Overactivation of the adipose tissue renin angiotensin system contributes to insulin resistance in high‐fat diet‐induced obesity

Abstract

Although obesity is associated with overactivation of the adipose tissue renin angiotensin system (RAS), a causal link between the latter and metabolic complications of obesity is not established. Using mice overexpressing angiotensinogen (Agt) in adipose tissue via the aP2 promoter (aP2‐Agt mice), we investigated the effects of RAS overactivation or blockade on insulin resistance and glucose tolerance in high‐fat (HF) diet‐induced obesity. On a low‐fat diet, the aP2‐Agt mice were significantly more glucose‐intolerant than their wild type littermates. Interestingly, these differences were eliminated when both strains were fed high‐fat diets. Moreover, in both aP2‐Agt and control littermates, glucose intolerance was significantly improved by treatment with the angiotensin converting enzyme inhibitor, captopril. Further studies investigating potential mechanisms associated with these metabolic changes demonstrated that the insulin resistance of the aP2‐Agt mice was mainly due to reduced insulin‐stimulated glucose uptake by skeletal muscle and heart. Additional proteomic studies and cytokine assays showed that adipose Agt overproduction increases markers of adipose inflammation, lipogenesis and lipolysis. Thus, this study provides evidence for a causal link between adipose RAS overactivation and insulin resistance in obesity.