Nobiletin can play a role in improving inflammation by inhibiting the NF-kB and MAPK pathways in muscle cells.

Introduction: Insulin resistance and inflammation plays a major role in the pathogenesis of metabolic diseases such as diabetes and metabolic syndrome. Increased circulating fatty acids and inflammatory cytokines are among the most important factors that induce inflammation and subsequent insulin resistance. Studies indicate that fatty acids, especially palmitate, play a role in inducing inflammation and increasing inflammatory cytokines such as TNF-ɑ and IL-6 and stimulating the NF-kB and MAPK (especially JNK) signaling pathways. Nobiletin (Nob) as a natural polyphenol has anti-diabetic and anti-inflammatory effects. However, its mechanism in muscle cells is unclear, which was addressed in this study. Materials and methods: The increase in inflammatory cytokines TNF-ɑ and IL-6 caused by palmitate was evaluated by Real-time PCR. The expression of NF-kB and JNK proteins caused by palmitate was also measured by Western blotting. The effect of Nob on cytokines and inflammatory pathways in palmitate-treated C2C12 cells was assessed by Real-time PCR and Western blotting. Intracellular ROS levels were also measured using the DCFH-DA probe. Results: Palmitate significantly increased the expression and secretion of inflammatory genes TNF-α, IL-6, and IL-1β and the phosphorylation of NF-KB and JNK in muscle cells, and in contrast, nobiletin at a concentration of 100 µM significantly decreased the expression of inflammatory genes TNF-α, IL-6, and IL-1β and the phosphorylation of NF-KB and JNK in muscle cells treated with palmitate. Intracellular ROS levels were increased by palmitate, which was reduced by nobiletin treatment, but this decrease was not statistically significant. Conclusion: This study showed that the beneficial anti-inflammatory effects of nobiletin in muscle cells are accompanied by suppression of ROS production and reduction of MAPK activity (especially JNK) and inhibition of the NF-kB signaling pathway. We introduce nobiletin as a potential anti-inflammatory and anti-diabetic natural compound so that its therapeutic effects can be further studied.