Obesity is a disease defined as abnormal or excessive fat accumulation that presents a health risk, with a body mass index (BMI) over 30 (World Health Organization). Signalling mediated by hypothalamus-expressed membrane proteins from the GPCR family regulates food intake and metabolism. The orphan GPCR GPR61 was linked to the regulation of metabolism and, here, we identify 34 mutations in the GPR61 gene which are present with much higher frequency in severe obesity samples from the UK10K obesity screen than in the normal population. The cumulative sum of mutations was higher for the GPR61 gene compared to the highly mutated and well-established target, melanocortin 4 receptor (MC4R). The majority of the GPR61 mutations reduced cell surface expression of overexpressed HiBiT-GPR61 in HEK293A cells. Additionally, the mutations T92P, R236C and R262C reduced ligand-independent GPR61-induced cAMP production, and R236C compromised Gs protein activation. Therefore, we suggest that GPR61 indeed represents a Gs-coupled receptor with a potential role in the regulation of metabolism. Our data warrant further studies to assess the role of this orphan GPCR in metabolism in greater detail.

The authors have declared no competing interest.

This study did not receive any direct funding. Research projects in the lab are supported by grants for PK from Karolinska Institutet, the Swedish Research Council (2022-01398) and the Jeanssons Foundation (2023-0071).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

UK10K Project Data Access Agreement 15267

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The authors declare that the majority of the data supporting the findings of this study are contained within the paper. MD data that support the findings of this study will be deposited on gpcrmd.org buty they also are available on request from the corresponding author.