Introduction: The GLP-1R is a therapeutic target for the treatment and management of type 2 diabetes and obesity. Despite its important therapeutic role, the importance of the signalling pathways mediating therapeutically beneficial effects in different tissues ex vivo and in disease states in vivo is limited. We determined that mutation of specific amino acid residues within the GLP-1R can confer signalling bias: mutation of Q394 to A results in a GLP-1R that preferentially signals via Gs/cAMP compared to beta-arrestin, while a triple A mutation of K334, L335, K336 results in a GLP-1R that preferentially signals to beta-arrestin compared to Gs/cAMP.
Aim: To determine the relevance of signalling bias at the human GLP-1R in diet induced obesity
Methods: Humanised male GLP-1R knockIn (KI), Q394A KI and KLK KI mice were generated. Mice were placed on a high fat diet for 12 weeks before being treated daily with exendin-4 for 4 weeks. Body weight, food intake, glucose tolerance, and insulin tolerance were measured.
Results: Daily exendin-4 treatment decreased body weight in KI mice (control vehicle treated 4.3% increase, exendin treated 2.5% decrease), which was associated with a reduction in food intake. In Q394A KI mice, exendin reduced body weight (control vehicle treated 4.8% increase, exendin-4 treated 4.3% decrease), which was independent of effects on food intake. Exendin-4 had no effect on body weight in KLK KI mice (controls 3.0% increase, exendin treated 2.7% increase) despite promoting a reduction in food intake. Improvements in glucose tolerance were more pronounced in the Q394A KI mice, while no alterations in insulin tolerance were observed in any of the mouse strains.
Outcomes: These results indicate divergent roles of cAMP and beta-arrestin signalling on metabolic functions mediated by the GLP-1R, which provides insights into development of novel GLP-1R agonists.