[Abstract unavailable

Early studies demonstrated that whole-body androgen receptor (AR)-knockout mice with hypogonadism exhibit insulin resistance. However, details about the mechanisms underlying how androgen/AR signaling regulates insulin sensitivity in individual organs remain unclear. We therefore generated hepatic AR-knockout (H-AR ؊/y ) mice and found that male H-AR ؊/y mice, but not female H-AR ؊/؊ mice, fed a high-fat diet developed hepatic steatosis and insulin resistance, and aging male H-AR ؊/y mice fed chow exhibited moderate hepatic steatosis. We hypothesized that increased hepatic steatosis in obese male H-AR ؊/y mice resulted from decreased fatty acid ␤-oxidation, increased de novo lipid synthesis arising from decreased PPAR␣, increased sterol regulatory element binding protein 1c, and associated changes in target gene expression. Reduced insulin sensitivity in fat-fed H-AR ؊/y mice was associated with decreased phosphoinositide-3 kinase activity and increased phosphenolpyruvate carboxykinase expression and correlated with increased protein-tyrosine phosphatase 1B expression. Conclusion: Together, our results suggest that hepatic AR may play a vital role in preventing the development of insulin resistance and hepatic steatosis. AR agonists that specifically target hepatic AR might be developed to provide a better strategy for treatment of metabolic syndrome in men. (HEPATOLOGY 2008;47:1924-1935

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Epidemiological evidence suggests that sex differences exist in type 2 diabetes. Men seem to be more susceptible than women to the consequences of obesity and sedentary lifestyle, possibly because of differences in insulin sensitivity and regional body fat deposition. Thus, lacking androgen receptor (AR) in male individuals may promote insulin resistance. To determine whether lacking AR in male individuals contributes to in vivo insulin resistance, an AR knockout model (AR Ϫ/y ) was used to study the correlation between AR and insulin resistance. Progressive reduced insulin sensitivity and impaired glucose tolerance were seen in AR

Cyclophilin A promotes atherosclerosis in part by inducing reactive oxygen species and promoting endothelial cell apoptosis and macrophage recruitment into lesions.