Nomenclature: C57BL/6NTac-Glp1r^{tm1.1(GLP1R*)Tac}

As obesity drug development advances beyond first-generation GLP-1 therapies, preclinical models must evolve to reflect human receptor pharmacology. This humanized GLP-1 receptor knock-in mouse replaces the endogenous murine receptor with the human GLP-1 receptor, enabling more predictive evaluation of therapeutics that may not fully translate in wild-type mice.

Maintained on the B6NTac background, this model is well-suited for metabolic research, including studies of obesity, insulin sensitivity, and related cardiometabolic endpoints. To support diverse study designs, mice can be ordered directly or preconditioned for induction of diet-induced obesity (DIO), MASH, or other metabolic disease states.

As the first in a planned series of humanized incretin receptor models, this offering provides a foundation for evaluating increasingly complex therapeutic strategies, including combination and multi-target approaches, within a controlled and translationally relevant in vivo system.

Origin

This model was created by homologous recombination to generate a constitutive humanization of the glucagon-like peptide 1 receptor (Glp1r) with a Flag tag in the C57BL/6NTac background. The coding region in mouse exon 2, as well as the splice donor-site in intron 2, has been replaced with a human GLP1R cDNA. The targeting vector was generated using BAC clones from the RPCI-23 BAC Library and was transfected into a B6NTac ES cells. Homologous recombinant clones were isolated using positive selection facilitated by the presence of a PuroR marker flanked by FRT sites and inserted downstream of the additional polyadenylation signal (hGHpA). The humanized allele was obtained after Flp-mediated removal of the selection marker. The resulting human GLP1R-Flag fusion protein will be expressed under the control of the endogenous mouse Glp1r promoter and therefore recapitulate expression of the mouse gene. Mouse GLP1R protein is expected to no longer be expressed.