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Anti-obesity effects of the dual-active adenosine A(2A)/A(3) receptor-ligand LJ-4378

BACKGROUND AND OBJECTIVES: A(2A) adenosine receptor (A(2A)AR)-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 A(2A)AR agonist and A(3) adenosine receptor (A(3)AR) antagon...

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Detalles Bibliográficos
Autores principales: Kim, Kyungmin, Im, Hyeonyeong, Son, Yeonho, Kim, Minjae, Tripathi, Sushil Kumar, Jeong, Lak Shin, Lee, Yun-Hee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9678795/
https://www.ncbi.nlm.nih.gov/pubmed/36167764
http://dx.doi.org/10.1038/s41366-022-01224-x
Descripción
Sumario:BACKGROUND AND OBJECTIVES: A(2A) adenosine receptor (A(2A)AR)-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 A(2A)AR agonist and A(3) adenosine receptor (A(3)AR) 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 A(2A)AR agonist or A(3)AR 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.