Orbitofrontal cortex volume and brain reward response in obesity.

BACKGROUND/OBJECTIVES: What drives overconsumption of food is poorly understood. Alterations in brain structure and function could contribute to increased food seeking. Recently, brain orbitofrontal cortex (OFC) volume has been implicated in dysregulated eating but little is known how brain structure relates to function. SUBJECTS/METHODS: We examined obese (n=18, age=28.7±8.3 years) and healthy control women (n=24, age=27.4±6.3 years) using a multimodal brain imaging approach. We applied magnetic resonance and diffusion tensor imaging to study brain gray and white matter volume as well as white matter (WM) integrity, and tested whether orbitofrontal cortex volume predicts brain reward circuitry activation in a taste reinforcement-learning paradigm that has been associated with dopamine function. RESULTS: Obese individuals displayed lower gray and associated white matter volumes (P<0.05 family-wise error (FWE)- small volume corrected) compared with controls in the orbitofrontal cortex, striatum and insula. White matter integrity was reduced in obese individuals in fiber tracts including the external capsule, corona radiata, sagittal stratum, and the uncinate, inferior fronto-occipital, and inferior longitudinal fasciculi. Gray matter volume of the gyrus rectus at the medial edge of the orbitofrontal cortex predicted functional taste reward-learning response in frontal cortex, insula, basal ganglia, amygdala, hypothalamus and anterior cingulate cortex in control but not obese individuals. CONCLUSIONS: This study indicates a strong association between medial orbitofrontal cortex volume and taste reinforcement-learning activation in the brain in control but not in obese women. Lower brain volumes in the orbitofrontal cortex and other brain regions associated with taste reward function as well as lower integrity of connecting pathways in obesity (OB) may support a more widespread disruption of reward pathways. The medial orbitofrontal cortex is an important structure in the termination of food intake and disturbances in this and related structures could contribute to overconsumption of food in obesity.

Effect of dietary macronutrient composition on AMPK and SIRT1 expression and activity in human skeletal muscle.

Adenosine monophosphate-activated protein kinase (AMPK), silent mating type information regulation 2 homologue 1 (SIRT 1), and peroxisome proliferator-activated receptor γ co-activator α (PGC1α) constitute an energy sensing cellular network that controls mitochondrial biogenesis. Caloric restriction activates both AMPK and SIRT-1 to increase ATP production from fat oxidation. We characterized AMPK and SIRT 1 expression and activity in human skeletal muscle in response to dietary fat or carbohydrate intake on the background of either overfeeding or caloric restriction. AMPK phosphorylation and acetylation of PGC1α (as a measure of SIRT activity) were determined. Euglycemic-hyperinsulinemic clamp and muscle biopsies were performed in human subjects participating in 2 separate studies. In study 1, 21 lean healthy individuals were overfed for 5 days, while in study 2, 18 obese otherwise healthy individuals consumed a calorie-restricted diet for 5 days. Under both conditions - overfeeding and caloric restriction - high fat/low carbohydrate (HF/LC) diet significantly increased phosphorylation of AMPK and deacetylation of PGC1α in skeletal muscle without affecting total amounts of AMPK, PGC1α, or SIRT 1. In contrast, low fat/high carbohydrate (LF/HC) hypocaloric diet reduced phosphorylation of AMPK and deacetylation of PGC1α. Our data indicate that a relative deficiency in carbohydrate intake or, albeit less likely, a relative excess of fat intake even in the absence of caloric deprivation is sufficient to activate the AMPK-SIRT 1-PGC1α energy-sensing cellular network in human skeletal muscle.

Nutritional upregulation of p85alpha expression is an early molecular manifestation of insulin resistance.

AIMS/HYPOTHESIS: We sought to define early molecular alterations associated with nutritionally induced insulin resistance in humans. METHODS: Insulin sensitivity was assessed using a hyperinsulinaemic-euglycaemic clamp in eight healthy women while on an isocaloric diet and after 3 days of overfeeding (50% above eucaloric diet). Expression of phosphatidylinositol (PI) 3-kinase subunits p85alpha and p110 was assessed and measurements were made of IRS-1-associated PI 3-kinase activity, tyrosine and serine phosphorylation of IRS-1, and serine and threonine phosphorylation of p70S6 kinase. Measurements were made in skeletal muscle biopsies obtained before and after overfeeding. RESULTS: Three days of overfeeding resulted in a reduction of insulin sensitivity accompanied by: (1) increased expression of skeletal muscle p85alpha; (2) an alteration in the ratio of p85alpha to p110; (3) a decrease in the amount of IRS-1-associated p110; and (4) a decrease in PI 3-kinase activity. Increases in expression of p85alpha and in the p85alpha:p110 ratio demonstrated a highly significant inverse correlation with insulin sensitivity, and changes in PI 3-kinase activity correlated with changes in insulin sensitivity. Tyrosine and serine phosphorylation of IRS-1 and serine and threonine phosphorylation of p70S6 kinase were unaffected by 3 days of overfeeding. CONCLUSIONS/INTERPRETATION: We identified a novel mechanism of nutritionally induced insulin resistance in healthy women of normal weight. We conclude that increased expression of p85alpha may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding.

Insulin resistance as a modifier of the relationship between dietary fat intake and weight gain.

OBJECTIVE: To investigate whether insulin resistance modifies the rate of weight gain associated with a high percent of energy intake from dietary fat. DESIGN: Longitudinal, observational population study. SUBJECTS: A total of 782 nondiabetic Hispanic and non-Hispanic white free-living adult residents of the San Luis Valley in Colorado. MEASUREMENTS: Subjects were seen up to three times over a 14-y period. Weight, height, fasting insulin and glucose, diet by 24 h recall, and self-reported physical activity were collected at each visit. RESULTS: Percentage of energy intake from dietary fat was positively associated with weight gain over time (P=0.0103). High intake of dietary fat was more strongly related to weight gain in women than in men, and in those with lower total energy intake levels. The relationship between weight change and relative macronutrient intake also varied by baseline insulin sensitivity (P=0.0025). Weight gain over time in individuals with relative insulin resistance at baseline, as measured by QUICKI, was the greatest among those who consumed a higher percent of energy from fat. CONCLUSION: Percentage of total intake from dietary fat predicts weight change independent of total energy intake. Nondiabetic, insulin-resistant individuals are particularly susceptible to the weight gain associated with high levels of dietary fat intake. Further investigation into the relationship between insulin resistance, diet, and weight gain is warranted.

Influence of moderate chronic wine consumption on insulin sensitivity and other correlates of syndrome X in moderately obese women.

Epidemiologic studies indicate that alcohol consumption is associated with improved insulin sensitivity; however, scant experimental evidence confirms this observation. To determine the effects of regular moderate wine consumption on insulin sensitivity, 20 overweight women (body mass index [BMI], 29.8 +/- 2.2 kg/m2) participated in a 20-week free-living randomized crossover trial. The subjects, serving as their own controls, consumed wine (190 mL red wine, 13% vol/vol ethanol, 5 days per week) for 10 weeks and abstained for 10 weeks or vice versa. The dependent variables (body weight, BMI, percent body fat, blood pressure, fasting blood glucose and insulin, blood lipids, dietary intake, and insulin sensitivity by intravenous glucose tolerance test [IVGTT]) were measured at the pretest, at the 10-week crossover, and at the 20-week completion of the study. Data were analyzed at the pretest and at completion of the wine drinking and abstention periods of the study using ANOVA by order of treatment. Fasting glucose remained unchanged (mean +/- SD; P > .05) throughout the experiment (pretest, drinking, and abstention, 91.1 +/- 9.2, 91.6 +/- 9.1, and 88.5 +/- 11.2 mg/dL), as did the measures of insulin sensitivity, fasting insulin (pretest, drinking, and abstention, 8.6 +/- 3.3, 8.6 +/- 4.1, and 9.1 +/- 4.7 microU/mg) and the insulin sensitivity index (3.60 +/- 2.96, 3.25 +/- 2.17, and 3.30 +/- 1.84). Body composition and blood lipids also remained unchanged (P > .05) during treatment. Moderate wine consumption at this dose in overweight women did not improve or impair insulin sensitivity, nor did it change any of the known correlates of insulin sensitivity, including body weight and composition, blood lipids, and blood pressure.

Disposition of dietary ethanol carbons in rats: effects of gender and nutritional status.

Dietary ethanol is an important contributor to total caloric intake and has been associated with gender-specific alterations in body weight and the risk for coronary heart disease. To understand the metabolic basis of these effects, it is important to first clarify the effects of gender and nutritional state on the metabolic fate of dietary ethanol. Tracer studies were therefore performed using 14C-labeled ethanol in fasted or fed male and female Sprague-Dawley rats (N = 64) previously unexposed to ethanol. 1-(14C)-ethanol (4.5 microCi) was mixed with unlabeled ethanol (for a total ethanol dose equal to 10% of total daily caloric intake) and a 3-kcal liquid meal and administered through gastric feeding tubes. 14CO2 production was measured over the subsequent 8 hours. The 14C content of skeletal muscle, liver, adipose tissue, gastrointestinal (GI) tract, brain, heart, kidney, and serum was determined at 4 time points following tracer administration (20 minutes and 3, 8, and 24 hours; n = 4 at each time point). Tracer content on a whole-body level was significantly greater in skeletal muscle compared with liver in all groups (1.32 +/- 0.02 x 10(6) v 0.27 +/- 0.02 x 10(6) dpm, P < .001). Skeletal muscle tracer content decreased rapidly after 3 hours, whereas liver tracer content remained fairly constant throughout the study period. Fed female rats were the exception, with a significant increase in the tracer content of total liver and liver lipid at 8 hours. The tracer content was higher in the lipid extracts in liver from fed rats compared with fasted rats (1.08 +/- 0.19 x 10(5) v 0.48 +/- 0.08 x 10(5) dpm, P = .002). While male rats exhibited a fairly constant tracer content in adipose tissue throughout the 24-hour period, female rats showed an increase in adipose tissue tracer content at 8 and 24 hours, with levels 3 to 4 times those of the male animals (5.91 +/- 1.42 x 10(4) v 1.55 +/- 0.42 x 10(4) dpm, P = .02). These results demonstrate that (1) skeletal muscle plays an important role in the metabolism of dietary ethanol, (2) the fed state appears to favor the conversion of ethanol-derived carbons to lipid, and (3) female rats have a greater propensity to convert ethanol-derived carbons to lipid and to store these carbons in adipose tissue.