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<p>We previously developed LJ-4378, a dual ligand for A<sub>2A</sub> and A<sub>3</sub> 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&#xa0;weeks were treated with vehicle, LJ-4378, or TZP for 14&#xa0;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&#xa0;days, and the mice remained on the HFD for an additional 4&#xa0;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.</p>

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Comparative analysis of LJ-4378 and tirzepatide in mouse models of obesity and weight regain

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月7日

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  • Heeseong Kim,
  • Seung Woo Kim,
  • Cheoljun Choi,
  • SungUg Joo,
  • Gibae Kim,
  • Minjae Kim,
  • Eunsuk Yang,
  • Jangwon Lee,
  • Sukjae Chung,
  • Lak Shin Jeong,
  • Yun-Hee Lee

摘要

We previously developed LJ-4378, a dual ligand for A2A 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.