This study investigated the mechanism by which exercise improves high-fat diet-induced depression in mice. Mice were fed a high-fat diet (HFD) for 8 weeks, with one group also receiving daily treadmill exercise. Exercise attenuated HFD-induced depressive-like behaviors and reversed hippocampal gene expression changes. RNA sequencing identified *Wnt5a* as a key mediator. Exercise activated neuronal autophagy in the hippocampal CA1 region via the *Wnt5a*/Camkll signaling pathway, enhancing synaptic plasticity. A *Wnt5a* inhibitor blocked the beneficial effects of exercise. The study highlights the crucial role of *Wnt5a* in exercise's ability to ameliorate HFD-induced depression.

Jialin Wu, Huachong Xu, Shiqi Wang, Huandi Weng, Zhihua Luo, Guosen Ou, Yaokang Chen, Lu Xu, Kwok-Fai So, Li Deng, Li Zhang, Xiaoyin Chen