College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.
Int J Obes (Lond). 2022 Dec;46(12):2128-2136. doi: 10.1038/s41366-022-01224-x. Epub 2022 Sep 27.
A adenosine receptor (AAR)-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 AAR agonist and A adenosine receptor (AAR) antagonist activity. The current study aimed to investigate the anti-obesity effects of LJ-4378 and its underlying molecular mechanisms.
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.
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 AAR agonist or AAR 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.
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.
脂肪组织中的腺苷受体（AAR）介导的信号转导已被研究作为肥胖相关代谢疾病的潜在治疗靶点。LJ-4378 已被开发为具有 AAR 激动剂和 A 腺苷受体（AAR）拮抗剂活性的双重作用配体。本研究旨在探讨 LJ-4378 的抗肥胖作用及其潜在的分子机制。
使用永生化棕色脂肪细胞进行体外分析。使用高脂肪饮食（HFD）诱导的肥胖和诱导细胞死亡的 DFFA 样效应因子 A 报告小鼠模型进行体内实验。使用免疫印迹、线粒体染色和耗氧量分析评估 LJ-4378 对脂肪分解和线粒体代谢的影响。使用间接测热法、身体成分分析、葡萄糖耐量试验和组织化学分析评估 LJ-4378 的体内抗肥胖作用。
体外 LJ-4378 处理增加了棕色脂肪细胞标志物和线粒体蛋白的水平，包括解偶联蛋白 1。LJ-4378 对脂肪细胞脂肪分解的作用比 AAR 激动剂或 AAR 拮抗剂更强。在体内，与载体对照组相比，LJ-4378 处理使能量消耗增加了 17.0%（P 值<0.0001）。LJ-4378（1mg/kg，腹腔注射）治疗 10 天可使 HFD 喂养的小鼠体重和脂肪含量分别降低 8.24%（P 值<0.0001）和 24.2%（P 值=0.0044），并改善葡萄糖耐量。LJ-4378 增加了肩胛间棕色和腹股沟白色脂肪组织中棕色脂肪细胞标志物和线粒体蛋白的表达水平。
这些发现支持 LJ-4378 的体内抗肥胖作用，并为对抗肥胖和相关代谢疾病提供了一种新的治疗方法。
