Humanised GLP-1 Receptor Mouse Unlocks Oral Weight-Loss Drug Testing

GLP-1 receptor agonists (GLP1RAs) like semaglutide have transformed obesity and diabetes treatment, but their requirement for injection limits patient adherence and access. Oral small-molecule GLP1RAs such as orforglipron represent a promising alternative, yet a critical bottleneck has been that these compounds are inactive at the mouse GLP-1 receptor — preventing standard rodent preclinical studies from predicting human outcomes. This translational gap motivated the creation of the hGLP1R mouse.

Using CRISPR-Cas9 gene editing, researchers at Gubra A/S replaced the endogenous murine Glp1r gene with the full human GLP1R coding sequence in C57BL/6N mice. Immunohistochemistry confirmed human GLP1R expression in pancreatic β-cells and key brain appetite-regulatory regions, with complete absence of the murine receptor in these tissues. cAMP accumulation assays in isolated pancreatic islets demonstrated that orforglipron and danuglipron potently activated the receptor in hGLP1R islets but were completely inactive in wild-type islets, while semaglutide and GLP-1(7-37) worked in both genotypes.

In lean hGLP1R mice, acute and subchronic administration of both semaglutide (subcutaneous) and orforglipron (oral) significantly reduced body weight and food intake, improved glucose tolerance in oral glucose tolerance tests, and induced conditioned taste aversion — a marker of GI side effects also seen clinically. High-resolution 3D whole-brain c-Fos imaging revealed overlapping neuronal activation patterns for both agonists across hypothalamic and brainstem regions involved in appetite and energy balance, suggesting shared central mechanisms.

In diet-induced obese (DIO) hGLP1R mice treated chronically, both semaglutide and orforglipron produced robust and comparable reductions in body weight (>10% from baseline), food intake, and plasma lipids including triglycerides and cholesterol. Wild-type DIO mice responded to semaglutide but showed no response to orforglipron, confirming the model's specificity for human GLP1R pharmacology. No gross safety signals or adverse phenotypes were observed in hGLP1R mice under basal conditions.

This work establishes the hGLP1R mouse as the first thoroughly validated preclinical model retaining the native human GLP1R sequence — not a sensitised or modified variant — enabling authentic pharmacological evaluation of small-molecule GLP1RAs. It provides a critical tool for the drug development pipeline as multiple oral GLP1RAs advance through clinical trials, and may also support mechanistic studies comparing peptide versus small-molecule agonism of the same receptor in vivo.