Ellen Konings

Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation

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 PO2), thereby affecting AT inflammation and insulin sensitivity. Methods and Results— We developed an optochemical measurement system for continuous monitoring of AT PO2 using microdialysis. The effect of alterations in ATBF on AT PO2 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 PO2, whereas infusion of isoprenaline (vasodilator) evoked opposite effects. Ingestion of a glucose drink increased ATBF and AT PO2 in lean subjects, but these responses were blunted in obese individuals. However, AT PO2 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 PO2. 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.

The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men

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.

PUFAs acutely affect triacylglycerol-derived skeletal muscle fatty acid uptake and increase postprandial insulin sensitivity

BACKGROUND Dietary fat quality may influence skeletal muscle lipid processing and fat accumulation, thereby modulating insulin sensitivity. OBJECTIVE The objective was to examine the acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA processing and postprandial insulin sensitivity in obese, insulin-resistant men. DESIGN In a single-blind, randomized, crossover study, 10 insulin-resistant men consumed 3 high-fat mixed meals (2.6 MJ), which were high in SFAs, MUFAs, or PUFAs. Fasting and postprandial skeletal muscle FA processing was examined by measuring differences in arteriovenous concentrations across the forearm muscle. [²H₂]Palmitate was infused intravenously to label endogenous triacylglycerol and FFAs in the circulation, and [U-¹³C]palmitate was added to the meal to label chylomicron-triacylglycerol. Skeletal muscle biopsy samples were taken to assess intramuscular lipid metabolism and gene expression. RESULTS Insulin and glucose responses (AUC) after the SFA meal were significantly higher than those after the PUFA meal (P = 0.006 and 0.033, respectively). Uptake of triacylglycerol-derived FAs was lower in the postprandial phase after the PUFA meal than after the other meals (AUC₆₀₋₂₄₀; P = 0.02). The fractional synthetic rate of the triacylglycerol, diacylglycerol, and phospholipid pool was higher after the MUFA meal than after the SFA meal. PUFA induced less transcriptional downregulation of oxidative pathways than did the other meals. CONCLUSION 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.

Effect of polydextrose and soluble maize fibre on energy metabolism, metabolic profile and appetite control in overweight men and women.

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 cross-over 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.

Thirty days of resveratrol supplementation does not affect postprandial incretin hormone responses, but suppresses postprandial glucagon in obese subjects

Resveratrol, a natural polyphenolic compound produced by various plants (e.g. red grapes) and found in red wine, has glucose‐lowering effects in humans and rodent models of obesity and/or diabetes. The mechanisms behind these effects have been suggested to include resveratrol‐induced secretion of the gut incretin hormone glucagon‐like peptide‐1. We investigated postprandial incretin hormone and glucagon responses in obese human subjects before and after 30 days of resveratrol supplementation.

Altered Skeletal Muscle Fatty Acid Handling in Subjects with Impaired Glucose Tolerance as Compared to Impaired Fasting Glucose

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.

PS9 - 45. Differences in skeletal muscle fatty acid handling between subjects with impaired fasting glucose and impaired glucose tolerance

Impairments in skeletal muscle (SM) fatty acid (FA) handling may contribute to insulin resistance and type 2 diabetes mellitus. The objective of the present study was to determine fasting and postprandial SM FA handling in subjects with impaired fasting glucose (IFG) (n=12) and combined IFG/impaired glucose tolerance (IGT) (n=14).

Response to Letter Regarding Article, “Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation”

We thank Drs Lecoultre and Tam for their thoughtful comments and interest in our recent publication.1 They question whether the higher adipose tissue (AT) oxygen partial pressure (Po2) in obese insulin resistant men compared with lean insulin sensitive men should be considered as hyperoxia. Abdominal subcutaneous AT Po2 showed substantial interindividual variation both in our study (range 24–85 mm Hg)1 and in another human study that assessed AT Po2 in subcutaneous AT of the abdomen.2 We also demonstrated that pharmacological and physiological manipulation of AT blood flow induced concomitant alterations in AT Po2 in lean subjects. In our opinion, these findings indicate substantial flexibility of AT …

Expression of genes involved in lipid metabolism in men with impaired glucose tolerance: impact of insulin stimulation and weight loss.

Background:The impaired glucose tolerance (IGT) state is characterized by insulin resistance. Disturbances in fatty acid (FA) metabolism may underlie this reduced insulin sensitivity. The aim of this study was to investigate whether the prediabetic state is accompanied by changes in the expression of genes involved in FA handling during fasting and in insulin-mediated conditions and to study the impact of weight loss. Methods:Seven IGT men and 5 men with normal glucose tolerance (NGT), comparable in terms of age and BMI, participated in the study. The 5 IGT men followed a 12-week weight loss program. Muscle biopsies were taken and the expression of 6 genes was investigated. Results:Subjects had a reduction of 15.5 ± 4.3 kg in body weight. Baseline gene expression was not different between NGT and IGT men. After a hyperinsulinemic clamp, there was an overall upregulation of PGC1α, SREBP-1c, SREBP-2, and ACC-2. The upregulation of SREBP-2 was more pronounced in IGT men (p = 0.049). Weight loss significantly increased insulin sensitivity by 71%, which was not reflected in altered gene expression profiles. Conclusions:SREBP-2 shows altered insulin responsiveness in IGT men compared with NGT men, while there were no differences in basal gene expression.