Fig. 3E illustrates signaling mechanism involved Resistin/TLR4/MAPK/NF-κB. Obesity is a pernicious public health problem commonly associated with type 2 diabetes and insulin resistance state. Recent studies linked different obesity complications

and insulin resistance state with high resistin levels [13]. Resistin is an important adipokine that is positively correlated with high-fat mass and has been associated with a proinflammatory state as reported in chronic liver diseases [16]. Resistin also modulates the synthesis and secretion of key proinflammatory cytokines such as TNF-α and IL-6 through a NF-κB-dependent pathway [17]. Despite of several recent studies describing resistin Rucaparib chemical structure pathophysiology, only a small part of resisitin signaling is known and its importance in inflammation process has just started to be investigated. In the present study we evaluated for the first time the effects of oral Angiotensin-(1–7) administration in the inhibition of the inflammatory pathway – resistin/TLR4/MAPK/NF-κB in the liver of obese rats. Recent studies demonstrated the benefit of metabolic effects of the Ang-(1–7)/Mas axis find more activation [2], [19], [20] and [21]. In the present study we mainly observed that oral formulation of Ang-(1–7) produced an important reduction in body weight and adipose tissue mass associated with decreased serum total cholesterol and triglycerides levels followed by ameliorated

insulin sensitivity, glucose tolerance and diminished expression of proinflammatory

cytokine mRNAs. Additionally, we showed a decrease in TLR4 and MAPK expression in the liver associated with decreased ACE and increased ACE2 expression. Liver is a complex and important organ and plays an essential role on lipid and glucose metabolic regulation. Several studies showed that many RAS components are expressed in the liver meddling metabolic and inflammatory processes [2] and [29]. The increased expression of Ang II induced non-alcoholic fatty liver disease and modulates inflammatory cell recruitment into OSBPL9 the liver during liver injury [8] and [29]. Additionally, it was previously demonstrated that ACE2/Ang-(1–7)/Mas axis expression is down-regulated during obesity [20] and [21]. Rats with increased Ang-(1–7) levels had lower body weight and decreased IL-1β and COX-2 in adipose tissue associated with improved liver glucose metabolism [2]. Our results are in agreement with these data showing an elevated expression of ACE2 and decreased ACE in the livers of HFD + Ang-(1–7) treated rats. It has been shown that lipid and glycemic parameters can be modulated by resistin expression. [22], especially considering that resistin is produced by adipocytes, which are augmented in obese liver. Kushiyama et al. showed that resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes and induces diabetes, hyperlipidemia and fatty liver in transgenic mice on a high fat diet model [9].