Journal Article

Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index

Khalid, Shareef, Currie, Treeve, Khera, Amit V., Saeed, Subhan, Lamarche, Lindsey, Denning, Daniel, Caplan, Shari, Rasheed, Syed Zahed, Dominy, John, Gurtan, Allan, Rasheed, Asif, Danesh, John, Sultana, Raffat, Shah, Nabi, Richards, Sean, Memon, Fazal-ur-Rehman, Jalal, Anjum, Gurinovich, Anastasia, Hameed, Shahid, Saleheen, Danish, Vong, Linh, Ishaq, Mohammad, Frossard, Philippe, Shpektor, Diana, Abbas, Shahid, Saleem, Imran

2022

Overview

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 further investigate 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 eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151 +/+ mice, Gpr151 -/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alleles / Animals / Biobanks / Biology and Life Sciences / Body Mass Index / Body weight / Cell receptors / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - genetics / Engineering and Technology / Exome / Gene Frequency / Genes / Genomes / Health aspects / High fat diet / Humans / Medicine and Health Sciences / Metabolic disorders / Mice / Mortality / Obesity / Obesity - genetics / Physical Sciences / Proteins / Receptors, G-Protein-Coupled - metabolism / Research and Analysis Methods / Risk factors / Therapeutic targets / Type 2 diabetes / Weight control