Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we follow up on GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify 3 GPR151 putative loss-of-function (plof) variants (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7) with a cumulative allele frequency of 2.2% and present at homozygosity. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits. GPR151 deficiency is not associated with a significant difference in BMI. Moreover, loss of GPR151 confers a nominally significant increase in risk of T2D (odds ratio = 1.2, p value = 0.03). Relative to wild-type mice, Gpr151-/- animals exhibit no difference in body weight on normal chow, and higher body weight on a high-fat diet, consistent with the findings in humans. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach for obesity.
Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index