Trilobatin, a Naturally Occurring GPR158 Ligand, Alleviates Depressive-like Behavior by Promoting Mitophagy

The G-protein-coupled receptor (GPR158), an orphan receptor, is highly expressed in the medial prefrontal cortex (mPFC) and identified as a novel therapeutic target for depression. Trilobatin is a naturally occurring food additive with potent neuroprotective properties. However, its pharmacological effects and molecular mechanisms against depression remain unknown. Therefore, we explored whether trilobatin alleviates depression by targeting GPR158. Our results indicated that trilobatin alleviated chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in mice. Mitophagy contributed to the antidepressant-like effect of trilobatin, as evidenced by the qRT-PCR array. Furthermore, trilobatin up-regulated autophagy-associated protein expression, restored mitochondrial dynamic balance, and inhibited oxidative stress of mPFC in mice after CUMS insult and in corticosterone-induced primary neuron injury. Intriguingly, trilobatin directly bound to GPR158 and decreased its level of protein expression. GPR158 deficiency attenuated depressive-like behavior through promoting mitophagy, while the antidepressant effect of trilobatin was strengthened in GPR158-deficient mice. Our findings highlight that GPR158-mediated mitophagy acts as a crucial pharmacological target for depression and reveal a new-found pharmacological property of trilobatin: serving as a novel naturally occurring ligand of GPR158 to safeguard from depression by oxidative stress by promoting mitophagy.