The Role and Mechanism of Nrf2 in Ameliorating Oxidative Stress and Inflammation in IR Mice by Aerobic Exercise

This study explored the regulatory role of nuclear factor E2-related factor 2 (Nrf2) in aerobic exercise improving oxidative stress and inflammatory responses in mice with insulin resistance (IR) induced by a high-fat diet. We established an IR mouse model through a high-fat diet, then subjected the IR mice to aerobic exercise, intraperitoneal injection of luteolin, or a combined intervention. After 6 weeks of intervention, we measured serum lipid and glucose profiles; evaluated skeletal muscle morphology by H&E staining; quantified mRNA expression levels of Nrf2 and its downstream targets in the skeletal muscle by RT-qPCR; and determined protein abundance, localization, and expression patterns of Nrf2 and NOD-like receptor protein 3 (NLRP3) inflammasome by Western blotting and immunohistochemistry, respectively. In the skeletal muscle of IR mice, Nrf2 and its downstream targets were significantly down-regulated, whereas NLRP3 inflammasome was markedly up-regulated (p < 0.05 or p < 0.01). IR mice subjected to aerobic exercise exhibited reduced serum glucose and lipid levels together with a lower insulin-resistance index (p < 0.05 or p < 0.01); morphologically, inter-myofibrillar spaces were narrowed, intrafiber vacuoles diminished, and cellular integrity restored. Concomitantly, Nrf2 and its downstream targets were up-regulated, whereas NLRP3 inflammasome components were down-regulated in the skeletal muscle (p < 0.05 or p < 0.01). Intraperitoneal administration of luteolin during exercise, however, partially attenuated or reversed these exercise-induced improvements by inhibiting the activation of Nrf2 (p < 0.05 or p < 0.01). These results indicate that aerobic exercise confers protective effects against IR by activating the Nrf2 signaling pathway, thereby attenuating oxidative stress and inflammation; these benefits are markedly attenuated when Nrf2 activity is pharmacologically inhibited.