Genetic research has revealed that popular weight loss medication in the form of glucagon-like peptide 1 receptor agonists (GLP1RAs) is unlikely to directly affect behavior through its impact on the cardiometabolic system.
The UK Biobank study, published in the journal Diabetes, Obesity and Metabolism, showed that links to risk taking, decreased anxiety and less chronic pain were unlikely to happen through the GLP1 receptor (GLP1R).
Genetic variants in the GLP1R gene had consistent associations with body mass index, blood pressure, and Type 2 diabetes among people of different ethnic backgrounds in the study.
But the genetic variants affecting these cardiometabolic traits (CMts) differed to those linked with behavioral changes and were separate to those that affected GLP1R gene expression.
“Whilst it is not possible to directly compare genetic findings to the effects of a drug, our results suggest that behavioral changes are unlikely to be a direct result of the GLPRAs,” explained corresponding author Rona Strawbridge, PhD, from the University of Glasgow.
“Exactly how these indirect effects are occurring is currently unclear.”
GLP1RA have improved the treatment of Type 2 diabetes and could revolutionize the treatment of obesity, the researchers point out.
GLP1RA mimics the action of the hormone GLP-1 which binds to GLP1R in the brain and pancreas, helping to control insulin and blood glucose levels and decreasing appetite by promoting feelings of fullness.
Strawbridge and co-workers examined the impact of common genetic variants in the GLP1R gene among 408,774 White-British, 50,314 White-European, 7667 South-Asian, and 7641 African-Caribbean individuals as well as 10,437 of mixed ancestry.
Genetic variants in GLP1R were linked with the CMts of body mass index, blood pressure and Type 2 diabetes among individuals of all ancestries.
All participants except those of South-Asian descent also had significant associations between GLP1R variants and mental health but the results were less consistent, with various links to decreased mood instability (odds ratio [OR]=0.85), increased risk-taking behavior (OR=1.05), and decreased chronic pain (OR=0.65).
Trans-ancestry meta-analysis revealed predominantly consisted effects in the size and direction of metabolic traits but discordant directions in terms of mental ill health (MIH).
Only signals for chronic pain, stroke and body mass index influenced expression of GLP1R, the researchers report.
The genetic variants influencing CMt were separate from those influencing behavioral changes and separate from those influencing expression levels of the GLP1R gene.
The researchers concluded that there was no evidence to suggest that there were shared effects on CMt and MIH with GLP1RA drugs.
“Our data provide no evidence that these drugs might improve MIH, but more importantly there is no suggestion of worsening of MIH, which supports current literature,” they concluded.
“Collectively, these data do not suggest that GLP1RA drugs are likely to induce depression or other serious mental health disorders through the GLP-1 receptor.”
