Zhang Tan, Fan Jingcheng, Wen Xin, Duan Xuemei
School of Exercise and Health, Shanghai University of Sport, Shanghai, 200438, PR China.
Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai, 200438, PR China.
J Physiol Biochem. 2025 Apr 7. doi: 10.1007/s13105-025-01077-8.
Exercise has been proved to be effective in ameliorating diabetes but the underlying mechanisms remain obscure. It has been recently demonstrated that overactivation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome led to hepatic insulin resistance. Therefore, we aimed to explore the role and underlying mechanism of NLRP3 inflammasome in exercise-mediated hepatic insulin resistance. Wild type and db/db mice were sedentary or subjected to 8-week moderate intensity exercise, liver tissues and primary hepatic macrophages were isolated. Exercise mitigated hepatic steatosis and enhanced the hepatic insulin sensitivity of db/db mice. More importantly, exercise reduced the protein expression of two-pore domain weak inwardly rectifying K channel 2 (TWIK2) to suppress cellular K efflux, blunted the generation of mitochondrial ROS (mROS) and the release of oxidized mitochondrial DNA (ox-mtDNA) into cytosol, leading to the inhibition of NLRP3 inflammasome in hepatic macrophages of db/db mice. Accordingly, the hepatic macrophages switched from pro-inflammatory phenotype to anti-inflammatory phenotype and the infiltration of macrophages into liver was decreased in response to exercise. Moreover, inhibition of TWIK2 expression with TWIK2 inhibitor or shRNA interference in hepatic macrophages blunted the TWIK2-mtDNA-NLRP3 inflammasome signaling. The macrophages switched to anti-inflammatory phenotype upon TWIK2 deficiency. Additionally, the insulin sensitivity was elevated in primary hepatocytes which were exposed to culture medium from hepatic macrophages with TWIK2 deficiency, suggesting that inhibition of TWIK2-mtDNA-NLRP3 inflammasome signaling in hepatic macrophages could attenuate hepatic insulin resistance Taken together, we first observed the inhibition of TWIK2-mtDNA-NLRP3 inflammasome signaling in hepatic macrophages of diabetic mice in response to exercise intervention, implying a probable role for TWIK2-mtDNA-NLRP3 inflammasome signaling in exercise-mediated alleviation of hepatic inflammation and insulin resistance, hoping to provide theoretical basis and new target for the prevention and treatment of metabolic diseases.
运动已被证明对改善糖尿病有效，但其潜在机制仍不清楚。最近有研究表明，核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体的过度激活会导致肝脏胰岛素抵抗。因此，我们旨在探讨NLRP3炎性小体在运动介导的肝脏胰岛素抵抗中的作用及潜在机制。将野生型和db/db小鼠分为久坐组或进行为期8周的中等强度运动，随后分离肝脏组织和原代肝巨噬细胞。运动减轻了db/db小鼠的肝脏脂肪变性并增强了其肝脏胰岛素敏感性。更重要的是，运动降低了双孔域内向整流钾通道2（TWIK2）的蛋白表达，以抑制细胞钾外流，减弱线粒体活性氧（mROS）的产生以及氧化型线粒体DNA（ox-mtDNA）向细胞质的释放，从而抑制db/db小鼠肝巨噬细胞中NLRP3炎性小体的活性。相应地，肝巨噬细胞从促炎表型转变为抗炎表型，并且运动后巨噬细胞向肝脏的浸润减少。此外，用TWIK2抑制剂或shRNA干扰抑制肝巨噬细胞中TWIK2的表达会减弱TWIK2-线粒体DNA-NLRP3炎性小体信号通路。TWIK2缺乏时，巨噬细胞转变为抗炎表型。此外，暴露于TWIK2缺乏的肝巨噬细胞培养基中的原代肝细胞的胰岛素敏感性升高，这表明抑制肝巨噬细胞中TWIK2-线粒体DNA-NLRP3炎性小体信号通路可减轻肝脏胰岛素抵抗。综上所述，我们首次观察到运动干预后糖尿病小鼠肝巨噬细胞中TWIK2-线粒体DNA-NLRP3炎性小体信号通路受到抑制，这意味着TWIK2-线粒体DNA-NLRP3炎性小体信号通路在运动介导的减轻肝脏炎症和胰岛素抵抗中可能发挥作用，有望为代谢性疾病的预防和治疗提供理论依据和新靶点。
