Anti-obesity effects of the dual-active adenosine A2A/A3 receptor-ligand LJ-4378

Kyungmin Kim, Hyeonyeong Im, Yeonho Son, Minjae Kim, Sushil Kumar Tripathi, Lak Shin Jeong, Yun Hee Lee

Research output: Contribution to journalArticlepeer-review


Background and objectives: A2A adenosine receptor (A2AAR)-mediated signaling in adipose tissues has been investigated as a potential target for obesity-related metabolic diseases. LJ-4378 has been developed as a dual-acting ligand with A2AAR agonist and A3 adenosine receptor (A3AR) antagonist activity. The current study aimed to investigate the anti-obesity effects of LJ-4378 and its underlying molecular mechanisms. Methods: Immortalized brown adipocytes were used for in vitro analysis. A high-fat diet (HFD)-induced obesity and cell death-inducing DFFA-like effector A reporter mouse models were used for in vivo experiments. The effects of LJ-4378 on lipolysis and mitochondrial metabolism were evaluated using immunoblotting, mitochondrial staining, and oxygen consumption rate analyses. The in vivo anti-obesity effects of LJ-4378 were evaluated using indirect calorimetry, body composition analyses, glucose tolerance tests, and histochemical analyses. Results: In vitro LJ-4378 treatment increased the levels of brown adipocyte markers and mitochondrial proteins, including uncoupling protein 1. The effects of LJ-4378 on lipolysis of adipocytes were more potent than those of the A2AAR agonist or A3AR antagonist. In vivo, LJ-4378 treatment increased energy expenditure by 17.0% (P value < 0.0001) compared to vehicle controls. LJ-4378 (1 mg/kg, i.p.) treatment for 10 days reduced body weight and fat content by 8.24% (P value < 0.0001) and 24.2% (P value = 0.0044), respectively, and improved glucose tolerance in the HFD-fed mice. LJ-4378 increased the expression levels of brown adipocyte markers and mitochondrial proteins in interscapular brown and inguinal white adipose tissue. Conclusion: These findings support the in vivo anti-obesity effects of LJ-4378, and suggest a novel therapeutic approach to combat obesity and related metabolic diseases.

Original languageEnglish
Pages (from-to)2128-2136
Number of pages9
JournalInternational Journal of Obesity
Issue number12
Publication statusPublished - 2022 Dec

Bibliographical note

Funding Information:
The authors acknowledge Heeseong Kim for technical support. This research was supported by the National Research Foundation of Korea (NRF) grants (2019R1C1C1002014 and 2018R1A5A2024425 to YHL) funded by the Korean government (Ministry of Science and ICT).

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Medicine (miscellaneous)
  • Nutrition and Dietetics


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