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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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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 |
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author | Kim, Kyungmin Im, Hyeonyeong Son, Yeonho Kim, Minjae Tripathi, Sushil Kumar Jeong, Lak Shin Lee, Yun-Hee |
author_facet | Kim, Kyungmin Im, Hyeonyeong Son, Yeonho Kim, Minjae Tripathi, Sushil Kumar Jeong, Lak Shin Lee, Yun-Hee |
author_sort | Kim, Kyungmin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9678795 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96787952022-11-23 Anti-obesity effects of the dual-active adenosine A(2A)/A(3) receptor-ligand LJ-4378 Kim, Kyungmin Im, Hyeonyeong Son, Yeonho Kim, Minjae Tripathi, Sushil Kumar Jeong, Lak Shin Lee, Yun-Hee Int J Obes (Lond) Article 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. Nature Publishing Group UK 2022-09-27 2022 /pmc/articles/PMC9678795/ /pubmed/36167764 http://dx.doi.org/10.1038/s41366-022-01224-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kim, Kyungmin Im, Hyeonyeong Son, Yeonho Kim, Minjae Tripathi, Sushil Kumar Jeong, Lak Shin Lee, Yun-Hee Anti-obesity effects of the dual-active adenosine A(2A)/A(3) receptor-ligand LJ-4378 |
title | Anti-obesity effects of the dual-active adenosine A(2A)/A(3) receptor-ligand LJ-4378 |
title_full | Anti-obesity effects of the dual-active adenosine A(2A)/A(3) receptor-ligand LJ-4378 |
title_fullStr | Anti-obesity effects of the dual-active adenosine A(2A)/A(3) receptor-ligand LJ-4378 |
title_full_unstemmed | Anti-obesity effects of the dual-active adenosine A(2A)/A(3) receptor-ligand LJ-4378 |
title_short | Anti-obesity effects of the dual-active adenosine A(2A)/A(3) receptor-ligand LJ-4378 |
title_sort | anti-obesity effects of the dual-active adenosine a(2a)/a(3) receptor-ligand lj-4378 |
topic | Article |
url | 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 |
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