OBJECTIVES: To identify novel targets to treat obesity, we focused on the equilibrative nucleoside transporter 1 (ENT1), which is a key regulator of extracellular adenosine levels in adipose tissue. Adenosine has been shown to control multiple aspects of metabolic homeostasis through P1 purinergic receptors (mainly A1, A2A, and A2B receptors) that belong to the family of G protein coupled receptors. Prior studies showed that ENT1 deletion in adipose tissue protects mice from diet-induced obesity. Herein, we explored whether pharmacological ENT1 inhibition could offer a novel therapeutic approach for obesity.
METHODS: We assessed EOS-518, a newly developed selective ENT1 inhibitor, in vitro and in vivo using a diet-induced obesity (DIO) mouse model, comparing its efficacy to incretin mimetics, namely semaglutide.
RESULTS: In DIO mice, EOS-518 treatment led to marked reductions in body weight, food intake, fat mass, cholesterol, glucose, and insulin levels. ENT1 inhibition preserved VO₂ consumption, promoted fatty acid oxidation, and decreased inflammatory markers such as IFNγ response and TNFα in white adipose tissue. Notably, combining EOS-518 with semaglutide produced greater weight loss than either agent alone, indicating a synergistic effect between ENT1 inhibition and GLP-1 receptor agonism. Furthermore, initiating EOS-518 after semaglutide-induced weight loss plateau resulted in a significantly lower final body weight compared to semaglutide monotherapy.
CONCLUSIONS: EOS-518 promotes weight loss, improves metabolic parameters, restores adipose tissue function, and reduces inflammation in DIO mice. Altogether, this study positions ENT1 as a promising therapeutic target for the treatment of obesity and associated metabolic disorders.