Participação das citocinas IL-18 E TNF, e do receptor CCR5 em alterações metabólicas e inflamatórias na obesidade induzida por dieta

Abstract

Obesity is characterized as an exacerbated expansion of adipose tissue associated with metabolic and inflammatory dysfunction, and with a low-grade chronic inflammation state. In this context, the role of proinflammatory pathways and mediators have been shown on the development of that metabolic disease. The inflammatory response observed is an integration between differents pathways of the immune system, and during besity, there is a marked increase in proinflammatory cytokines in the adipose tissue. Leukocytes and adipocytes contribute to the high level of cytokines, and that cytokines can also stimulate the transcription of other proinflammatory mediators. Thus, the present study evaluated the role of the cytokines IL-18 and TNF, and also the role of CCR5 receptor on the adipose tissue remodeling and on the metabolic complications of obesity. IL-18-/-, TNFR1-/- , CCR5-/- and wild type mice, fed with chow or rich in refined carbohydrates diet (HC) were used. Lack of IL-18 or TNF receptor 1 have led to increased cytokine production in the liver and higher histopathological score, even in the lean animals (fed on a control diet). However, HC diet did not exacerbate hepatic inflammation. About adipose tissue expansion, TNFR1-/- mice gained more adiposity regardless of diet composition. Also, they showed decreased levels of TNF, IL-6 and IL-10 cytokines on the tissue. On the other hand, the ablation of TNFR1-/- mice improved insulin sensitivity during a challenge with HC diet. The IL-18-/- mice gained more weight and adiposity, and have shown increased proinflammatory cytokines in adipose tissue, associated to a decreased glucose tolerance even when fed with control diet. HC diet challenge did not exacerbate those responses. We also studied a chimeric model, to evaluate which cells were involved in the IL-18 -/- mice phenotype. We have shown that the expansion of adipose tissue observed in IL-18-/- mice appears to be related to the deficiency of this cytokine in non-hematopoietic cells, whereas the decrease in glucose tolerance seems to be related to the cytokine ablation in hematopoietic cells. To evaluate the role of recruitment, we used CCR5-/- mice. We have shown that CCR5 absence did not alter body weight gain and visceral adiposity, but increased inguinal fat pad, impaired glucose and lipid metabolism and contributed to fat accumulation in the liver. When fed with HC diet, CCR5-/ - mice showed impaired insulin sensitivity, as well as hepatic steatosis. We concluded that despite different inflammatory pathways were associated with development and progression of obesity, they also seem to be related to maintenance of metabolic homeostasis.