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Subcellular localization

cilia

Functional category

• Small GTPases
• Signaling (Hedgehog
• GPCRs
• ion channels)

Function

We identified two missense mutations in G protein-coupled receptor 45 (Gpr45) that lead to obesity through hyperphagia. GPR45 was expressed in paraventricular nucleus of the hypothalamus (PVH), where it localized to cilia and recruited Gαs 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(40472089).