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Genome-wide association studies (GWASs) have been used to search for susceptibility genes for type 2 diabetes and obesity in the Pima Indians, a population with a high prevalence of both diseases. In these studies, a variant (rs2025804) in the LEPR gene was nominally associated with BMI in 1,082 subjects (P = 0.03 adjusted for age, sex, birth year, and family membership). Therefore the LEPR and leptin overlapping transcript (LEPROT) genes were selected for further sequencing and genotyping in larger population-based samples for association analyses with obesity-related phenotypes. Selected variants (n = 80) spanning these genes were genotyped in a sample of full-heritage Pima Indians (n = 2,842) and several common variants including rs2025804 were nominally associated with BMI (P = 0.05-0.003 adjusted for age, sex, birth year, and family membership). Four common tag variants associated with BMI in the full-heritage Pima Indian sample were genotyped in a second sample of mixed-heritage Native Americans (n = 2,969) and three of the variants showed nominal replication (P = 0.03-0.006 adjusted as above and additionally for Indian heritage). Combining both samples provided the strongest evidence for association (adjusted P = 0.0003-0.0001). A subset of these individuals (n = 403) had been metabolically characterized for predictors of obesity and the BMI risk alleles for the variants tagged by rs2025804 were also associated with lower 24-h energy expenditure (24hEE) as assessed in a human respiratory chamber (P = 0.0007 adjusted for age, sex, fat mass, fat-free mass, activity, and family membership). We conclude that common noncoding variation in the LEPR gene is associated with higher BMI and lower energy expenditure in Native Americans.

ContextPeripheral and central endocannabinoids and cognate acylethanolamides (AEs) may play important but distinct roles in regulating energy balance.ObjectiveWe hypothesized that in humans central/peripheral endocannabinoids are differently associated with adiposity and energy expenditure and differ by race.DesignWe examined associations of arachindonoylethanolamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide (OEA) assayed in plasma and cerebrospinal fluid (CSF) with race, adiposity, and energy expenditure.Setting/participantsIn this monitored clinical inpatient study, CSF was obtained by lumbar puncture in 27 individuals (12 Caucasian, 11 American Indian, and four African-American). Twenty-four hour and sleep energy expenditure were measured by indirect calorimetry in a respiratory chamber.Main outcome measureSamples were analyzed from a previous study originally designed to test a blood-brain barrier leptin transport deficit in human obesity.ResultsCSF (but not peripheral) 2-arachidonoylglycerol was significantly increased in American Indians compared with Caucasians (18.48 ± 6.17 vs. 10.62 ± 4.58 pmol/ml, P < 0.01). In the whole group, peripheral AEs were positively but in CSF negatively associated with adiposity. However, in multivariate models adjusted for the other peripheral and CSF AEs, peripheral arachindonoylethanolamide was the only AE significantly associated with adiposity. Interestingly, CSF OEA concentrations were positively associated with adjusted 24 hour and sleep energy expenditure (r = 0.47, P < 0.05; r = 0.42, P < 0.05), but peripheral OEA was not.ConclusionsThese data indicate a central alteration of the endocannabinoid system in American Indians and furthermore show that AEs in both compartments play an important but distinct role in human energy balance regulation.

Objective: Physiological systems responsible for water homeostasis and energy metabolism are interconnected. This study hypothesized altered responses to dehydration including thirst, ad libitum water intake, and copeptin in men with obesity.Methods: Forty-two men (22 lean and 20 with obesity) were stimulated by a 2-hour hypertonic saline infusion and a 24-hour water deprivation. In each dehydrating condition, thirst, ad libitum water intake after dehydration, and urinary and hormonal responses including copeptin were assessed.Results: After each dehydration condition, ad libitum water intake was similar between both groups (p > 0.05); however, those with obesity reported feeling less thirsty (p < 0.05) and had decreased copeptin response and higher urinary sodium concentrations when stressed (p < 0.05). Angiotensin II, aldosterone, atrial and brain natriuretic peptides, and apelin concentrations did not differ by adiposity group and did not explain the different thirst or copeptin responses in men with obesity. However, leptin was associated with copeptin response in lean individuals during the hypertonic saline infusion (p < 0.05), but the relationship was diminished in those with obesity.Conclusions: Diminished thirst and copeptin responses are part of the obesity phenotype and may be influenced by leptin. Adiposity may impact pathways regulating thirst and vasopressin release, warranting further investigation. [ABSTRACT FROM AUTHOR]

Objective: Weight stigma is associated with poor dietary adherence, yet adherence is essential for weight loss and maintenance. This study aimed to determine differences in dietary adherence and perceived hunger between lean individuals and two groups of individuals with obesity.Methods: In a 6-week outpatient dietary intervention (23 males; aged 48  [SD 14] years), lean participants (n = 23; BMI 23  [SD 2] kg/m2 ) received a weight-maintaining energy needs (WMEN) diet, and participants with obesity (BMI 36  [SD 7]) were randomized to either WMEN (n = 18) or a 35% calorie-reduced (CR) diet (n = 19). All food was provided, and multiple adherence and hunger ratings were assessed daily and weekly on an outpatient basis and in person at twice-weekly visits (e.g., 24-hour recall, diaries).Results: Weight decreased more in the group of CR individuals with obesity (β = -0.301 kg/wk, P = 0.02) compared with the group of lean individuals and the group of WMEN individuals with obesity. However, total percent adherence did not differ between groups (P = 0.60), and hunger scores did not change across groups over time (P = 0.08).Conclusions: Results indicate that there are no differences in dietary adherence between lean individuals and individuals with obesity and adherence is not associated with adiposity or hunger. Thus, the belief that nonadherence (e.g., lack of willpower) is unique to obesity is untrue and may perpetuate weight bias and stigma. [ABSTRACT FROM AUTHOR]

A greater decrease in 24-h energy expenditure (24 EE) during 24-h fasting defines a "thriftier" metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24 EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24-h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male; aged 36.6 ± 11.4 years; percentage body fat 34.8 ± 10.5%). Greater decrease in 24 EE during fasting (thriftier phenotype) was associated with less increase in 24 EE during COLD (i.e., less cold-induced thermogenesis). Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24-h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated with and mediated by the liver-derived hormone FGF21. Thus, the 24 EE response to COLD further identifies the "thrifty" versus "spendthrift" phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change. [ABSTRACT FROM AUTHOR]

Background Greater increase in 24-h energy expenditure (24EE) during overfeeding and smaller decrease in 24EE during fasting ("spendthrift" metabolic phenotype) are associated with more weight loss during sustained caloric restriction in overweight subjects. Objectives The aim of this study was to investigate whether these acute metabolic responses can also predict weight gain during sustained overfeeding in lean individuals. Methods Seven lean men participated in this study. Prior to overfeeding, 24EE responses to fasting and 200% normal-protein overfeeding were measured in a whole-room indirect calorimeter. Volunteers underwent 6 wk of 150% low-protein (2%) overfeeding followed by another wk of weight-maintaining diet, during which 24EE was revaluated. Body composition, 24EE, and various hormone concentrations, including fibroblast growth factor 21 (FGF21), were assessed at baseline, at wk 1, 3, and 6 of the overfeeding period, and 1 wk following overfeeding through the use of dual-energy X-ray absorptiometry, indirect calorimetry, and ELISA. Cumulative energy surplus was calculated from 24EE, daily physical activity, and direct measurements of calories of nutrient intake, feces, and urine by bomb calorimetry. Results The average weight gain during 6 wk of low-protein overfeeding was 3.8 kg (6.1%, min: +2.5%, max: +8.0%). During 24-h fasting at baseline, 24EE decreased on average (mean ± SD) by 158 ± 81 kcal/d (P  = 0.007). Subjects with less 24EE decrease during fasting (more metabolically spendthrift individuals) gained less weight (r  = −0.84, P  = 0.03), less fat mass (r  = −0.81, P  = 0.049), and stored less calories (r  = −0.91, P  = 0.03) during overfeeding. Following overfeeding, increased 24EE above requirements for achieved body size was associated with less weight and fat mass gain (r  = −0.78, P  = 0.04) and with the increase in 24EE during 200% normal-protein overfeeding measured at baseline (r  = 0.91, P  = 0.005). Serum FGF21 concentrations increased up to 44-fold during overfeeding (P  <  0.0001). Conclusions Low-protein overfeeding may be an important tool to identify metabolic phenotypes (spendthrift compared with thrifty) that characterize susceptibility to weight gain. This trial was registered at clinicaltrials.gov as NCT00687115. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • A low resting metabolic rate at age 10 years predicted weight gain in adolescence. • Resting metabolic rate at age 5 years was not related to weight gain in adolescence. • Total energy expenditure was not associated with weight gain at 5 and 10 years. [ABSTRACT FROM AUTHOR]

Objective: The association between food insecurity and obesity may be partially explained by overeating in response to unpredictable food availability cycles. The aim of this study was to measure objective food intake in food-insecure individuals.Methods: Eighty-two volunteers (53 m; BMI 29 ± 7; 38 ± 12 years) were admitted to our inpatient Clinical Research Unit and completed the Food Security Short Form, Three-Factor Eating Questionnaire, Gormally Binge Eating Scale, and body composition assessment (dual-energy x-ray absorptiometry). After 5 days of a weight-maintaining diet, participants self-selected food from an ad libitum vending machine paradigm for 3 days. Mean daily intake (kilocalories), macronutrient intake, and percentage of weight-maintaining energy needs (%WMEN) were calculated.Results: Based on Food Security Short Form cutoffs, food-insecure participants (n = 46; 56%) had higher body weight (P = 0.04), fat-free mass (P = 0.05), disinhibition (P = 0.008), hunger (P = 0.02), and binge-eating scores (P = 0.02) but not cognitive restraint (P = 0.37) compared with food-secure individuals. They overate more kilocalories (P = 0.001), %WMEN (P = 0.003), fat (P = 0.003), and carbohydrates (P = 0.004) during the vending machine paradigm, continued to increase their hourly rate of kilocalories (group × time; β = 37.7 cumulative kcal/h; P < 0.0001), and ate more total kilocalories across the 72 hours (β = 47.09 kcal/h; P = 0.003).Conclusions: Food insecurity may amplify susceptibility to weight gain via overeating during times of unlimited food access. [ABSTRACT FROM AUTHOR]

Objective Executive function impairments and depression are associated with obesity but whether they predict weight gain is unclear. Methods Forty-six individuals (35 m, 37 ± 10y) completed the Stroop Task, Iowa Gambling Task (IGT), Wisconsin Card Sorting Task (WCST), Inventory for Depressive Symptomatology (IDS-SR), Physical Anhedonia Scale (PAS), and Perceived Stress Scale (PSS). Body composition (DXA) and fasting glucose were also measured. Data from return visits were used to assess changes in weight. Results Poorer Stroop and WCST performance associated with higher BMI whereas poorer IGT and WCST performance associated with higher body fat (%; all p's ≤ 0.05). Stroop interference ( p = 0.04; p = 0.05) and IDS-SR ( p = 0.06; p = 0.02) associated with increased BMI and weight gain (%/yr). In a multivariate linear model Stroop interference (β = 0.40, p < 0.01; β = 0.35, p < 0.01) and IDS-SR (β = 0.38, p < 0.01; β = 0.37, p < 0.01) independently predicted increased BMI and weight gain (%/yr) even after controlling for baseline weight and glucose levels. Conclusions Poorer response inhibition and depressive symptoms, but not glucose levels, predicted weight gain. Evaluating neurocognitive and mood deficits could improve current treatment strategies for weight loss. Clinical Trial Registration Numbers NCT00523627 , NCT00342732 , NCT01224704 . clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Objective: This study sought to understand how the dietary source of carbohydrates, either high-fructose corn syrup (HFCS) or complex carbohydrates, affects energy expenditure (EE) measures, appetitive sensations, and hormones during 24 hours of overfeeding.Methods: Seventeen healthy participants with normal glucose regulation had 24-hour EE measures and fasting blood and 24-hour urine collection during four different 1-day diets, including an energy-balanced diet, fasting, and two 75% carbohydrate diets (5% fat) given at 200% of energy requirements with either HFCS or whole-wheat foods as the carbohydrate source. In eight volunteers, hunger was assessed with visual analog scales the morning after the diets.Results: Compared with energy balance, 24-hour EE increased 12.8% ± 6.9% with carbohydrate overfeeding (P < 0.0001). No differences in 24-hour EE or macronutrient utilization were observed between the two high-carbohydrate diets; however, sleeping metabolic rate was higher after the HFCS diet (Δ = 35 ± 48 kcal [146 ± 200 kJ]; P = 0.01). Insulin, ghrelin, and triglycerides increased the morning after both overfeeding diets. Urinary cortisol concentrations (82.8 ± 35.9 vs. 107.6 ± 46.9 nmol/24 h; P = 0.01) and morning-after hunger scores (Δ = 2.4 ± 2.0 cm; P = 0.01) were higher with HFCS overfeeding.Conclusions: The dietary carbohydrate source while overeating did not affect 24-hour EE, but HFCS overconsumption may predispose individuals to further overeating due to increased glucocorticoid release and increased hunger the following morning. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with reduced activation in the left dorsolateral prefrontal cortex (DLPFC), a region of the brain that plays a key role in the support of self-regulatory aspects of eating behavior and inhibitory control. Transcranial direct current stimulation (tDCS) is a noninvasive technique used to modulate brain activity. Objectives: We tested whether repeated anodal tDCS targeted at the left DLPFC (compared with sham tDCS) has an immediate effect on eating behavior during ad libitum food intake, resulting in weight change, and whether it might influence longer-term food intake-related appetite ratings in individuals with obesity. Design: In a randomized parallel-design study combining inpatient and outpatient assessments over 31 d, 23 individuals with obesity [12 men; mean ± SD body mass index (BMI; in kg/m²): 39.3 ± 8.42] received 15 sessions of anodal (i.e., enhancing cortical activity) or sham tDCS aimed at the left DLPFC. Ad libitum food intake was assessed through the use of a vending machine paradigm and snack food taste tests (SFTTs). Appetite was evaluated with a visual analog scale (VAS). Body weight was measured. We examined the effect of short-term (i.e., 3 sessions) and long-term (i.e., 15 sessions) tDCS on these variables. Results: Relative to sham tDCS, short-term anodal tDCS did not influence ad libitum intake of food from the vending machines. Accordingly, no effect on short-term or 4-wk weight change was observed. In the anodal tDCS group, compared with the sham group, VAS ratings for hunger and the urge to eat declined significantly more (P = 0.01 and P = 0.05, respectively), and total energy intake during an SFTT was relatively lower in satiated individuals (P = 0.01), after long-term tDCS. Conclusions: Short-term anodal tDCS of the left DLPFC did not have an immediate effect on ad libitum food intake or thereby weight change, relative to sham tDCS. Hunger and snack food intake were reduced only after a longer period of anodal tDCS in individuals with obesity. [ABSTRACT FROM AUTHOR]

Objective: To investigate the concurrent relationships between human plasma erythropoietin concentrations and energy expenditure (EE), body composition, plasma leptin concentrations, and associations with weight change.Methods: Plasma to measure erythropoietin and leptin; data for body composition; 24-h EE measured in a whole-room calorimeter; and 75 g oral glucose tolerance testing were available from 109 full-heritage Pima Indians (55% male) from a larger study designed to understand the causes of obesity. Seventy-nine subjects had data for weight at a later visit (mean follow-up = 4.3 ± 1.9 years) to calculate percent weight change per year.Results: Erythropoietin, adjusted for covariates, correlated with 24-h EE (r = 0.26, P = 0.007), sleeping EE (r = 0.29, P = 0.003), fat-free mass (r = 0.19, P = 0.05), and fat mass (r = 0.27, P = 0.005), but not insulin or glucose measures. The association of erythropoietin with 24-h EE was fully mediated by fat-free mass. Erythropoietin associated with leptin in women (ρ = 0.36, P = 0.01), but not in men (P = 0.9), independently from fat mass. The association of erythropoietin with percent weight change per year was in opposing directions (interaction: P = 0.002) in males (r = -0.35, P = 0.02) versus females (r = 0.37, P = 0.02).Conclusions: Non-hematopoietic endogenous erythropoietin action may be involved in body weight regulation in opposing directions in men and women, i.e., weight loss in men and weight gain in women. [ABSTRACT FROM AUTHOR]

Objective: Obesity is associated with decreased activity in the prefrontal cortex. Transcranial direct current stimulation (tDCS) modifies cortical excitability and may facilitate improved control of eating. The energy intake (EI) and body weight in subjects who received cathodal versus sham (study 1) and subsequent anodal versus sham (study 2) tDCS aimed at the left dorsolateral prefrontal cortex (LDLPFC) were measured.Methods: Nine (3m, 6f) healthy volunteers with obesity (94 ± 15 kg [M ± SD]; 42 ± 8 y) were admitted as inpatients for 9 days to participate in a double-blind, randomized, placebo-controlled crossover experiment. Study 1: following 5 days of a weight-maintaining diet, participants received cathodal or sham tDCS (2 mA, 40 min) on three consecutive mornings and then ate ad libitum from a computerized vending machine, which recorded EI. Weight was measured daily. Study 2: participants repeated the study, maintaining original assignment to active (this time anodal) and sham.Results: Participants tended to consume fewer kilocalories per day (P = 0.07), significantly fewer kilocalories from soda (P = 0.02) and fat (P = 0.03), and had a greater % weight loss (P = 0.009) during anodal versus cathodal tDCS.Conclusions: The results indicated a role for the LDLPFC in obesity and food intake. This proof of concept study suggested, for the first time, the potential application of anodal tDCS to facilitate weight loss. [ABSTRACT FROM AUTHOR]

Successful weight loss is variable for reasons not fully elucidated. Whether effective weight loss results from smaller reductions in energy expenditure during caloric restriction is not known. We analyzed whether obese individuals with a "thrifty" phenotype, that is, greater reductions in 24-h energy expenditure during fasting and smaller increases with overfeeding, lose less weight during caloric restriction than those with a "spendthrift" phenotype. During a weight-maintaining period, 24-h energy expenditure responses to fasting and 200% overfeeding were measured in a whole-room indirect calorimeter. Volunteers then underwent 6 weeks of 50% caloric restriction. We calculated the daily energy deficit (kilocalories per day) during caloric restriction, incorporating energy intake and waste, energy expenditure, and daily activity. We found that a smaller reduction in 24-h energy expenditure during fasting and a larger response to overfeeding predicted more weight loss over 6 weeks, even after accounting for age, sex, race, and baseline weight, as well as a greater rate of energy deficit accumulation. The success of dietary weight loss efforts is influenced by the energy expenditure response to caloric restriction. Greater decreases in energy expenditure during caloric restriction predict less weight loss, indicating the presence of thrifty and spendthrift phenotypes in obese humans. [ABSTRACT FROM AUTHOR]

Objective Neuroimaging studies have revealed abnormalities in brain structure, including the striatum, in obese people. In this study, the cellular and parenchymal basis for these findings in post-mortem brain tissue was investigated. Methods Design-based (unbiased) stereology combined with histochemical and immunocytochemical staining was used to quantify total number of neurons and astrocytes in post-mortem striatal brain samples from nine obese (BMI 40.2 ± 6.1 kg/m2) and eight lean (BMI 24.4 ± 1.0 kg/m2) donors. Total numbers of Nissl-stained neurons and glial fibrillary acidic protein-immunopositive astrocytes were counted in 10 systematic-random sections starting from the frontal pole of the striatum. Results There were no differences in mean total numbers of neurons (obese: 7.60 E+06; SD 2.50 E+06; lean: 7.85 E+06; SD 8.26 E+05; P < 0.78) or astrocytes (obese: 7.42 E+06; SD 2.27 E+06; lean: 7.43 E+06; SD 2.50 E+06; P < 0.99). A higher variance was found for number of neurons ( P < 0.007) but not astrocytes ( P < 0.72) in the obese group. Neuron/glia ratios were similar in both groups (obese: 1.07, SD 0.39; lean: 1.15, SD 0.37; P < 0.70) with an overall striatal neuron/glia ratio of 1.11 (SD 0.37) across the entire study population ( n = 17). Conclusions No difference was found in the average numbers of neurons and astrocytes in the anterior striatum between lean and obese people. The morphological basis for structural brain changes in obesity requires further investigation. [ABSTRACT FROM AUTHOR]

Awake and fed thermogenesis (AFT) is the energy expenditure (EE) of the nonactive fed condition above the minimum metabolic requirement during sleep and is composed of the thermic effect of food and the cost of being awake. AFT was estimated from whole-room 24-h EE measures in 509 healthy subjects (368 Native Americans and 141 whites) while subjects consumed a eucaloric diet. Follow-up data were available for 290 Native Americans (median follow-up time: 6.6 years). AFT accounted for ;10% of 24-h EE and explained a significant portion of deviations from expected energy requirements. Energy intake was the major determinant of AFT. AFT, normalized as a percentage of intake, was inversely related to age and fasting glucose concentration and showed a nonlinear relationship with waist circumference and BMI. Spline analysis demonstrated that AFT becomes inversely related to BMI at an inflection point of 29 kg/m². The residual variance of AFT, after accounting for covariates, predicted future weight change only in subjects with a BMI .29 kg/m² . AFT may influence daily energy balance, is reduced in obese individuals, and predicts future weight gain in these subjects. Once central adiposity develops, a blunting of AFT may occur that then contributes to further weight gain. [ABSTRACT FROM AUTHOR]

Background: Studies in mice indicate that the gut microbiome influences both sides of the energy-balance equation by contributing to nutrient absorption and regulating host genes that affect adiposity. However, it remains uncertain as to what extent gut microbiota are an important regulator of nutrient absorption in humans. Objective: With the use of a carefully monitored inpatient study cohort, we tested how gut bacterial community structure is affected by altering the nutrient load in lean and obese individuals and whether their microbiota are correlated with the efficiency of dietary energy harvest. Design: We investigated dynamic changes of gut microbiota during diets that varied in caloric content (2400 compared with 3400 kcal/d) by pyrosequencing bacterial 16S ribosomal RNA (rRNA) genes present in the feces of 12 lean and 9 obese individuals and by measuring ingested and stool calories with the use of bomb calorimetry. Results: The alteration of the nutrient load induced rapid changes in the gut microbiota. These changes were directly correlated with stool energy loss in lean individuals such that a 20% increase in Firmicutes and a corresponding decrease in Bacteroidetes were associated with an increased energy harvest of ≈150 kcal. A high degree of over- feeding in lean individuals was accompanied by a greater fractional decrease in stool energy loss. Conclusions: These results show that the nutrient load is a key variable that can influence the gut (fecal) bacterial community structure over short time scales. Furthermore, the observed associations between gut microbes and nutrient absorption indicate a possible role of the human gut microbiota in the regulation of the nutrient harvest. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant. RESEARCH DESIGN AND METHODS--This study was a randomized double-blind placebo-controlled trial consisting of 100 severely obese (mean BMI 34.6 ± 6.6 kg/m²) insulin-resistant children aged 6-12 years, randomized to 1,000 mg metformin (n = 53) or placebo (n = 47) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program. RESULTS--Eighty-five percent completed the 6-month randomized phase. Children prescribed metformin had significantly greater decreases in BMI (difference -1.09 kg/m², CI -1.87 to -0.31, P = 0.006), body weight (difference -3.38 kg, CI -5.2 to -1.57, P < 0.001), BMI Z score (difference between metformin and placebo groups -0.07, CI -0.12 to -0.01, P = 0.02), and fat mass (difference -1.40 kg, CI -2.74 to -0.06, P = 0.04). Fasting plasma glucose (P = 0.007) and homeostasis model assessment (HOMA) insulin resistance index (P = 0.006) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17%. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score; those treated continuously with metformin did not significantly change BMI Z score further. CONCLUSIONS--Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program. [ABSTRACT FROM AUTHOR]

Abstract: In the fasting state, approximately 83% of glucose uptake occurs via non–insulin-mediated mechanisms. A widely accepted static rate for NIMGU is 1.62 mg kg−1·min−1. To investigate the variability of NIMGU, we examined differences by glucose tolerance, sex, age, race (American Indian/African American/Caucasian), and adiposity in 616 volunteers (including individuals with normal glucose regulation [NGR] and impaired glucose regulation [IGR] and diabetes mellitus [DM]) using data from euglycemic-hyperinsulinemic clamp experiments. NIMGU was determined by plotting basal glucose output and insulin action against fasting and steady-state clamp insulin. The intercept with the y-axis after extrapolation was interpreted as NIMGU at zero insulin. Body composition was determined by dual-energy x-ray absorptiometry; and glucose regulation, by a 75-g oral glucose tolerance test. Energy expenditure was measured by indirect calorimetry in a metabolic chamber. In individuals with NGR (n = 385), NIMGU was 1.63 mg kgestimated metabolic body size (fat free mass + 17.7 kg) −1 min−1 (95% confidence interval, 1.59-1.66). NIMGU increased with IGR and DM (IGR: n = 189, 1.67 [1.62-1.72]; DM: n = 42, 2.39 [2.29-2.49]; P < .0001 across groups). NIMGU did not differ by sex (P = .13), age (P = .22), or race (P = .06); however, NIMGU was associated with percentage body fat (r 2 = 0.04, P < .0001). Furthermore, NIMGU was positively associated with 24-hour and sleep energy expenditure (r 2 = 0.002, P = .03; r 2 = 0.01, P < .01). Extrapolated NIMGU in individuals with NGR is remarkably consistent with previously published data. Our results indicate that NIMGU is associated with adiposity. NIMGU increases with declining glucose tolerance perhaps to preserve glucose uptake during increased insulin resistance. [ABSTRACT FROM AUTHOR]

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.Obesity (2009) 17 4, 772–777. doi:10.1038/oby.2008.620 [ABSTRACT FROM AUTHOR]

Objective: In severely obese individuals and patients with diabetes, accumulation and activation of macrophages in adipose tissue has been implicated in the development of obesity-associated complications, including insulin resistance. We sought to determine whether in a healthy population, adiposity, sex, age, or insulin action is associated with adipose tissue macrophage content (ATMc) and/or markers of macrophage activation.Research Design and Methods: Subcutaneous ATMc from young adult Pima Indians with a wide range of adiposity (13-46% body fat, by whole-body dual-energy X-ray absorptiometry) and insulin action (glucose disposal rate 1.6-9 mg/kg estimated metabolic body size/min, by glucose clamp) were measured. We also measured expression in adipose tissue of factors implicated in macrophage recruitment and activation to determine any association with ATMc and insulin action.Results: ATMc, as assessed by immunohistochemistry (Mphi) and by macrophage-specific gene expression (CD68, CD11b, and CSF1R), were correlated with percent body fat, age, and female sex. Gene expression of CD68, CD11b, and CSF1R but not Mphi was correlated negatively with glucose disposal rate but not after adjustment for percent body fat, age, and sex. However, adipose tissue expression of plasminogen activator inhibitor type-1 (PAI-1) and CD11 antigen-like family member C (CD11c), markers produced by macrophages, were negatively correlated with adjusted glucose disposal rate (r = -0.28, P = 0.05 and r = -0.31, P = 0.03).Conclusions: ATMc is correlated with age and adiposity but not with insulin action independent of adiposity in healthy human subjects. However, PAI-1 and CD11c expression are independent predictors of insulin action, indicating a possible role for adipose tissue macrophage activation. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Humans with functional variants in the melanocortin 4 receptor (MC4R) are obese, hyperphagic, and hyperinsulinemic but have been reported to have no difference in energy expenditure. RESEARCH DESIGN AND METHODS--We investigated the association of two MC4R variants, Arg165Gln (R165Q) and A insertion at nucleotide 100 (NT100), with adiposity in 3,074 full-heritage Pima Indians, a subset of whom had metabolic measures including 24-h energy expenditure (n = 252) and resting metabolic rate (RMR) (n = 364). RESULTS--Among the 3,074 subjects, 43 were heterozygous for R165Q and 14 for NT100 (frequency = 0.007 and 0.002). Mean (± SD) BMI was higher among subjects with R165Q (39.3 ± 8.6 kg/m²) or NT100 (41.2 ± 7.8) than subjects without either variant (37.1 ± 8.4) (P = 0.04 and 0.02, adjusted for age, sex, and birth year and accounting for family membership). The 24-h energy expenditure (four with NT100; three with R165Q) or RMR (six with NT100; two with R165Q) was lower in heterozygous subjects but only met statistical significance when heterozygous subjects were combined and compared with subjects without either variant: least-squares means, 2,163 kcal/24 h (95% CI 2,035-2,291) vs. 2,307 kcal/24 h (2,285-2,328), P = 0.03 for 24-h energy expenditure, and 1,617 kcal/24 h (1,499-1,734) vs. 1,754 kcal/24 h (1,736-1,772), P = 0.02 for RMR; adjusted for age, sex, fat-free mass, and fat mass). For RMR, this difference persisted, even after accounting for family membership. CONCLUSIONS--Pima Indians heterozygous for R165Q or NT100 in MC4R have higher BMIs and lower energy expenditure (by ∼140 kcal/day), indicating that lower energy expenditure was a component of the increased adiposity. Diabetes 57: 3267-3272, 2608 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The rising prevalence of obesity and high prevalence of diabetes among Pima Indians suggest that the incidence of diabetes has risen over time. We examined trends in the incidence rate of type 2 diabetes among Pima Indians between 1965 and 2003. RESEARCH DESIGN AND METHODS -- Incidence rates were computed independently in three 13-year time periods in Pima Indians aged ≥5 years. Diabetes was defined by the presence of at least one of two criteria: 1) 2-h plasma glucose concentration ≥200 mg/dl (11.1 mmol/l) or 2) hypoglycemic treatment. RESULTS -- Among 8,236 subjects without diabetes at baseline, 1,005 incident cases occurred during follow-up. Age- and sex-adjusted incidence rates of diabetes were 25.3 cases/ 1,000 patient-years (95% CI 22.5-28.0) in 1965-1977, 22.9 cases/i,000 patient years (20.0-25.8) in 1978-1990, and 23.5 cases/1,000 patient years (20.5-26.5) in 1991-2003 (P = 0.3). The incidence rate in subjects aged 5-14 years was 5.7 (1.9-17.4) times as high in the last as in the first period, but the rate declined in those aged 25-34 years (incidence rate ratio 0.6 [0.4-0.8]). Sex-adjusted prevalence increased significantly over time only in those aged 5-24 years (Ptrend < 0.0001). CONCLUSIONS -- The overall incidence of diabetes among Pima Indians remained stable over the past four decades, with a significant rise occurring only in the youth. [ABSTRACT FROM AUTHOR]

Background: Children who report episodes of binge eating gain more weight than do children not reporting binge eating. However, how binge eating affects children's food intake at meals is unknown. Objective: We compared the energy intake and postmeal satiety of children with and without a history of binge eating during buffet meals. Design: Sixty overweight children aged 6-12 y were categorized into those reporting past binge-eating episodes (n = 10) and those reporting no such episodes (n = 50). Children selected lunch twice from a multiple-item, 9835 kcal, buffet meal: after an overnight fast and after a standardized breakfast. Children ate ad libitum, until they reported they were full. The main outcome measures were energy intake during meals and duration of postmeal satiety, after adjustment for covariates, including age, race, sex, socioeconomic status, and body composition. Results: After the overnight fast, children in the binge-eating group consumed more energy [x (±SD): 1748 ± 581 compared with 1309 ± 595 kcal; P = 0.04] and exhibited a shorter satiety duration (194 ± 84 compared with 262 ± 89 min; P = 0.03) than did children in the non-binge-eating group. After the standardized breakfast, binge-eating children reported a shorter satiety duration (75 ± 62 compared with 132 ± 62min;P = 0.01) and consumed more energy at the postbreakfast meal (1874 ± 560 compared with 1275 ± 566 kcal; P = 0.004). Conclusion: The ability to consume large quantities of palatable foods, coupled with decreased subsequent satiety, may play a role in the greater weight gain found in binge-eating children. [ABSTRACT FROM AUTHOR]

We recently demonstrated that thrifty subjects, characterized by a greater decrease in 24 h energy expenditure (24hEE) during short-term fasting, have less capacity for cold-induced thermogenesis (CIT) during 24 h of mild cold exposure. As cold-induced brown adipose tissue activation (CIBA) is a determinant of CIT, we sought to investigate whether thrifty individuals also have reduced CIBA. Twenty-four healthy subjects (age: 29.8 ± 9.5y, body fat: 27.3 ± 12.4%, 63% male) were admitted to our clinical research unit and underwent two 24hEE assessments in a whole-room indirect calorimeter during energy balance and fasting conditions at thermoneutrality to quantify their degree of thriftiness. Positron emission tomography/computed tomography scans were performed after exposure to 16 °C for 2 h to quantify peak CIBA. A greater decrease in 24hEE during fasting was associated with lower peak CIBA (r = 0.50, p = 0.01), such that a 100 kcal/day greater reduction in 24hEE related to an average 3.2 g/mL lower peak CIBA. Our results indicate that reduced CIBA is a metabolic trait of the thrifty phenotype which might explain reduced CIT capacity and greater predisposition towards weight gain in individuals with a thrifty metabolism. • Thrifty subjects are defined by a greater decrease in metabolic rate during fasting. • Thriftiness is associated with reduced cold-induced brown fat activation. • Less cold-induced brown fat activation is associated with less lipid oxidation. • Cold-induced brown fat activation may reflect the susceptibility for weight gain. [ABSTRACT FROM AUTHOR]

Adaptive thermogenesis during prolonged energy deficit refers to the greater than expected reduction in energy expenditure (EE) independent of concomitant loss of metabolically active body mass. As inter-individual variability in the magnitude of adaptive thermogenesis may influence the extent of energy deficit thereby predicting the amount of weight reduction, we investigated whether early adaptive thermogenesis is a determinant of weight loss after 6 weeks of daily 50% caloric restriction in an inpatient setting. The current study reports the results of an exploratory, secondary analysis in overweight but otherwise healthy subjects (n = 11, 7 men, 35 ± 9y, BMI = 40 ± 7 kg/m2, body fat = 63.3 ± 5.3%). Body composition and 24-h EE (24hEE) measurement in a whole-room indirect calorimeter were used to calculate the magnitude of adaptive thermogenesis while on caloric restriction after 1, 3 and 6 weeks. Energy deficit during caloric restriction was quantified via food, stool, and urine bomb calorimetry. Fasting hormonal concentrations (FT4, FT3, FGF21, leptin) were obtained at baseline and at weeks 3 and 6 during caloric restriction. The magnitude of adaptive thermogenesis in 24hEE after 1 week of caloric restriction was −178 ± 137 kcal/day (mean ± SD), was overall stable during and following caloric restriction, and demonstrated remarkable intra-individual consistency. A relatively greater decrease in 24hEE of 100 kcal/d after 1 week of caloric restriction was associated on average with reduced energy deficit by 8195 kcal over 6 weeks and predicted 2.0 kg less weight loss, of which 0.5 kg was fat mass, after 6 weeks. No correlations were found between hormonal concentrations and weight loss. The extent of weight loss is influenced by the magnitude of adaptive thermogenesis in the early stage of caloric restriction. Although these results need replication in larger study groups with adequate statistical power, targeting adaptive thermogenesis may help to optimize long-term interventions in obesity therapy. • Adaptive thermogenesis (AT) refers to metabolic slowing during caloric restriction. • AT can be detected as early as the first week of daily caloric restriction (CR). • AT is consistent during prolonged CR and affects daily energy balance during CR. • Early AT predicts subsequent weight loss and fat mass loss following 6-week of CR. [ABSTRACT FROM AUTHOR]

Background: Plasma albumin is reduced during inflammation. Obesity, a strong risk factor for type 2 diabetes (T2D), is associated with adipose tissue inflammation. However, whether albumin is associated with adipose tissue inflammation and whether it predicts T2D are unclear. Methods: Adults (predominantly American Indian) from a longitudinal study were included. Macrophage content and gene expression related to recruitment/activation were measured from subcutaneous adipose tissue (n = 51). The relationship between plasma albumin and adiposity (dual-energy X-ray absorptiometry or hydrodensitometry), glucose (oral glucose tolerance test), insulin action (hyperinsulinemic-euglycemic clamp), and insulin secretion (intravenous glucose tolerance test) were evaluated (n = 422). Progression to T2D was evaluated by Cox regression (median follow-up 8.8 years; 102 progressors). Results: Albumin was associated with macrophage markers including C1QB (r = − 0.30, p = 0.04), CSF1R (r = − 0.30, p = 0.03), and CD11b (r = − 0.36, p = 0.01). Albumin was inversely associated with body fat percentage (r = − 0.14, p = 0.003), fasting plasma glucose (r = − 0.17, p = 0.0003), and 2 h plasma glucose (r = − 0.11, p = 0.03), and was reduced in impaired glucose regulation compared with normal glucose regulation (mean ± SD: 39.4 ± 3.6 g/l and 40.1 ± 3.9 g/l, respectively; p = 0.049). Albumin predicted T2D, even after adjustment for confounders (HR, 0.75; 95% CI 0.58–0.96; p = 0.02; per one SD difference in albumin). Conclusions: Reduced albumin is associated with an unfavorable metabolic profile, characterized by increased adipose tissue inflammation, adiposity, and glucose, and with an increased risk for T2D. [ABSTRACT FROM AUTHOR]

Background Accurate prediction of 24-hour energy expenditure (24EE) relies on knowing body composition, in particular fat-free mass (FFM), the largest determinant of 24EE. FFM is closely correlated with hematologic volumes: blood volume (BV), red cell mass (RCM), and plasma volume (PV). However, it is unknown whether predicted hematologic volumes, based on easily collected variables, can improve 24EE prediction. Objective The aim was to develop and validate equations to predict 24EE based on predicted BV, RCM, and PV and to compare the accuracy and agreement with models developed from FFM and with the Mifflin-St Jeor equation, which is recommended for clinical use by the Academy of Nutrition and Dietetics. Design Participants had body composition measured by underwater weighing and 24EE by respiratory chamber. BV, RCM, and PV were calculated from five published equations. Participants/setting Native American and white men and women were studied (n=351). Participants were healthy adults aged 18 to 49 years from the Phoenix, AZ, metropolitan area. Main outcome measure Accuracy to within ±10% of measured 24EE and agreement by Bland-Altman analysis. Statistical analysis Regression models to predict 24EE from hematologic and body composition variables were developed in half the dataset and validated in the other half. Results Hematologic volumes were all strongly correlated with FFM in both men and women ( r ≥0.94). Whereas the accuracy of FFM alone was 69%, four hematologic volumes were individually more accurate (75% to 78%) in predicting 24EE. Equations based on hematologic volumes plus demographics had mean prediction errors comparable to those based on body composition plus demographics; although the Mifflin-St Jeor had modestly better mean prediction error, body composition, hematologic, and Mifflin-St Jeor models all had similar accuracy (approximately 80%). Conclusions Prediction equations based on hematologic volumes were developed, validated, and found to be comparable to Mifflin-St Jeor and body composition models in this population of healthy adults. [ABSTRACT FROM AUTHOR]

The size of subcutaneous (SAT) and visceral adipose tissue (VAT) in the abdomen is negatively associated with insulin action. Deep portion of SAT (below subcutaneous fascia) and intraperitoneal portion of VAT (within abdominal cavity) are thought to be the principal determinants of this relationship, which according to some studies, is further modified by sex and obesity status. We studied obese Pima Indian men (n= 37) and women (n= 22) with normal glucose tolerance (mean age 27 [SD 8] years, BMI 36 [5] kg.m[sup -2]) who had measurements of body composition by DEXA, abdominal adipose tissue distribution by magnetic resonance imaging and insulin-mediated glucose disposal rate (M) by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU.m[sup -2]min[sup -1]). Women had more body fat (BF) and more superficial SAT compared to men (both P< 0.0001). After adjustment for age and BF, the differences in superficial SAT were no longer significant, while men had more total (P= 0.001) and deep SAT (P< 0.0001), and more total (P= 0.002) and intraperitoneal VAT (P= 0.003) compared to women. After adjustment for age and sex, M was related to SAT (r= -0.26, P= 0.05), deep SAT (r= -0.27, P=- 0.00), VAT (r= -0.36, P=0.006) and intraperitoneal VAT (r= -0.43, P= 0.0007). In sex specific analysis, deep SAT (r= -0.38, P= 0.02) and intraperitoneal VAT (r= -0.45, P= 0.006) were significant determinants of M in men but not in women (P= 0.7 and P= 0.1 respectively). Superficial SAT was the only significant determinant of M in women (-0.55, P= 0.01). The latter association was confirmed in the general linear regression analysis as significant gender-to-superficial SAT interaction (P= 0.000). Our results showed a sex-specific association between fat distribution in abdomen and insulin action in obese Pima Indians. This indicates that different mechanisms may underlie the association between abdominal obesity and insulin resistance in men and women. [ABSTRACT FROM AUTHOR]

Adipose tissue macrophage content increases with adiposity, and precedes obesity-induced hyperinsulinemia in animal models of insulin resistance. We investigated whether macrophage content in subcutaneous adipose tissue was associated with adiposity and insulin action in non-diabetic humans. We studied 65 Pima Indians (mean age 31 years [SD 8], BMI 34 [7] kg.m[sup -2], 24 women) who were enrolled in an ongoing study of risk factors for diabetes. For each subject measurements of body composition by DEXA, insulin action (M), as assessed by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU.m[sup -2].min[sup -1]), and aspiration biopsy of subcutaneous abdominal adipose tissue were obtained. Macrophage content was estimated by the number of CD68-expressing cells as determined by immunohistochemistry (CD68[sup +], in 45 subjects) and from the expression levels of macrophage markers (Cd68, Csf1r, Cd11b) determined by quantitative reverse transcriptase-polymerase chain reaction. The fraction of CD68[sup +] cells was associated with body fat (r= 0.33, P= 0.02) as was expression of macrophage markers (Cd68: r= 0.33, P= 0.007; Csf1r: r= 0.55, P< 0.0001; Cd11b: r=0.44, P= 0.0003) and these associations persisted after adjustment for age and sex (CD68[sup +]: P= 0.04; Cd68: P=0.05; Csf1r and Cd11b: P= 0.0008 both). M was. associated with body fat (r= -0.34, P= 0.006), expression of Csf1r (r= -0.33, P= 0.007) and Cd11b (r= -0.26, P=-0.04), and weakly with Cd68 expression (r= -0.24, P=0.06). M was not associated with the fraction of CD68[sup +] cells (r= -0.12, P= 0.4). The associations of M with Csf1r and Cd11b expression were not significant after adjustment for body fat (P= 0.2 and P= 0.5 respectively). Macrophage content in subcutaneous abdominal adipose tissue is associated with adiposity in Pima Indians. Our data indicate that increased macrophage content in subcutaneous adipose tissue does not provide a mechanistic link between increasing adiposity and worsening of insulin action. [ABSTRACT FROM AUTHOR]

Objective: Perceived stress; emotional eating; anhedonia; depression and dietary restraint, hunger, and disinhibition have been studied as risk factors for obesity. However, the majority of studies have been cross-sectional and the directionality of these relationships remains unclear. In this longitudinal study, we assess their impact on future weight change.Methods: Psychological predictors of weight change in short- (6month) and long-term (>1year) periods were studied in 65 lean and obese individuals in two cohorts. Subjects participated in studies of food intake and metabolism that did not include any type of medication or weight loss interventions. They completed psychological questionnaires at baseline and weight change was monitored at follow-up visits.Results: At six months, perceived stress predicted weight gain (r(2)=0.23, P=0.02). There was a significant interaction (r(2)=.38, P=0.009) between perceived stress and positive emotional eating, such that higher scores in both predicted greater weight gain, while those with low stress but high emotional eating scores lost weight. For long-term, higher anhedonia scores predicted weight gain (r(2)=0.24, P=0.04). Depression moderated these effects such that higher scores in both predicted weight gain but higher depression and lower anhedonia scores predicted weight loss.Conclusion: There are different behavioral determinants for short- and long-term weight change. Targeting perceived stress may help with short-term weight loss while depression and anhedonia may be better targets for long-term weight regulation. [ABSTRACT FROM AUTHOR]

Transcranial direct stimulation (tDCS) targeted to the dorsolateral prefrontal cortex (DLPFC) reduces food intake and hunger, but its effects on circulating factors are unclear. We assessed the effect of repeated administration of tDCS to the left DLPFC (L-DLPFC) on concentrations of pro/anti-inflammatory and appetitive hormone concentrations. Twenty-nine healthy adults with obesity (12 M; 42±11 y; BMI=39±8 kg/m2) received 3 consecutive inpatient sessions of either anodal or sham tDCS targeted to the L-DLPFC during a period of ad libitum food intake. Fasting plasma concentrations of IL-6, orexin, cortisol, TNF-α, IL-1β, ghrelin, PYY, and GLP-1 were measured before the initial and after the final tDCS sessions. IL-6 (β=-0.92 pg/ml p=0.03) decreased in the anodal group compared with sham, even after adjusting for kcal intake; there were no changes in other hormones. Mean kcal intake was associated with higher IL-1β and ghrelin concentrations after the ad libitum period (β=0.00018 pg/ml/kcal, p=0.03; β=0.00011 pg/ml/kcal, p=0.02; respectively), but not differ by intervention groups. IL-6 concentrations were reduced following anodal tDCS to the L-DLPFC independent of ad libitum intake. IL-6 concentrations reflect the inflammatory state of adiposity and may affect eating behavior and weight gain. These findings provide evidence of therapeutic benefit of tDCS. • Anodal tDCS to the L-DLPFC diminished IL-6, a chronic inflammatory marker in obesity. • Reduction of IL-6 following tDCS was independent of ad libitum food intake. • tDCS affects IL-6 levels by modulating brain and sympathetic nervous system activity. • Study pioneers tDCS as a potential obesity intervention by influencing cytokines. [ABSTRACT FROM AUTHOR]

• The spendthrift phenotype is more prone to weight-loss and resistant to weight-gain. • Greater anhedonia traits were associated with the spendthrift metabolic phenotype. • Healthy participants with anhedonia may respond better to their homeostatic needs. • This association weakens when depressive symptoms increase. Obesity rates are increasing and affecting mental health. It is important to understand how behavioral traits such as anhedonia are associated with physiologic traits that may predict weight-change in clinical and non-clinical populations. We studied whether 24-hour energy expenditure (24hEE) changes with fasting and overfeeding are associated with anhedonia in a healthy cohort. We performed behavioral assessments (physical anhedonia scale (PAS) and inventory for depressive symptoms (IDS)) followed by measures of 24hEE and urinary catecholamines in a whole-room indirect calorimeter (respiratory chamber) during energy balance, and then randomly during fasting and 2 different overfeeding diets. Participants (n=98) were medically healthy, between 18 and 55 years of age, with normal glucose regulation and weight-stable 6 months before admission. Women were premenopausal and not pregnant. Higher PAS was significantly associated with lesser decrease in 24hEE with fasting and higher urinary catecholamine excretion rates – consistent with spendthrift metabolism. As IDS increased, the association between anhedonia and the change in 24hEE from energy balance to fasting decreased (B-values were lower for change in EE). Here, higher PAS scores may reflect the ability to respond with appropriate homeostatic reactions which balance energy needs. IDS scores blunting this response may explain how anhedonia and depression can lead to weight gain. [ABSTRACT FROM AUTHOR]

Physiological systems controlling water and energy ingestion are coordinated. Whether maladaptive eating behavior and appetite for water are linked is unknown. Thus, we sought to investigate the association between maladaptive eating and both thirst and water drinking behavior with two dehydrating conditions. Twenty-two lean men and 20 men with obesity (mean age 32.3 ± 8.4 years and 30.0 ± 11.1 years, respectively) completed the Three-Factor Eating Questionnaire (TFEQ) and Gormally Binge Eating Scale. On separate days, volunteers were dehydrated by a 2-h hypertonic saline infusion and a 24-h water deprivation, and thirst was measured on a 100-mm visual analogue scale (VAS) during each procedure. After each dehydrating condition, ad libitum water intake was measured. In the saline infusion, higher Disinhibition on the TFEQ was associated with thirst in the lean group (β = 4.2 mm VAS, p = 0.03) but not in the group with obesity (p = 0.51). In the water-deprivation condition, higher Disinhibition was also associated with thirst in the lean group (β = 5.6 mm VAS, p = 0.01) with the strength of relationship being 3.5-fold stronger than that observed in the group with obesity (β = 1.6 mm VAS, p = 0.0003). Hunger, Restraint, and binge-eating scores were not associated with thirst in either dehydrating condition (all p > 0.05). Maladaptive eating behaviors were not associated with ad libitum water intake (all p > 0.05). Disinhibition is associated with higher thirst perception in healthy weight individuals and may be attenuated in obesity. The characteristics of disinhibition which typically includes a heightened readiness to eat, may reflect a more general phenotype that also reflects a readiness to drink. [ABSTRACT FROM AUTHOR]

Elevated body mass index and post-prandial state are associated with disadvantageous choices on the Iowa Gambling Task (IGT). Whether physiological factors including percent body fat, and peripheral glucose, insulin, and leptin concentrations, are associated with IGT performance is unknown. In196 healthy adults without diabetes, we measured body fat by DXA scan, glucose, insulin and leptin ( n = 138) concentrations during an oral glucose tolerance test and IGT performance after a standardized meal. Glucose was not associated with IGT performance. Disadvantageous IGT performance was associated with higher percent body fat ( r = − 0.16, p = 0.03), 30-min insulin concentrations (insulin 30 , r = − 0.27, p < 0.001), and 30-min leptin concentrations (leptin 30 , r = − 0.23, p = 0.008). Mediation analysis demonstrated that leptin 30 was almost completely responsible for the percent body fat effect on IGT performance. Even adjusted for age, sex, race, and education, insulin 30 ( b = − 46.5, p = 0.03) and leptin 30 ( b = − 50.9, p = 0.03) concentrations remained independently associated with IGT performance and interacted together such that higher leptin 30 blunted effects of higher insulin 30 ( b = 23.8, p = 0.048). These findings may indicate an internal metabolic signature of energy availability (higher body fat, insulin, and leptin levels) associated with disadvantageous IGT performance. [ABSTRACT FROM AUTHOR]

As executive function may influence eating behaviors, our aim was to determine whether measures of executive function predict ad libitum food intake in subjects seeking weight loss. 78 obese, healthy individuals (40 female/38 male; age 36 ± 10 y; BMI 37.8 ± 7.2 kg/m 2 ) completed the Iowa Gambling Task to evaluate decision making, the Stroop Word Color Task to assess attention, the Wisconsin Card Sorting Task to measure perseveration, and the Three Factor Eating Questionnaire to measure disinhibition and cognitive restraint. Ad libitum energy intake over 3-days was then collected using a validated vending paradigm. When expressed as a percentage of an individual's weight maintaining energy needs (%WMEN), intake correlated positively with perseveration (r = 0.24, p = 0.03) and negatively with restraint (r = −0.51, p < 0.0001). In a regression model of %WMEN (r 2  = 0.59, p < 0.0001), an interaction between perseveration and restraint was observed (p = 0.05). Increased perseveration intensified the effect of restraint such that subjects with both high restraint and perseveration ate the least (median (IQR) = 70 (62, 94) %WMEN), while those with low restraint and high perseveration ate the most (130 (102, 153) %WMEN). Subjects with low perseveration and high versus low restraint ate a median of 84 (70, 86) and 112 (98, 133) %WMEN, respectively. The effects of perseveration on food intake are conditional on restraint, and may contribute to extremes of dietary intake in some individuals. [ABSTRACT FROM AUTHOR]

Abstract: Background: Type 2 diabetes is a risk factor for development of cognitive dysfunction. Impairments in glucose regulation have been associated with poorer performance on tests of executive function and information processing speed. Methods: We administered the Stroop Color Word Task, where higher interference scores are indicative of decreased selective attention, to 98 non-diabetic volunteers (64m; %fat=37±12; age=36±9yrs, race=41 NA/30 C/13 H/14 AA) on our inpatient unit. After 3d on a weight maintaining diet, % body fat was measured by DXA and a 75g oral glucose tolerance test (OGTT) was administered. Impaired glucose regulation (IGR) was defined as: fasting plasma glucose ≥100 and ≤125mg/dL and/or 2h plasma glucose between ≥140 and ≤199mg/dL (IGR; n=48; NGR; n=50). Total and incremental area under the curve (AUC) for insulin and glucose were calculated. Results: Stroop interference scores were not significantly associated with any measure of adiposity or insulin concentrations. Individuals with IGR had significantly higher interference scores than those with normal glucose regulation (NGR; p=0.003). Higher interference scores were significantly correlated with fasting plasma glucose concentrations (r=0.26, p=0.007) and total glucose AUC (r=0.30, p=0.02) and only trending so for iAUC and 2h plasma glucose (r=0.18, p=0.08; r=0.17, p=0.09 respectively). In separate multivariate linear models, fasting plasma glucose (p=0.002) and total glucose AUC (p=0.0005) remained significant predictors of Stroop interference scores, even after adjustment for age, sex, race, education and %fat. Conclusions: Individuals with IGR had decreased performance on a test of selective attention. Fasting plasma glucose was more strongly associated with lower performance scores than 2h plasma glucose. Our results indicate that even mild hyperglycemia in the non-diabetic range is associated with attentional processing difficulties in a sample of younger adults. Whether these impairments precede or are induced by impaired glucose regulation is not clear. [Copyright &y& Elsevier]

Abstract: Obesity has been associated with alterations of both functional and structural aspects of the human central nervous system. In obese individuals both fat mass (FM; primarily consisting of adipose tissue) and fat-free mass (FFM; all non-adipose tissues) are increased and it remains unknown whether these compartments have separate effects on human brain morphology. We used voxel-based morphometry to investigate the relationships between measures of body composition and regional gray matter volume (GMV) in 76 healthy adults with a wide range of adiposity (24 F/52 M; age 32.1±8.8 years; percentage of body fat [PFAT%] 25.5±10.9%; BMI 29.8±8.9). Fat-free mass index (FFMI kg×m−2) showed negative associations in bilateral temporal regions, the bilateral medial and caudolateral OFC, and the left insula. Fat mass index (FMI kg ×m−2) showed similar, but less extensive negative associations within temporal cortical regions and the left caudolateral orbitofrontal cortex (OFC). In addition, negative associations were seen for FMI with GMV of the cerebellum. Associations of FFMI with temporal and medial orbitofrontal GMV appeared to be independent of adiposity. No associations were seen between measures of adiposity (i.e. FM and PFAT) and GMV when adjusted for FFM. The majority of regions that we find associated with FFM have been implicated in the regulation of eating behavior and show extensive projections to central autonomic and homeostatic core structures. These data indicate that not adipose tissue or relative adiposity itself, but obesity related increases in absolute tissue mass and particularly FFM may have a more predominant effect on the human brain. This might be explained by the high metabolic demand of FFM and related increases in total energy needs. [Copyright &y& Elsevier]

Abstract: Objective: Adipose tissue macrophages are associated with adiposity and may play a role in obesity related co-morbidities. We examined whether abdominal subcutaneous adipose tissue macrophage content (ATMc) was associated with fasting serum total cholesterol (TC), high density lipoprotein (HDL-C) and triglycerides (TG) concentrations. Methods: 52 (35 male) of Pima Indians without diabetes participated in the study. ATMc was assessed by histochemistry (CD68+ cells) (Mphi) and gene expression of macrophage-specific markers including CD68, CSF1r, CD11b and CD11c. Results: HDL-C was negatively associated with CD68, CSF1R, CD11b and CD11c expression (r =−0.31, p =0.02; r =−0.38, p <0.01; r =−0.40, p <0.01; r =−0.26, p =0.04, respectively). After adjustment for age, sex and BMI, the associations between HDL-C and CSF1R, CD11b were still significant (r =−0.31, p =0.01 and r =−0.3, p =0.02), but borderline for CD68 (r =−0.24, p =0.06). Conclusions: ATMc is associated with lower HDL-C independent of BMI indicating a link between ATMc and cardiovascular risk factors. [Copyright &y& Elsevier]

Abstract: We have previously demonstrated that obese people have reduced grey matter (GM) in several brain areas, including regions implicated in the regulation of taste (i.e., inferior frontal operculum and postcentral gyrus), reward (i.e., putamen), and behavioural processing (i.e., middle frontal gyrus), compared with their lean counterparts. It is well established that the brain may serve as a direct target for adiposity signals, one of the most important being leptin. We investigated the relationships between fasting plasma leptin concentrations and brain tissue composition in a group of 32 young adult Caucasians (12M/20F, age 32±1 years, body fat 29±1%, mean±S.E.) with normal glucose tolerance by using voxel-based morphometry of magnetic resonance imaging scans. Fasting plasma leptin concentrations were positively correlated with GM volumes of the left cerebellum and left inferior temporal gyrus and negatively associated with GM volumes of the left inferior frontal operculum, left postcentral gyrus, and right putamen (P <0.001, uncorrected for multiple comparisons) after adjustment for sex, percent body fat, age, fasting plasma insulin concentrations (i.e., the major determinants of plasma leptin), and global GM volume (thus allowing for an assessment of regional effects only). This study showed an independent, negative correlation between fasting plasma leptin concentrations, which are increased in obesity, and the volumes of GM in brain areas where obese people have reduced GM compared to their lean counterparts. These relationships may explain some of the abnormalities in brain morphology recently found to be associated with excess body fatness. [Copyright &y& Elsevier]

Presents the results of a study of adiponectin and development of type 2 diabetes in the Pima Indian population. Expression of adipose tissue; Prevalence of type 2 diabetes and obesity among Pima Indians in Arizona; Results of a population assessment; Conclusion that the concentration of adiponectin was lower in cases than in controls and individuals with high concentrations of this protein were less likely to develop type 2 diabetes than those with low concentrations.