Objective: Human obesity is closely associated with a state of chronic low-grade inflammation, which also involves the adipose tissue with enhanced production of bioactive substances (adipokines). Calorie restriction (CR) reduces adipocytokine production and improves metabolic profile in rodents. Some of these effects are mediated through activation of the sirtuin 1 (Sirt1) enzyme, and in this study, we investigate whether the natural phytoalexin, resveratrol (RSV), which is a potent Sirt1 activator, has anti-inflammatory effects in human adipose tissue explants. Design: The effect of RSV on interleukin 1b (IL1b)-induced change of adipokine mRNA gene expression and secretion were measured in human adipose tissue explants. Results: Exposure of human adipose tissue in vitro to IL1b for 24 h increased secretion of the proinflammatory adipokines IL6, IL8 and monocyte chemoattractant protein 1 (MCP-1) 3-7.7-fold (Po0.05) and increased IL6, IL8, MCP-1, IL1b and PAI-1 mRNA expression 1.3-7.2-fold (Po0.05) accordingly. Concomitant incubations with RSV reversed the IL1b-stimulated secretion (16-36%) and gene expression (25-48%) of these adipokines. IL1b reduced adiponectin mRNA expression (40%), a decrement that was reversed by RSV treatment. Similar effects were observed in differentiated human preadipocytes in primary culture, indicating that human adipocytes are a potential target for RSV effects. Finally, the effects were neutralized by sirtinol, a Sirt1 inhibitor. Conclusion: This study is the first to show anti-inflammatory effects of RSV on adipokine expression and secretion in human adipose tissue in vitro through the SIRT1 pathway. Thus, RSV is hypothesized to possess beneficial effects and might improve the metabolic profile in human obesity.

Objective: Calorie restriction increases the life span in a number of different organisms. This effect is dependent upon activation of the Sirt1 enzyme, and many of the beneficial effects of calorie restriction can be mimicked using resveratrol, which activates the Sirt1 enzyme. Nothing is known about this system in human adipose tissue; therefore, we investigated this system in human adipose tissue. Design: Sirt1 mRNA was measured in adipose tissue biopsies from human volunteers before and after 6 days of total fasting. In addition, adipose tissue from lean and obese individuals was compared and in vitro investigations were performed. Results: Long-term total fasting (6 days) of nine human volunteers increased Sirt1 mRNA expression in subcutaneous adipose tissue more than twofold (0.197-0.454 arbitrary units, Po0.05). Likewise, lean women (n ¼ 12) had more than twofold higher Sirt1 expression in subcutaneous adipose tissue compared to obese women (n ¼ 12; 0.33-0.73 arbitrary units, Po0.05). Sirt1 was equally expressed in the stroma-vascular fraction and the isolated adipocyte fraction. Finally, in vitro, we demonstrated that resveratrol (a Sirt1 activator) significantly enhanced the lipolytic effect of epinephrine in human adipose tissue (Po0.05). Conclusion: Human adipose tissue contains Sirt1 and the expression of Sirt1 can be regulated by calorie restriction as in other species. Furthermore, we demonstrated that resveratrol affects human fat-cell metabolism similar to the effects in rodents (that is, increased epinephrine induced lipolysis). These findings indicated that the beneficial effects of calorie restriction in humans might involve the activation of Sirt1. Thus, based on these findings, we propose that Sirt1 might play important roles for the beneficial effects of calorie restriction in humans.

The primary aim of the present study was to investigate if overweight and obese compared to lean individuals displayed differences in levels of inflammatory markers in circulation, skeletal muscle (SM) and adipose tissue (AT) after acute exercise. Fifteen lean (BMI: 22.4 ± 2 kg/m(2)) and 16 overweight or obese (BMI 31.8 ± 3 kg/m(2)) individuals were included in the study. They completed 120 min of ergometer bicycling at 55-60 % of maximal heart rate. Blood samples were obtained at baseline (T = 0), after 60 (T = 60) and 120 min of exercise (T = 120), and analyzed using an ELISA method. SM and AT biopsies were obtained at T0 and T120, and mRNA expression was investigated using a Real-time RT-PCR method. Circulating IL-6, TNF-α, IL-8, and IL-15 all increased at T = 120 min (p < 0.01). Circulating IL-6 and IL-15 increased in all subjects at T = 120 min (p < 0.01), but only the increase of IL-6 was significantly higher in overweight and obese subjects (p < 0.05), and was positively correlated with body fat percentage (p < 0.01). Circulating IL-8 and TNF-α were increased in overweight and obese (p < 0.05) but not in lean subjects. Acute exercise induced an increase in IL-6 mRNA expression in SM biopsies (p < 0.05). IL-6 as well as adiponectin mRNA expression was increased in AT biopsies (p < 0.05); however, no effect of body weight was found. The findings suggest that the systemic inflammatory response to acute exercise is different in lean compared to overweight and obese subjects, with a more pronounced increase in inflammatory markers (e.g., IL-6, IL-8, and TNF-α) in overweight and obese individuals.

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Adipose tissue inflammation is believed to play a pivotal role in the development obesity-related morbidities such as insulin resistance. However, it is not known how this (low-grade) inflammatory state develops. It has been proposed that the leakage of lipopolysaccharides (LPS), originating from the gut microbiota, through the gut epithelium could drive initiation of inflammation. To get a better understanding of which proteins and intracellular pathways are affected by LPS in adipocytes, we performed SILAC proteomic analysis and identified proteins that were altered in expression. Furthermore, we tested the anti-inflammatory compound resveratrol. A total of 927 proteins were quantified by the SILAC method and of these 57- and 64 were significantly up- and downregulated by LPS, respectively. Bioinformatic analysis (GO analysis) revealed that the upregulated proteins were especially involved in the pathways of respiratory electron transport chain and inflammation. The downregulated proteins were especially involved in protein glycosylation. One of the latter proteins, GALNT2, has previously been described to regulate the expression of liver lipases such as ANGPTL3 and apoC-III affecting lipid metabolism. Furthermore, LPS treatment reduced the protein levels of the insulin sensitizing adipokine, adiponectin, and proteins participating in the final steps of triglyceride- and cholesterol synthesis. Generally, resveratrol opposed the effect induced by LPS and, as such, functioning as an ameliorating factor in disease state. Using an unbiased proteomic approach, we present novel insight of how the proteome is altered in adipocytes in response to LPS as seen in obesity. We suggest that LPS partly exerts its detrimental effects by altering glycosylation processes of the cell, which is starting to emerge as important posttranscriptional regulators of protein expression. Furthermore, resveratrol could be a prime candidate in ameliorating dysfunctioning adipose tissue induced by inflammatory stimulation.