Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.

Background-Adipose tissue (AT) dysfunction in obesity contributes to chronic, low-grade inflammation that predisposes to type 2 diabetes mellitus and cardiovascular disease. Recent in vitro studies suggest that AT hypoxia may induce inflammation. We hypothesized that adipose tissue blood flow (ATBF) regulates AT oxygen partial pressure (AT PO 2 ), thereby affecting AT inflammation and insulin sensitivity. Methods and Results-We developed an optochemical measurement system for continuous monitoring of AT PO 2 using microdialysis. The effect of alterations in ATBF on AT PO 2 was investigated in lean and obese subjects with both pharmacological and physiological approaches to manipulate ATBF. Local administration of angiotensin II (vasoconstrictor) in abdominal subcutaneous AT decreased ATBF and AT PO 2 , whereas infusion of isoprenaline (vasodilator) evoked opposite effects. Ingestion of a glucose drink increased ATBF and AT PO 2 in lean subjects, but these responses were blunted in obese individuals. However, AT PO 2 was higher (hyperoxia) in obese subjects despite lower ATBF, which appears to be explained by lower AT oxygen consumption. This was accompanied by insulin resistance, lower AT capillarization, lower AT expression of genes encoding proteins involved in mitochondrial biogenesis and function, and higher AT gene expression of macrophage infiltration and inflammatory markers. Conclusions-Our findings establish ATBF as an important regulator of AT PO 2 . Nevertheless, obese individuals exhibit AT hyperoxia despite lower ATBF, which seems to be explained by lower AT oxygen consumption. This is accompanied by insulin resistance, impaired AT capillarization, and higher AT gene expression of inflammatory cell markers. Clinical Trial Registration-URL: http://www.trialregister.nl. Unique identifier: NTR2451. (Circulation. 2011;124:67-76.)

Polyphenolic compounds, such as resveratrol, have recently received widespread interest because of their ability to mimic effects of calorie restriction. The objective of the present study was to gain more insight into the effects of 30 days resveratrol supplementation on adipose tissue morphology and underlying processes. Eleven healthy obese men were supplemented with placebo and resveratrol for 30 days (150 mg per day), separated by a 4-week washout period in a double-blind randomized crossover design. A postprandial abdominal subcutaneous adipose tissue biopsy was collected to assess adipose tissue morphology and gene expression using microarray analysis. Resveratrol significantly decreased adipocyte size, with a shift toward a reduction in the proportion of large and very-large adipocytes and an increase in small adipocytes. Microarray analysis revealed downregulation of Wnt and Notch signaling pathways and upregulation of pathways involved in cell cycle regulation after resveratrol supplementation, suggesting enhanced adipogenesis. Furthermore, lysosomal/phagosomal pathway and transcription factor EB were upregulated reflecting an alternative pathway of lipid breakdown by autophagy. Further research is necessary to investigate whether resveratrol improves adipose tissue function.

Our data suggest that 30 days of resveratrol supplementation does not affect fasting or postprandial incretin hormone plasma levels in obese humans, but suppresses postprandial glucagon responses.

PUFAs reduced triacylglycerol-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity, a more transcriptional oxidative phenotype, and altered intramyocellular lipid partitioning and may therefore be protective against the development of insulin resistance.

Altered skeletal muscle fatty acid (FA) metabolism contributes to insulin resistance. Here, we compared skeletal muscle FA handling between subjects with impaired fasting glucose (IFG; n = 12 (7 males)) and impaired glucose tolerance (IGT; n = 14 (7 males)) by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously, labeling circulating endogenous triacylglycerol (TAG) and free fatty acids (FFA), whereas [U-13C]-palmitate was incorporated in a high-fat mixed-meal, labeling chylomicron-TAG. Skeletal muscle biopsies were taken to determine muscle TAG, diacylglycerol (DAG), FFA, and phospholipid content, their fractional synthetic rate (FSR) and degree of saturation, and gene expression. Insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp. Net skeletal muscle glucose uptake was lower (p = 0.018) and peripheral insulin sensitivity tended to be reduced (p = 0.064) in IGT as compared to IFG subjects. Furthermore, IGT showed higher skeletal muscle extraction of VLDL-TAG (p = 0.043), higher muscle TAG content (p = 0.025), higher saturation of FFA (p = 0.004), lower saturation of TAG (p = 0.017) and a tendency towards a lower TAG FSR (p = 0.073) and a lower saturation of DAG (p = 0.059) versus IFG individuals. Muscle oxidative gene expression was lower in IGT subjects. In conclusion, increased liver-derived TAG extraction and reduced lipid turnover of saturated FA, rather than DAG content, in skeletal muscle accompany the more pronounced insulin resistance in IGT versus IFG subjects.

High-fibre diets offer several beneficial health effects. The objective of the present study was to investigate whether replacement of 30 % of the available carbohydrates with polydextrose (PDX) or soluble maize fibre (SCF) at breakfast and lunch would result in an increased fat oxidation rate and satiety, which may be of relevance for body weight control and diabetes prevention. In a single-blind, randomised crossover study, eighteen overweight men and women underwent four different dietary interventions, which consisted of a PDX diet, a SCF diet and two control diets (full energetic and isoenergetic, comparable with PDX with respect to g or energy percentage of macronutrients, respectively). Glycaemic profile, energy expenditure and substrate oxidation were measured for 24 h in a respiration chamber. Circulating insulin, NEFA and TAG concentrations were determined over a 14 h period during daytime. Appetite ratings were assessed using visual analogue scales. The replacement of available carbohydrates with PDX or SCF reduced the peak glucose response, which was accompanied by reduced postprandial insulin responses. Moreover, higher concentrations of circulating NEFA were observed after consumption of both fibre diets, which were accompanied by an increased fat oxidation over 24 h. This effect was mainly attributed to the lower energetic value of the fibre diets and not to the fibres per se. Besides increasing fat oxidation, PDX exerted a pronounced suppressive effect on appetite ratings. The replacement of available carbohydrates with PDX may be of special interest because of its beneficial effects on metabolic profile and it may affect body weight control in the long term.

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