MC4R is one of the key regulators of body weight in humans. Variants in MC4R are the most commonly identified genetic cause of obesity. In collaborative work published in Cell, Prof Sadaf Farooqi’s group at MRL and the team from the MRC Epidemiology Unit led by Dr Claudia Langenberg and Prof Nick Wareham, have demonstrated that some variants found in MC4R can also protect against obesity and its metabolic complications.
The researchers studied 61 MC4R variants identified in nearly half a million participants from the UK Biobank cohort. Farooqi’s team characterised the signalling properties of all missense variants in vitro and showed that some of these variants can result in the receptor’s gain-of-function. Moreover, they demonstrated that some gain-of-function variants showed signalling bias towards β-arrestin recruitment over the canonical MC4R signalling pathway leading to cAMP production. Statistical analysis conducted by researchers from the MRC Epidemiology Unit showed that thosevariants with gain-of-function β-arrestin recruitment-bias provided protection against obesity and its complications. Based on epidemiological data from the UK Biobank they found that people with two copies of these particular variants were on average 2.5kg lighter compared to control subjects and had a 50% reduced risk of Type 2 diabetes and cardiac disease.
This work suggests that designing new drugs, which specifically target or modulate the β-arrestin recruitment pathway could mimic the effect of the protective variants in MC4R and in doing so provide a new pharmacological approach for weight loss treatment.