Obesity‐associated mutant MC4 receptors with normal Gαs coupling frequently exhibit other discoverable pharmacological and biochemical defects

: Mutations in the melanocortin-4 receptor (MC4R) are the most common cause of early syndromic obesity known. Most of these mutations result in a loss of protein expression, α-melanocyte-stimulating hormone binding, receptor trafficking or coupling to the stimulatory G-protein, Gαs . However, approximately 26% of the obesity-associated mutations characterised to date exhibit none of these pharmacological defects. In the present study, we investigated seven of these apparently normal mutant MC4R in more detail and found that the majority (five of the seven) exhibit marked defects including defective binding of another endogenous melanocortin ligand, defective glycosylation, and defective recruitment of β-arrestin. These data provide support for two hypotheses: (i) that the majority of these rare, obesity-associated mutations are likely defective and causative of obesity and (ii) that β-arrestin recruitment is a valuable marker of normal MC4R function. Recent work has demonstrated a statistical correlation between the efficacy of β-arrestin recruitment to the MC4R and body mass index; however, the data reported here demonstrate both decreased and increased β-arrestin signalling in obesity-associated MC4R mutations.