Wnt10b knockdown promotes UCP1 expression in brown adipose tissue in mice

The effect of Wnt10b overexpression on adipose tissue development has been reported. However, the impact of Wnt10b knockdown on the function of brown adipose tissue (BAT) is yet largely unknown. Here, we used the CRISPR/Cas9 technique to generate Wnt10b-knockdown (Wnt10b^+/- ) mice. We compared the development and thermogenic gene expression of interscapular BAT (iBAT) between Wnt10b^+/- and Wnt10b^+/+ mice under a chow diet, high-fat diet (HFD), and cold exposure conditions. Moreover, the effect of Wnt10b knockdown on brown adipocyte function was tested via in vitro experiments. Results indicated that Wnt10b knockdown decreased the iBAT mass and the brown adipocyte size and enhanced thermogenic gene expression, including UCP1, under chow diet conditions. In addition, Wnt10b^+/- mice appeared to be able to maintain their body temperature better than the control in a cold environment, accompanied by higher UCP1 protein expression. Intriguingly, even under HFD conditions, Wnt10b^+/- mice still showed higher UCP1 expression, which was associated with an alleviated obesity phenotype. In vitro studies further evidenced the Wnt10b knockdown stimulation of UCP1 expression and suppression of the adipogenic program. This study indicates that Wnt10b knockdown enhances UCP1 expression and inhibits the adipogenic differentiation of brown adipocytes, providing a novel option for therapeutic interventions in adiposity.