The anti-obesity effect of namodenoson, an A3 adenosine receptor agonist.

Abstract

Namodenoson-a selective A3 adenosine receptor (A3AR) agonist-is currently in clinical trials for hepatocellular carcinoma and metabolic dysfunction-associated steatotic liver disease. This preclinical study investigated its potential utility as a weight-loss drug. In 3T3-L1 adipocyte cells, namodenoson exhibited a dose-dependent inhibitory effect on the proliferation and accumulation of lipid droplets. Compared to vehicle, 5 and 10&#x2009;nM of namodenoson inhibited adipocyte proliferation (determined usingH-thymidine incorporation assay) by 26&#x2009;&#xb1;&#x2009;12% (P&#x2009;<&#x2009;0.05) and 54&#x2009;&#xb1;&#x2009;5% (P&#x2009;<&#x2009;0.001), respectively, and lipid accumulation (determined by Oil-Red-O staining) by 22&#x2009;&#xb1;&#x2009;8% (P&#x2009;<&#x2009;0.05) and 41&#x2009;&#xb1;&#x2009;9% (P&#x2009;<&#x2009;0.001), respectively. Western blot analyses using 3T3-L1 adipocyte cells demonstrated that namodenoson led to downregulation of A3AR, PPAR&#x3b3;, C/EBP&#x3b1;, C/EBP&#x3b2;, p-AKT, PI3K, NF-kB, and &#x3b2;-catenin, and upregulation of adiponectin. In-vivo experiments in a murine model of diet-induced obesity demonstrated that administering daily namodenoson (100&#x2009;&#x3bc;g/kg) to high-fat-fed mice led to a significant difference in weight after 4 weeks of treatment compared to high-fat-fed mice without namodenoson (44.3&#x2009;&#xb1;&#x2009;2.2 vs 47.2&#x2009;&#xb1;&#x2009;3.4&#x2009;g, respectively, P&#x2009;=&#x2009;0.001), representing a difference in weight of 6.1%. The same experiment on mice fed a lean diet demonstrated no namodenoson effect (mean weight: 33.5&#x2009;&#xb1;&#x2009;3.9 vs 33.0&#x2009;&#xb1;&#x2009;0.6&#x2009;g, respectively). In conclusion, our findings support continued investigation of namodenoson as a weight-loss drug candidate.