Tks4 ‐Targeted Gene Therapy Inhibited White Adipocyte Hypertrophy in Mice

Obesity is one of the most prevalent public health issues worldwide, which substantially increases the risk of many metabolic disorders. Anti-obesity medications and bariatric surgery are clinical treatments for obesity, but suffer from certain limitations. Gene therapy with effective and safe targets provides a novel approach for obesity intervention. Tks4 has been shown to play an essential role in preadipocyte to adipocyte differentiation. However, it is still elusive if it could be a drug target against obesity in vivo. Here, we found the expression levels of Tks4 correlate with adipocyte development and hypertrophy in mice. By generating a Tks4 KO mouse model, we showed Tks4 deletion significantly restricted adipocyte hypertrophy and reduced blood glucose and lipid levels. We further used an adeno-associated viral (AAV) vector to mediate sustained Tks4 silencing. For a single administration, the adipocyte hypertrophy at the injection site was significantly reduced in a dosage-dependent manner. The TAG biosynthesis defect was also verified by lipidomics analysis of the infected WAT, though an elevation of TAG in blood was also detected. These data support the potential of Tks4 gene therapy to treat obesity.