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 nM of namodenoson inhibited adipocyte proliferation (determined using 3 H-thymidine incorporation assay) by 26 ± 12% ( P < 0.05) and 54 ± 5% ( P < 0.001), respectively, and lipid accumulation (determined by Oil-Red-O staining) by 22 ± 8% ( P < 0.05) and 41 ± 9% ( P < 0.001), respectively. Western blot analyses using 3T3-L1 adipocyte cells demonstrated that namodenoson led to downregulation of A3AR, PPAR γ , C/EBP α , C/EBPβ, p-AKT, PI3K, NF-kB, and β-catenin, and upregulation of adiponectin. In-vivo experiments in a murine model of diet-induced obesity demonstrated that administering daily namodenoson (100 μg/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 ± 2.2 vs 47.2 ± 3.4 g, respectively, P = 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 ± 3.9 vs 33.0 ± 0.6 g, respectively). In conclusion, our findings support continued investigation of namodenoson as a weight-loss drug candidate.