Development of a non-invasive bioassay for adiponectin target engagement in mice

Adiponectin-based therapeutic strategies are promising for managing metabolic diseases and reducing inflammation, prompting the development of adiponectin receptor agonists. However, monitoring their pharmacodynamic actions in clinical applications is challenging. This study aimed to identify peripheral biomarkers to monitor adiponectin actions using ALY688, an adiponectin receptor agonist peptide. RNA sequencing analysis of whole blood identified a cluster of genes that were significantly increased in the ALY688-treated group compared to the control. This gene cluster was validated by qPCR and further confirmed in human peripheral blood mononuclear cells treated with ALY688 <i>ex vivo</i>. We also confirmed a functional outcome of ALY688 action in mice as our study also demonstrated the anti-inflammatory effect of ALY688 in a sublethal LPS mouse model. In summary, a newly identified gene cluster signature is suitable for assessing the pharmacodynamic action of adiponectin or its mimetics in blood samples.