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Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index
Allan Gurtan1, John Dominy1, Shareef Khalid2,3,4
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
Abstract:
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.
Insights
Genetic studies revealed that G protein-coupled receptor 151 (GPR151) loss-of-function variants do not significantly impact body mass index (BMI) or Type 2 Diabetes (T2D) risk in humans. Therefore, GPR151 antagonism is unlikely to be an effective obesity treatment.
Area of Science:
- Genetics
- Metabolic Disease
- Pharmacology
Background:
- Obesity affects 650 million people globally, driving cardiovascular and metabolic diseases.
- The GPR151 gene, specifically the Arg95Ter variant, was previously linked to reduced BMI and Type 2 Diabetes (T2D) risk.
- Novel therapeutic targets are crucial for managing obesity and its associated health risks.
Purpose of the Study:
- To investigate the role of G protein-coupled receptor 151 (GPR151) loss-of-function (plof) in human metabolic traits.
- To evaluate GPR151 deficiency as a potential therapeutic target for obesity and T2D.
- To analyze GPR151 plof variants in the Pakistan Genome Resource (PGR) exome biobank.
Main Methods:
- Identified GPR151 putative loss-of-function (plof) variants in PGR participants, including homozygous carriers.
- Confirmed identified GPR151 alleles as loss-of-function in vitro.
- Assessed the association of GPR151 plof with BMI, T2D, and metabolic traits in humans and Gpr151-/- mice.
Main Results:
- Three homozygous GPR151 plof variants (Arg95Ter, Tyr99Ter, Phe175LeufsTer7) were identified with a cumulative allele frequency of 2.2%.
- GPR151 deficiency in human knockouts showed no clinically significant differences in BMI, T2D, or metabolic traits.
- Gpr151-/- mice did not differ in body weight on a normal diet but showed increased weight on a high-fat diet compared to controls.
Conclusions:
- GPR151 deficiency does not appear to be associated with significant alterations in human BMI or T2D risk.
- GPR151 antagonism is not a promising therapeutic strategy for obesity treatment.
- Further research may be needed to explore other pathways involved in obesity and metabolic regulation.
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