InactivationofAdiposeAngiotensinogen Reduces inflammatory Adipokines and Adipose Tissue Macrophages

Abstract

Adiposerennin-angiotensin systemhasbeen linked to obesity and metabolic syndrome. Previously we showed that overexpression of Angiotensinogen(Agt) in adipose tissue increased insulin resistance, adipose and systemic inflammation in mice fed a low fat(LF)diet. To further dissect the direct role of adipose Agt in metabolic disorders,we have created an adipose specific Agt knockout (Agt-KO)mice using the Cre-LoxPsystem.Agt-KO and control(WT) littermates were fed either a low-fat (LF) or high-fat (HF) diet to assess metabolic changes. Surprisingly, most metabolic parameters (body weight and fat mass, glucose and insulin tolerance tests) were comparable between the WT and Agt-KO littermates in both diets. Analyses of adipose tissue gene expression indicated shifts in angiogenesis and insulin signaling in the Agt-KO mice fed LF diets when compared to the WT mice. MCP1 gene expression was also downregulated in adipose tissue of the Agt-KO vs. WT littermates. These changes correlated with MCP-1 and Leptin protein expression, both of which were downregulated in the Agt-KO. Moreover,targeted inactivation of adipose Agt reduced total macrophage infiltration in both the LF and HF fed Agt-KO mice. This was in contrast to the total adipocyte area,which did not change between the two genotypes. In conclusion, despite the lack of an obvious phenotype in adipose Agt deficient mice, cellular and molecular changes observed are consistent with previously reported functions of RAS in insulin resistance, and inflammation.