Overproduction of Angiotensinogen from Adipose Tissue Induces Adipose Inflammation, Glucose Intolerance, and Insulin Resistance

Abstract

Although obesity is associated with overactivation of the white adipose tissue (WAT) renin–angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NF κB-dependent increases in WAT inflammation.

Combating obesity in Sri Lanka – Understanding the enemy

“…To test this, we genetically overexpressed Agt specifically in adipose tissue of mice. These mice developed insulin resistance as indicated by euglycemic, hyperinsulinemic clamp studies, confirming our hypothesis 16 . These findings were published in the journal "Obesity".…”

Angiotensin II receptor blockade and insulin sensitivity in overweight and obese adults with elevated blood pressure

“…202 The increased expression appears to occur via Ang II type 1 receptor-mediated and NF-κB-dependent pathways. 202 Moreover, multiple investigations have observed significant reductions in adipose tissue gene expression of proinflammatory cytokines and macrophages as well as elevations in adiponectin levels after ARB administration in obese rodents. 101,170,201 These inflammatory alterations were associated with an improvement in whole-body insulin sensitivity.…”

Myocardial Insulin Resistance: An Overview of Its Causes, Effects, and Potential Therapy

“…Adipose tissue RAS over-activity may also contribute to systemic insulin resistance since Ang II from adipose tissue contributes to circulating Ang II levels. This was well demonstrated by a study investigating the effect of adipose tissue angiotensinogen (Agt) over-expression on systemic glucose tolerance and insulin resistance [142]. The overexpression of Agt in adipose tissue caused cardiac and skeletal insulin resistance and reduced muscle glucose uptake.…”