GPR45 modulates Gα_s at primary cilia of the paraventricular hypothalamus to control food intake.

Abstract

The melanocortin system centrally regulates energy homeostasis, with key components such as melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3) in neuronal primary cilia. Mutations in <i>MC4R</i> and <i>ADCY3</i> as well as ciliary dysfunction lead to obesity, but how melanocortin signaling works in cilia remains unclear. Using mouse random germline mutagenesis, we identified two missense mutations in <i>G protein-coupled receptor 45 (Gpr45)</i> that lead to obesity through hyperphagia. GPR45 was expressed in paraventricular nucleus of the hypothalamus (PVH), where it localized to cilia and recruited Gα_s to increase ciliary cyclic adenosine monophosphate (cAMP) via ADCY3. GPR45 colocalized with MC4R in PVH cilia and promoted ciliary MC4R activation. Loss of GPR45 in the PVH or MC4R⁺ neurons caused obesity. These findings establish GPR45 as a key regulator of the ciliary melanocortin system, bridging MC4R and ADCY3.