<p>Metabolic dysregulation is a core pathological feature of and a major risk factor for depression. In this study, the role of G protein-coupled receptor 75 (GPR75), a brain-enriched metabolic sensor, in the pathogenesis of depression was explored and its potential role as a therapeutic target was evaluated. In chronic social defeat stress (CSDS) models, GPR75 expression was specifically upregulated in the arcuate nucleus glutamatergic (ARC^Vglut2) neurons of susceptible mice, a finding corroborated by analyses of postmortem brains from patients with depression. Conditional (GPR75-cKO) or local (GPR75-lKO) genetic knockout of GPR75 in these neurons resulted in robust antidepressant-like effects, alleviation of depression-like behaviors, and normalization of the hypothalamic–pituitary–adrenal (HPA) axis function. Pharmacological inhibition of GPR75 with an antagonist (AAA) elicited similar antidepressant-like effects. Conversely, overexpression or activation of GPR75 in ARC^Vglut2 neurons promoted depression-like behaviors in naïve mice. Mechanistically, GPR75 signaling acts through the Gαq-PLCβ-IP3R1 pathway to enhance Ca²⁺ release from the endoplasmic reticulum and increase neuronal excitability. This facilitates glutamate release in the paraventricular nucleus (PVN), resulting in HPA axis activation. Chemogenetic inhibition of ARC^Vglut2 neurons or the ARC^Vglut2-PVN circuit replicated the antidepressant-like effects of GPR75 ablation, whereas their activation abolished these benefits. These findings establish GPR75 expression in ARC^Vglut2 neurons as a critical mediator of depression and a potential target for novel antidepressants.</p>