Mechanisms Linking the Adipocyte Renin Angiotensin System, Inflammation and Endoplasmic Reticulum (ER) Stress
Authors: Menikdiwela Kalhara R. , Ramalingam Latha , Kalupahana Nishan S. , Scoggin Shane , Moustaid‐Moussa Naima 
Published: June 2021

One of the critical pathways involved in obesity is the Renin angiotensin system (RAS) which is classically known to regulate blood pressure and fluid balance. Components of RAS are expressed in adipose tissue; however, mechanisms governing RAS‐obesity interactions are not well identified. Both ER stress and inflammation are increased in adipose tissue and we proposed that it is through ER stress and inflammatory pathways, that RAS contributes to obesity and regulates adipocyte function. This hypothesis was tested using male wild type C57BL/6 mice (Wt) and transgenic mice (Agt‐Tg) overexpressing angiotensinogen (Agt) via P2 promoter in the adipose tissue. Mice were fed a low fat (LF) or a high fat (HF) diet with or without RAS inhibition (captopril, an angiotensin converting enzyme inhibitor). Furthermore, for mechanistic analyses, we used mouse and human adipocytes treated with various inhibitors of RAS (Telmisartan, P‐186), inflammation (11‐7082), and ER stress (PBA).Markers of ER stress such as BiP (Binding immunoglobulin protein), ATF4 (activating transcription factor 4), XBP1 (X‐box binding protein 1) and CHOP (CCAAT/‐enhancer‐binding protein homologous protein) were significantly higher in Agt‐Tg mice compared to Wt mice. Moreover, adipose tissue mRNA and serum levels for pro‐inflammatory markers MCP‐1 (Monocyte Chemoattractant Protein‐1), and IL‐6 (interleukin‐6) were also significantly higher in Agt‐Tg compared to Wt mice. By contrast, anti‐inflammatory cytokine IL‐10 was significantly lower in Agt‐Tg mice compared to Wt mice. Captoril‐treated Agt‐Tg mice demonstrated a significantly lower expression of both ER stress and pro‐inflammatory markers indicating the importance of RAS in these metabolic pathways. To gain further insight into direct mechanisms by which RAS induces obesity, in vitro experiments were conducted. Inhibitors of angiotensin type 1 and type 2 receptors (Agtr) were used to determine the pathway through which RAS induces ER stress and inflammation. Inhibition of Agtr1 receptor significantly reduced RAS effect in both mouse and human adipocytes. As anticipated PBA and 11‐7082 reduced RAS‐induced ER stress and inflammation in vitro further confirming the involvement of RAS. In agreement with these findings, captopril and telmisartan prevented angiotensin‐II (Ang II) induced expression of ER stress, and pro inflammatory markers in both cell types. Further studies are ongoing in cultured adipocytes to dissect molecular mechanisms linking RAS to ER stress and inflammation in obesity.In conclusion, overexpression of RAS in adipose tissue and adipocytes increases inflammation and ER stress. These effects are mediated by Agtr1 receptors. These pathways could be used as potential targets to reduce RAS induced obesity and related metabolic diseases.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.