Therapeutic Potential of AAV-FL-Klotho in Obesity: Impact on Weight Loss and Lipid Metabolism in mice

Klotho, an anti-aging protein, has gained attention for its protective effects against various diseases, including metabolic disorder, through recombinant Klotho administration. However, the potential of Klotho as a target for gene therapy needs further exploration and is barely studied with regard to metabolic disorder. In this study, we demonstrate that AAV-FL(full length)-Klotho administration induces weight loss in mice and provides protection against high-fat diet (HFD)-induced obesity and hepatic steatosis, concurrently reducing the weights of white adipose tissue and liver. AAV-FL-Klotho administration also enhanced thermogenic gene expression in brown adipose tissue (BAT) and improved the morphology of interscapular BAT. The weight loss effect of AAV-FL-Klotho was found to be, at least in part, mediated by UCP1-dependent thermogenesis in brown adipocytes, potentially influenced by hepatokines secreted from AAV-FL-Klotho-transduced hepatocytes. These findings suggest that AAV-FL-Klotho is an attractive candidate for gene therapy to combat obesity. Nevertheless, unbiased experiments have also revealed disturbances in lipid metabolism due to AAV-FL-Klotho, as evidenced by the emergence of lipomas and increased expression of hepatic lipogenic proteins.