Adipose Angiotensinogen Overexpression Promotes Adipose Associated Inflammation and Endoplasmic Reticulum Stress

Abstract

Obesity is a chronic low‐grade inflammatory condition that afflicts more than a third of the American population. Angiotensin II (Ang II), a major regulator of blood pressure and fluid balance, is generated from the Renin Angiotensin System (RAS) and has been associated with obesity. Angiotensinogen (Agt), the precursor of Ang II, is also secreted locally in adipose tissue with elevated levels observed under obesogenic conditions. Furthermore, adipose overexpression of Agt causes insulin resistance in part via modulation of adipose inflammation; however, the exact mechanisms remains undetermined yet. Hence, we hypothesize that adipose enrichment of Agt leads to activation of inflammatory cascades and endoplasmic reticulum (ER) stress, thereby contributing to obesity. To test this hypothesis, microarray analysis was conducted in adipose tissue of mice, specifically over‐expressing Agt in the fat (Agt‐Tg) versus wild‐type controls. Microarray and real time PCR data revealed increases in pro‐inflammatory adipokines and decreases in anti‐inflammatory adipokines. Furthermore, increased mRNA levels for ER markers such as CHOP and BIP were observed in these Agt‐Tg. Detailed analysis using immunoblotting and immunohistochemistry methods are currently underway to confirm these findings. In conclusion, overexpression of Agt activates inflammatory and ER cascades; these mechanisms may mediate obesity associated RAS activation thereby promoting obesity. In future, we will use pharmacological and/or genetics approaches to determine whether these effects are mediated by Ang II via renin or Angiotensin Converting Enzyme.