A GLP-1 analogue optimized for cAMP-biased signaling improves weight loss in obese mice.

ABSTRACT:

Objective

Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism is foundational to modern obesity pharmacotherapies. These compounds were engineered for maximal G protein alpha(s) (Gsα) signaling potency and downstream cAMP production. However, this strategy requires reconsideration as partial, biased GLP-1R agonists characterized by decreased Gsα signaling and disproportionate reductions in β-arrestin recruitment relative to the native ligand provide greater weight loss than full, balanced agonists in preclinical models.

Methods

We tested the hypothesis that in vitro signaling bias, which considers both cAMP signaling and β-arrestin recruitment, better predicts weight loss efficacy in diet induced obese (DIO) rodents than cAMP potency alone.

Results

Our data demo

SUBMITTER: Douros JD 

PROVIDER: S-EPMC12398856 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature