Mechanisms linking the adipocyte renin angiotensin system to obesity, inflammation and endoplasmic reticulum stress

The Renin Angiotensin System (RAS), the primary regulator of blood pressure, has been linked to several metabolic disorders including obesity. Its components are highly expressed in various tissues and organs such as adipose, liver, and kidney. During obesity, levels of angiotensin II (Ang II) and angiotensinogen (Agt), the key components of RAS system, are significantly elevated. Accumulated evidence over the past few decades demonstrated that adipose overexpression of RAS components disrupts metabolic homeostasis in the adipose tissue promoting chronic environment leading to metabolic disorders. Obesity and its co-morbidities are reaching epidemic portion, therefore, research that can unravel mechanistic involvement of RAS in obesity is urgently needed. Finding effective treatment strategies for RAS-induced obesity will help us get one step closer to addressing the global health concerns associated with RAS (obesity, diabetes and cardiovascular diseases) which is the primary focus of this dissertation study. Animal models with RAS overexpression or inactivation provide excellent tools to understand the involvement of RAS in obesity. Agt overexpression specifically in mice adipose tissue, showed elevated expression of pro-inflammatory cytokines with lower amounts of anti-inflammatory cytokines. Additionally, in vivo and in vitro studies conducted in cardiovascular system have demonstrated that RAS component Ang II activates several physiological processes including endoplasmic reticulum (ER) stress, oxidative stress, autophagy and inflammation. However, the role of RAS overactivation in adipose tissue during obesity and how these processes are regulated, remain to be elucidated. MicroRNAs (miRNA) are potential mediators as they are capable of regulating multiple genes post-transcriptionally. Previous research conducted in our lab has reported that overexpression of Agt in adipose tissue (Agt-Tg) induces obesity, inflammation and ER stress through yet unidentified mechanisms. Accordingly, we hypothesized that adipose overactivation of angiotensinogen leads to stimulation of inflammation, and ER stress which could contribute to obesity. We further hypothesize that RAS-induced metabolic alterations are mediated via miRNAs. The two main objectives of this research were: (1) To determine the effects of RAS in adipose inflammation, and ER stress. Wild type (Wt), Agt-Tg and Agt-knockout (KO) mice along with clonal mice and human adipocytes were used to test this objective. We identified that RAS overactivation significantly activates the expression of ER stress, inflammation and autophagic markers. We also found that RAS increases ER stress in part via Nuclear factor kappa B- Yin Yang 1 (NF-κB-YY1) axis through Angiotensin II receptor type 1 (AT1) receptor. Furthermore, studies performed with RAS inhibitors such as angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blockers and KO mice showed reduced levels of pro-inflammatory markers. Corroborating these results, we reported that AT1 blocker, telmisartan reduced ER stress and inflammation in cells further confirming potential RAS function via AT1 receptor. (2) To determine mechanisms by which RAS induces metabolic alterations in adipose tissue and identify miRNAs mediating effects of RAS during obesity. From our mechanistic studies related miRNAs, we showed that several miRNAs were affected by RAS overactivation. Out of 31 differentially expressed miRNAs, miR-690 was significantly overexpressed in Agt Tg mice compared to wild type mice. Interestingly, miR-690 appears to have a protective role during RAS induced obesity, targeting mitogen-activated protein kinase kinase 3 (MAP2K3). We showed that miR-690 ameliorates downstream inflammatory and ER stress markers associated with p38MAPKs pathway by inhibiting MAP2K3 expression. In conclusion, this study contributed significantly to a better understanding of how RAS overactivation disrupts metabolic homeostasis in the adipose tissue during obesity. Adipose RAS overexpression affects signaling pathways (inflammation, ER stress and autophagy) and miRNAs which regulate these molecular pathways. Additionally, this work provides science-based rationale for detrimental effects of RAS overexpression in the adipose tissue, suggesting novel molecular targets that could be used in the development of future therapeutic.

This dissertation won 1st Place in the Texas Tech University Outstanding Thesis and Dissertation Award, Biological Life Sciences, 2021.

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