Department of Anatomy and Histology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China.
Department of Physical Education, Huanghuai University, Zhumadian 463000, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Oct;1869(7):166792. doi: 10.1016/j.bbadis.2023.166792. Epub 2023 Jun 17.
Chronic inflammation is a major contributor to the development of metabolic disorders and is commonly seen in studies of diet-induced obesity in humans and rodents. Exercise has been shown to have anti-inflammatory properties, though the exact mechanisms are still not fully understood. Sestrins and Nrf2 are of interest to researchers as they are known to protect against inflammation and oxidative stress. In this study, we aim to explore the interconnection between Sestrin2 (SESN2) and Nrf2 and their roles in exercise benefits on chronic inflammation. Our data showed that SESN2 knockout aggravated the abnormalities of body weight, fat mass, and serum lipid that were induced by a high-fat diet (HFD), and a concomitant increase of TNF-α, IL-1β and IL-6 in both serum and skeletal muscle. Notably, exercise was found to reverse these changes, and SESN2 was found to be necessary for exercise to reduce the inflammatory response in skeletal muscles, though not in serum. Immunoprecipitation and bioinformatics prediction experiments further revealed that SESN2 directly binds to Nrf2, indicating a protein-protein interaction between the two. Furthermore, our data demonstrated that SESN2 protein is necessary for exercise-induced effects on Nrf2 pathway in HFD-fed mice, and Nrf2 protein is necessary to enable SESN2 to reduce the inflammation caused by palmitic acid (PA)+ oleic acid (OA) treatment in vitro. Our findings indicate that exercise mitigates chronic inflammation induced by HFD through SESN2 in an Nrf2-dependent manner. Our study reveals a novel molecular mechanism whereby the SESN2/Nrf2 pathway mediates the positive impact of exercise on chronic inflammation.
慢性炎症是代谢紊乱发展的一个主要因素，在人类和啮齿动物的饮食诱导肥胖研究中经常观察到。运动已被证明具有抗炎特性，尽管其确切机制仍不完全清楚。Sestrins 和 Nrf2 引起了研究人员的兴趣，因为它们已知可预防炎症和氧化应激。在这项研究中，我们旨在探讨 Sestrin2（SESN2）和 Nrf2 之间的相互联系及其在运动对慢性炎症的益处中的作用。我们的数据表明，SESN2 敲除加剧了高脂肪饮食（HFD）引起的体重、脂肪量和血清脂质的异常，同时血清和骨骼肌中的 TNF-α、IL-1β 和 IL-6 也增加。值得注意的是，运动被发现可以逆转这些变化，并且 SESN2 是运动减少骨骼肌炎症反应所必需的，尽管在血清中不是必需的。免疫沉淀和生物信息学预测实验进一步表明，SESN2 直接与 Nrf2 结合，表明两者之间存在蛋白质-蛋白质相互作用。此外，我们的数据表明 SESN2 蛋白是运动对 HFD 喂养小鼠 Nrf2 通路产生影响所必需的，并且 Nrf2 蛋白是 SESN2 降低体外棕榈酸（PA）+油酸（OA）处理引起的炎症所必需的。我们的研究结果表明，运动通过 SESN2 以 Nrf2 依赖的方式减轻 HFD 引起的慢性炎症。我们的研究揭示了一种新的分子机制，即 SESN2/Nrf2 途径介导了运动对慢性炎症的积极影响。
