Neuronal GPR75 deficiency protects against diet-induced obesity in a humanized mouse model

GPR75, a G protein-coupled receptor implicated in human obesity through loss-of-function variants, has emerged as a promising regulator of energy and metabolic homeostasis. To dissect its tissue-specific functions, we generated a humanized floxed Gpr75 mouse model with conditional deletions in the brain and adipose tissue. Mice with brain-specific Gpr75 deletion using Nestin-Cre were resistant to diet-induced obesity, primarily through suppressed food intake and modest increases in energy expenditure. In contrast, adipocyte-specific deletion of Gpr75 had minimal effects on systemic metabolism but modestly enhanced mitochondrial oxygen consumption in brown adipose tissue under cold exposure. Gpr75 expression was up-regulated in key brain regions and down-regulated in white adipose tissue under high-fat diet conditions, supporting a predominant central role in metabolic adaptation. Histological and transcriptomic analyses further revealed depot-specific effects on adipocyte morphology and hepatic lipid accumulation in global knockouts. These findings position GPR75 as a critical regulator of central energy balance and provide a mechanistic framework for developing brain-targeted therapies against obesity.