In obese mice, both the experimental drug LJ-4378 and the approved drug tirzepatide helped lose weight, improve blood sugar control, and boost energy use. LJ-4378 did this without cutting food intake and, after stopping the drug, mice regained far less weight than those that stopped tirzepatide, keeping many of the metabolic benefits. This suggests a new way to keep weight off after a treatment ends, though LJ-4378 isn’t available for people yet.

We previously developed LJ-4378, a dual ligand for A_2A and A₃ adenosine receptors, as a potential anti-obesity agent. In this study, we compared the anti-obesity effects of LJ-4378 with those of tirzepatide (TZP), a dual agonist of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, and one of the most potent FDA-approved obesity therapeutics. Using a mouse model of diet-induced obesity, we assessed the effects of LJ-4378 and TZP on body weight loss, metabolic parameters, and post-treatment weight rebound. Mice fed a high-fat diet (HFD) for 10 weeks were treated with vehicle, LJ-4378, or TZP for 14 days. Both LJ-4378 and TZP significantly reduced body weight, adipose tissue mass, and abdominal fat volume; improved glucose tolerance; reduced white adipose tissue inflammation; and enhanced energy expenditure. To assess the durability of the treatment effects, drug administration was discontinued after 14 days, and the mice remained on the HFD for an additional 4 weeks. Notably, LJ-4378-treated mice exhibited attenuated body weight regain, stable food intake, persistent metabolic benefits, and sustained enhancement of energy metabolism, compared to TZP-treated mice. These findings highlight LJ-4378 as an anti-obesity agent that functions independently of appetite suppression and may offer superior long-term benefits by limiting post-treatment weight rebound and preserving metabolic improvements.