Avaliação dos Efeitos da Angiotensina-(1-7) Sobre o Tecido Adiposo, Inflamação e Microbiota Intestinal, e o Impacto do Uso de Probiotico na Expressão do Sistema Renina Angiotensina

Abstract

Adipose tissue has recently been recognized as an important endocrine and metabolic organ responsible for the synthesis of adipokines that control metabolism, body homeostasis, and inflammation. Recent evidence suggests the important role of Angiotensin- (1-7) in the treatment of obesity and metabolic disorders due to its anti-inflammatory action and for being the main counter-regulator of the AngII axis of the renin-angiotensin system (RAS). Also, it is important to consider other important metabolic regulators, such as the intestinal microbiota and its modulation using probiotics. In this context, the present thesis aims to evaluate the effects of Ang- (1-7) on adipose tissue, inflammation, and intestinal microbiota, as well as the impact of probiotic use on the expression of the RAS. For this, three products were produced.Regarding product 1, we conducted a review on the findings related to the ECA2/Ang-(1-7)/MasR axis focusing on its role in the regulation of adipokine secretion and processes related to acute and chronic inflammation. It is important to emphasize the endocrine role of adipose tissue in the synthesis of adipokines, modulating their secretion and regulating various processes associated with acute and chronic inflammation, as well as their relevance in the body's homeostasis. The importance of molecular pathways involved in the mechanisms of action of adipokines has created the need for new studies aimed at investigating therapeutic interventions, as well as new tools to clarify the unknown mechanisms. The interaction and relevance of Ang- (1-7) in the expression and inflammation of adipokines have been discussed in regards to obesity, type 2 diabetes, cardiovascular diseases, renal and hepatic disorders, among others. In this perspective, we conclude that inflammation can be modulated by adipokines and Ang- (1-7) in different organs and they may be important targets for the treatment and prevention of inflammatory responses. In relation to product 2, we evaluated the effects of oral administration with Ang- (1-7) on the intestinal microbiota of obese mice. Male Swiss mice were divided into four groups: obese and non-obese/treated and not treated with ANG- (1-7). A significant decrease in fasting glycemia, total cholesterol, triglycerides, and LDL levels, and an increase in HDL in animals treated with ANG- (1-7) were observed. Histological analysis showed a reduction of intestinal villus height in ANG-(1-7)treated mice. In addition, an increase in the abundance of Bacteroidetes and a reduction inFirmicutes (increased Bacteroidetes/Firmicutes ratio) and Enterobacter cloacae were observed in the HFD + ANG- (1-7) group. Intestinal mRNA expression of the TLR4 receptor was reduced in the HFD + ANG- (1-7) group. Finally, intestinal expression of B0AT1 was increased in obese animals treated with ANG- (1-7), showing a possible mechanism associated with tryptophan uptake. The results of the present study suggest, for the first time, an interaction between RAS and the modulation of the intestinal microbiota. Finally, concerning product 3, we evaluated the effect of Bifidobacterium longum supplementation on metabolic parameters and the expression of the renin-angiotensin system in obese mice. Male Swiis mice were divided into four groups: obese and non-obese/treated and not treated with B. longum. After four weeks of treatment, obese mice that received B. longum showed a significant decrease in body weight, adiposity, serum glycemia levels, and total cholesterol, as well as an improvement in glucose tolerance. Furthermore, histological analyses demonstrated a reduction in the accumulation of hepatic triglycerides in the obese-treatedgroup. Analyses of mRNA showed a significant increase in the expression of angiotensin-converting enzyme 2 ECA2 and RMAS in the obese mice that received B. longum. Our data suggest for the first time the modulation of RAS by the B. longumstrain.