeletal muscle.

A low resting metabolic rate in late childhood is associated with weight gain in adolescence.

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 10years, with 126 children having biennial follow-up assessments of weight and height after age 10years until age 20years. 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 10years 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 5years and with adjusted TEE and physical activity level assessed at age 5 or 10years. CONCLUSIONS: Lower adjusted RMR at age 10years 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.

The 24-h carbohydrate oxidation rate in a human respiratory chamber predicts ad libitum food intake.

BACKGROUND: The 24-h respiratory quotient (24-h RQ) and 24-h carbohydrate balance (24-h CHO-Bal) are predictors of weight change. Whether these relations are mediated by the effects of substrate oxidation and balance on food intake is not known. OBJECTIVE: We tested whether substrate oxidation and balance predict future ad libitum food intake. DESIGN: Substrate oxidation and balance were measured in a respiratory chamber in 112 normoglycemic subjects (83 Pima Indians and 29 whites; 67 men and 45 women) in energy balance for 3 d before tests were performed. The subjects then self-selected their food ad libitum for the following 3 d. RESULTS: The 24-h RQ, 24-h carbohydrate oxidation (24-h CHO-Ox), and 24-h CHO-Bal in the respiratory chamber predicted subsequent ad libitum food intake over 3 d (as a percentage of weight maintenance energy needs; %EN-WM). The 24-h CHO-Ox explained 15% of the variance in %EN-WM. The weight change over the 3-d ad libitum period was associated positively with 24-h CHO-Ox and negatively with 24-h CHO-Bal in the chamber; these associations were no longer significant after adjustment for %EN-WM. CONCLUSION: Carbohydrate oxidation and balance predict subsequent ad libitum food intake and can influence short-term weight changes, which indicates that carbohydrate balance is a contributing metabolic factor affecting food intake.

Less activation in the left dorsolateral prefrontal cortex in the reanalysis of the response to a meal in obese than in lean women and its association with successful weight loss.

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 postmeal (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.

Serum gamma-glutamyl transpeptidase is a determinant of insulin resistance independently of adiposity in Pima Indian children.

CONTEXT: Elevated activities of serum enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-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 (beta = 0.004; P = 0.008) and GGT (beta = 0.20; P = 0.004; total R(2) = 0.62; P < 0.0001). CONCLUSION: Significant relationships between adiposity and hepatic 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.

Lower total fasting plasma adiponectin concentrations are associated with higher metabolic rates.

CONTEXT: 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. OBJECTIVE: 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. DESIGN: This was a cross-sectional study. SETTING: The study was an inpatient clinical research unit. PARTICIPANTS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.

Estimating the effects of energy imbalance on changes in body weight in children.

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.

Less activation of the left dorsolateral prefrontal cortex in response to a meal: a feature of obesity.

BACKGROUND: In an exploratory positron emission tomography study of postprandial regional cerebral blood flow, which is a marker of neuronal activity, obese men differed from lean men in several brain regions, including the prefrontal cortex. The subjects received a meal proportional to their body size; therefore, the meal volume was different for each person. OBJECTIVE: We investigated whether differences in the brain responses of obese and lean men to a meal represent satiety or feelings of gastric distension. DESIGN: We studied 9 lean (x +/- SD body fat: 15 +/- 5%; age: 33 +/- 10 y) and 9 obese (body fat: 31 +/- 4%; age: 32 +/- 10 y) men given a fixed amount (400 mL) of a liquid meal. We compared their results with those in 11 lean (body fat: 16 +/- 5%; age: 35 +/- 8 y) and 11 obese (body fat: 33 +/- 5%; age: 28 +/- 5 y) previously studied men given a meal proportional to their body size. We performed analyses by using a two-level, random-effects approach in the STATISTICAL PARAMETRIC MAPPING software package and a significance level of P < or = 0.001, uncorrected for multiple comparisons. RESULTS: Compared with lean men, obese men had consistently less postprandial activation in the left dorsolateral prefrontal cortex, irrespective of meal size. CONCLUSION: Because the dorsolateral prefrontal cortex has been implicated in the inhibition of inappropriate behavior, satiety, and meal termination, differential responses of neuronal activity to food intake in this area may contribute to a propensity for obesity or to the difficulty in losing weight experienced by obese men.

A human model of dietary saturated fatty acid induced insulin resistance.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 p<0.001). 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). CONCLUSIONS: 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.

Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children.

CONTEXT/OBJECTIVE: 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. DESIGN/PARTICIPANTS: 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. RESULTS: 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. CONCLUSION: 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.

Habitual physical activity in children: the role of genes and the environment.

BACKGROUND: Understanding the factors that contribute to physical inactivity in children is important because sedentary behavior strongly relates to metabolic disorders such as obesity and diabetes. OBJECTIVE: We aimed to quantify the genetic and environmental influences on physical activity energy expenditure (PAEE) in 100 sex-concordant dizygotic (n = 38) and monozygotic (n = 62) twin pairs aged 4-10 y. DESIGN: Resting metabolic rate (RMR) was assessed by using respiratory gas exchange, total energy expenditure (TEE) by using doubly labeled water, and body composition by using dual-energy X-ray absorptiometry. Structural equation modeling was used to partition the phenotypic variance into additive genetic (a2) and common (c2) and unshared (e2) environmental components. RESULTS: Because PAEE [TEE - (RMR + 0.1 x TEE)] depends on body weight, which is highly heritable, we tested several models: 1) after adjustment for age, sex, ethnicity, study date, season, and weight, a2 explained none of the phenotypic variance in PAEE (95% CI: 0%, 38%), whereas c2 and e2 accounted for 69% (33%, 77%; P = 0.001) and 31% (23%, 39%; P < 0.001) of the variance, respectively; 2) after adjustment for the cofactors in model 1, a2 explained 19% of the phenotypic variance in TEE (0%, 60%; P = 0.13), whereas c2 and e2 accounted for 59% (16%, 79%; P = 0.007) and 23% (17%, 31%; P < 0.0001) of the variance, respectively; 3) in models adjusted as above (excluding weight), a2 explained no variance in physical activity level (TEE/RMR) (0%, 32%; P = 0.50), whereas c2 and e2 explained 65% (34%, 60%; P = 0.001) and 35% (28%, 45%; P < 0.0001) of the variance, respectively. CONCLUSIONS: Our data suggest that the familial resemblance in physical activity in these children is explained predominantly by shared environmental factors and not by genetic variability.

Lack of relationship between calcium intake and body size in an obesity-prone population.

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.

Weight, adiposity, and physical activity as determinants of an insulin sensitivity index in pima Indian children.

OBJECTIVE: To determine whether measures of physical activity are related to an insulin sensitivity index ([ISI] 10(4)/fasting insulin x 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.

Cross-sectional and prospective relationships of fasting plasma ghrelin concentrations with anthropometric measures in pima Indian 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.

Negative relationship between fasting plasma ghrelin concentrations and ad libitum food intake.

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, P < 0.001) and remained higher after adjustment for age, gender, and body weight (P < 0.0001). 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.

Plasma adiponectin concentrations in children: relationships with obesity and insulinemia.

Adiponectin, a novel adipokine with anti-inflammatory and insulin-sensitizing properties, has been found to have independent negative associations with obesity and hyperinsulinemia/insulin resistance in adults. We measured fasting plasma adiponectin and insulin concentrations and body composition (dual-energy x-ray absorptiometry or doubly labeled water) in 30 5-yr-old (11 boys and 19 girls) and 53 10-yr-old (17 boys and 36 girls) Pima Indian children. A subgroup of 20 children (5 boys and 15 girls) had all measurements at both 5 and 10 yr of age. Cross-sectionally, plasma adiponectin concentrations were negatively correlated with percentage body fat and fasting plasma insulin concentrations at both 5 yr (r = -0.35, P = 0.06, r = -0.42, P = 0.02) and 10 yr (r = -0.46, P = 0.001, r = -0.38, P = 0.005) of age. At age 10 yr, percentage body fat (P = 0.03) but not fasting plasma insulin (P = 0.59) was independently associated with fasting plasma adiponectin concentrations. Longitudinally, plasma adiponectin concentrations decreased with increasing adiposity. In summary, these results confirm our previously reported findings in adults of an inverse relationship between plasma adiponectin concentrations and adiposity in children. Longitudinal analyses indicated that hypoadiponectinemia is a consequence of the development of obesity in childhood. We did not find evidence that adiponectin is an early mediator of obesity-induced insulin resistance, a preliminary observation that needs to be confirmed in studies using a more direct measurement of insulin action than the one used in this investigation.

High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome.

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 (dual-energy 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.

Taste preferences and body weight changes in an obesity-prone population.

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 ( +/- 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.

Sex differences in the human brain's response to hunger and satiation.

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 dorsolateral prefrontal cortex than did the men (P < 0.005); in contrast, the men tended to have greater activation in the ventromedial 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.

Neuroimaging and obesity: mapping the brain responses to hunger and satiation in humans using positron emission tomography.

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.