ENT1 inhibition enhances weight control and metabolic health in diet-induced obesity

Authors
Lucas Chaible, Julie Preillon, Charlotte Philippart, Alizee Canevat, Laura Saerens, Dimitri Kondratow, Michael Deligny, Alexis Goffaux, Anne-Catherine Michaux, Marie-Claire Letellier, Nicolas Rosewick, David Carbonez, Joao Marchante, Francesco Strozzi, Erica Houthuys, Reece Marillier, Yvonne McGrath, Steven Van der Plas, Alexander Pfeifer, Julie Chesne


Lab
iTeos Therapeutics, Gosselies, Belgium

Journal
Biomedicine & Pharmacotherapy

Abstract
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.

Keywords/Topics
Tissue homeostasisObesityInflammationENT1 inhibitorAdenosine

BIOSEB Instruments Used:
OXYLET- Indirect Calorimeter (OXYLET)

Source :

https://www.sciencedirect.com/science/article/pii/S075333222501042X?via%3Dihub

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