SAT-683 - Metabolic Effects of Peptide and Small‑‑Molecule GLP‑‑1R Agonists in Wild‑‑Type and Humanized GLP‑‑1R Mouse Obesity Models

Background: GLP-1 receptor agonists have emerged as a leading therapeutic class for type 2 diabetes and obesity, driving efforts to optimize efficacy, safety, and delivery [1]. Unlike peptide agonists, the oral small‑molecule GLP‑1 receptor agonist has been reported to preferentially engage Gs‑mediated cAMP signaling while reducing β‑arrestin recruitment, a bias that may enhance metabolic efficacy and mitigate certain β‑arrestin–associated adverse responses [2]. In this study, we evaluated two types of GLP‑1R agonists (peptide and small‑molecule）across multiple preclinical metabolic outcomes in wild‑type and humanized GLP‑1R mice.

Methods: Male C57BL/6J and h-GLP-1R mice (N=8 per group) received semaglutide (0.12 mg/kg, SQ, every 3 days) or orforglipron (1 mg/kg, oral, daily) for 31 days. Metabolic endpoints including body weight, food intake, and body composition were measured; biochemical assessments of fasting blood glucose, serum insulin and leptin were performed; and a two‑bottle saccharin (5%) preference test was conducted.

Results: Semaglutide (0.12 mg/kg) and orforglipron (1 mg/kg) produced significant metabolic effects in h‑GLP‑1R mice, inducing substantial body weight loss (−13.11% and −24.11%, respectively) and reductions in fat mass (−4.26 g and −8.08 g), together with decreases in fasting blood glucose (−41.1% and −38.7%), serum insulin and leptin. Food intake acutely declined after dosing (−1.80 g and −1.62 g) with partial recovery over the treatment course. A single semaglutide administration reduced saccharin preference and total water intake. Semaglutide elicited consistent effects in both C57BL/6J and h‑GLP‑1R mice, whereas orforglipron produced comparable outcomes only in h‑GLP‑1R mice; no pharmacological effects were observed with orforglipron in wild‑type C57BL/6J mice.

Conclusions: Both peptide and small‑molecule GLP‑1 receptor agonists elicited robust metabolic responses in humanized GLP‑1R mice, whereas the small‑molecule agonist failed to activate the receptor in wild‑type C57BL/6J mice, indicating species‑specific receptor pharmacology. These findings support the evaluation of small‑molecule GLP‑1R agonists in humanized receptor models to improve translational relevance.

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