Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe, 650-0017, Japan.
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, 658-8558, Japan.
Biochem Biophys Res Commun. 2018 Jul 7;502(1):123-128. doi: 10.1016/j.bbrc.2018.05.131. Epub 2018 May 24.
Browning of white adipose tissue is a promising strategy to tackle obesity. Recently, Janus kinase (JAK) inhibition was shown to induce white-to-brown metabolic conversion of adipocytes in vitro; however effects of JAK inhibition on browning and systemic metabolic health in vivo remain to be elucidated. Here, we report that systemic administration of JAK inhibitor (JAKi) ameliorated obesity-related metabolic disorders. Administration of JAKi in mice fed a high-fat diet increased UCP-1 and PRDM16 expression in white adipose tissue, indicating the browning of white adipocyte. Food intake was increased in JAKi-treated mice, while the body weight and adiposity was similar between the JAKi- and vehicle-treated mice. In consistent with the browning, thermogenic capacity was enhanced in mice treated with JAKi. Chronic inflammation in white adipose tissue was not ameliorated by JAKi-treatment. Nevertheless, insulin sensitivity was well preserved in JAKi-treated mice comparing with that in vehicle-treated mice. Serum levels of triglyceride and free fatty acid were significantly reduced by JAKi-treatment, which is accompanied by ameliorated hepatosteatosis. Our data demonstrate that systemic administration of JAKi has beneficial effects in preserving metabolic health, and thus inhibition of JAK signaling has therapeutic potential for the treatment of obesity and its-related metabolic disorders.
白色脂肪组织的褐变是解决肥胖问题的一种很有前途的策略。最近，研究表明，Janus 激酶（JAK）抑制可在体外诱导脂肪细胞的白色到棕色代谢转化；然而，JAK 抑制对体内脂肪褐变和全身代谢健康的影响仍有待阐明。在这里，我们报告称，全身性给予 JAK 抑制剂（JAKi）可改善肥胖相关代谢紊乱。在高脂肪饮食喂养的小鼠中给予 JAKi 可增加白色脂肪组织中 UCP-1 和 PRDM16 的表达，表明白色脂肪细胞的褐色化。JAKi 处理的小鼠食物摄入量增加，而 JAKi 处理组和载体处理组的体重和肥胖程度相似。与褐色化一致，JAKi 处理的小鼠的产热能力增强。慢性炎症在白色脂肪组织中未得到 JAKi 治疗的改善。然而，与载体处理的小鼠相比，JAKi 处理的小鼠胰岛素敏感性得到了很好的保留。JAKi 处理可显著降低血清甘油三酯和游离脂肪酸水平，同时改善肝脂肪变性。我们的数据表明，全身性给予 JAKi 对维持代谢健康具有有益作用，因此抑制 JAK 信号转导具有治疗肥胖及其相关代谢紊乱的潜在治疗作用。
