Participação do TNF e da IL-18 no remodelamento do tecido adiposo induzido pela baixa disponibilidade de nutrientes.

Abstract

Introduction: The role of inflammatory mediators in adipose tissue remodeling resulting from both obesity and weight loss has been described in the literature. Paradoxically, both low and high nutrient availability induce an inflammatory response in white adipose tissue (WAT), which favors an increase or reduction in adiposity. Tumor necrosis factor (TNF) is a cytokine that increases in WAT both in the context of obesity and under the stimulus of fasting. In vitro studies have consistently demonstrated that this cytokine participates in lipolytic stimulation. Additionally, TNF signaling in adipocytes stimulates the secretion of interleukin 18 (IL-18), a cytokine that participates in lipolytic regulation. However, the role of both cytokines in adiposity reduction induced by dietary restriction remains unknown. The objective of the present study was to evaluate the participation of TNF and IL-18 in adipose tissue remodeling induced by low nutrient availability in animal models and humans. Methods: This work included 5 five experimentais approaches. Initially, we used C57/Bl6 male mice, wild-type (WT), knockout of TNF receptor 1 (TNFR1-/-), and knockout of IL-18 (IL-18-/-) subjected or not (control) to fasting for 24 or 48 h to evaluate the morphometry, metabolism, and inflammation of epididymal adipose tissue (eWAT) and subcutaneous adipose tissue (iWAT). To mimic the response to fasting, WT and TNFR1-/- mice were treated with CL316,243, a selective β3 adrenergic receptor agonist, or PBS and after 24h they were euthanized. We performed an ex vivo evaluation in which portions of eWAT and iWAT from C57/Bl6 mice were collected, conditioned in culture medium, treated with a TNF inhibitor antibody (infliximab, for 24h and stimulated for 90 min with CL316,243. C57/Bl6 mice were also treated with Infliximab or PBS and fasted for 48 h (control). In a more translational approach, we analyzed the expression of TNFR1, ATGL, HSL, adiponectin, leptin, and IL-18 in omental adipose tissue (oWAT) and subcutaneous adipose tissue (sWAT) of patients with severe obesity. The expression of these genes was correlated with anthropometric and metabolic data before and one year after bariatric surgery. Results: WT mice fasted for 24 h showed reduced adiposity, whereas TNFR1-/- mice were resistant to fat pad loss, even after fasting for a prolonged period of 48 h. The non-responsiveness of TNFR1-/- mice appears to be due to lower expression of lipases and cytokines in WAT. TNFR1-/- mice were also resistant to CL316,243 induced adiposity reduction. Furthermore, mice treated with infliximab and fasted for 48 h were resistant to adiposity loss and had a lower number of resident macrophages in the iWAT. Interestingly, TNFR1 expression in the oWAT of obese patients was positively correlated with weight loss (r=0. 5846) and adiposity (r=0.5352) one year after bariatric surgery. Unlike TNF, IL-18 does not appear to participate in the adiposity loss induced by fasting or bariatric surgery, since IL-18-/- mice respond to fasting in a similar way to WT animals. Furthermore, IL-18 expression in oWAT and sWAT was not correlated with weight and body fat loss one year after bariatric surgery. Conclusion: We identified a cytokine-specific effect on the regulation of adiposity loss induced by fasting or bariatric surgery, where TNF plays a key role in adipose tissue remodeling, while IL-18 does not appear to play a significant role.