Endocrine Abstracts

Background: Obesity and diabetes are among the greatest public health challenges for the coming decades. Current glucagon-like peptide-1 receptor (GLP-1R) agonists are effective for Type 2 diabetes and obesity but are often limited by dose-dependent nausea, potentially linked to β-arrestin recruitment. Ex-Asp3 and Ex-Phe1 are modified exendin-4 analogues with single amino acid substitutions near the N-terminus. Ex-Phe1 functions as a partial and G protein–biased GLP-1R agonist that reduces receptor desensitisation in-vitro and nausea-like behaviour in vivo. This study aimed to investigate the role of β-arrestin-2 in modulating GLP-1R signalling and to determine how its knockout (KO) affects responses to Ex-Asp3 and Ex-Phe1, with a particular focus on appetite regulation, which has not been investigated in detail.

Methods: Glp1r-Cre × Arrb2 fl/fl mice were generated to knock out β-arrestin-2 specifically in GLP-1R-expressing cells, including anorectic neurons. Crossover intraperitoneal glucose tolerance tests and food intake studies were performed in knockout and littermate control mice to assess the impact of β-arrestin-2 knockout on appetite and glucose regulation following GLP-1R agonist administration.

Results: β-arrestin-2 KO did not markedly alter feeding or glucose responses, suggesting compensatory or redundant mechanisms.

Discussion: Several factors may explain the limited phenotype observed in β-arrestin-2 knockout mice, including incomplete knockout, compensation by β-arrestin-1, or developmental adaptations. Alternatively, β-arrestin–dependent effects may emerge only under specific conditions such as high fat diet exposure, or may involve β-arrestin–independent pathways.