近年來由於生活水平不斷提升，飲食趨向精緻化、活動量減少，使得罹患insulin resistance相關疾病機率大幅增加，因此改善insulin resistance是目前促進健康的重要議題。本研究目的在於探討多元不飽和脂肪酸對棕櫚酸 (palmitate, PA)誘發C2C12肌肉細胞發炎反應及胰島素阻抗之影響及其可能機轉。在PA誘發小鼠C2C12肌肉細胞發炎反應模式中，PA可藉由活化ERK1/2及PKC-θ兩條路徑促進IκBα降解，使NF-κB活化，從細胞質轉移至細胞核中，引發tumor necrosis factor-α (TNF-α)、interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2)等促發炎基因轉錄及表現，進而誘導發炎反應。本實驗結果發現多元不飽和脂肪酸DHA、EPA及AA可經由抑制ERK1/2及PKC-θ兩條路徑，降低PA所誘發IκBα降解和NF-κB活化，進而降低促發炎因子TNF-α、IL-6、COX-2表現，達到抗發炎效果。已知AMPK及AS160參與調控細胞質GLUT4轉移至細胞膜上的調控，增加肌肉細胞對於葡萄糖的攝入。本研究結果也證實了，PA可顯著降低AMPK及AS160磷酸化，降低基礎狀態下肌肉細胞對葡萄糖的攝取；同時給予DHA、EPA及AA處理時，可以顯著恢復PA所降低的肌肉細胞AMPK及AS160的磷酸化，因此可能有助於基礎狀態下，肌肉細胞對於葡萄糖的攝入，有益於維持血糖恆定。此外，本研究結果證實，單獨處理PA可顯著降低胰島素所調控的Akt磷酸化； DHA、EPA、AA，則可顯著恢復PA所造成的胰島素誘發之Akt磷酸化降低，改善PA對胰島素訊息傳遞受損的影響。綜合以上結果可知，PA可經由活化ERK1/2 /PKC-θ /NF-κB誘導發炎反應，亦可使胰島素訊息傳遞受阻，而多元不飽和脂肪酸DHA、EPA及AA可抑制PA所誘導的發炎反應，也可改善PA對胰島素訊息傳遞的傷害。
Lifestyle change and poor eating habits are related to metabolic disease pathogenesis such as insulin resistance which is a worldwide epidemiological issue now. Therefore, prevention and treatment of insulin resistance is important .The polyunsaturated fatty acids (PUFAs) are known to improve inflammatory responses and insulin sensitivity, but the mechanism is not clear. In this study, we explore the effect of long chain PUFAs on palmitate induced inflammatory responses and insulin resistance in C2C12 skeletal muscle cells. Data from this study showed that exposure of C2C12 skeletal muscle cells to 750 μM palmitate led to activation of the protein kinase C (PKC) and extracellular-regulated protein kinase (ERK), then activated nuclear factor-κB (NF-κB) pathway to enhance expression of the proinflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin 6 (IL-6) and cyclooxygenase-2 (COX-2). In C2C12 cells, co-incubation of palmitate with docosahexaenoic acid (DHA)、eicosapentaenoic Acid (EPA) and arachidonic acid (AA) could reversed palmitate -induced inflammatory events such as activation of ERK、PKC、NF-κB and expression of proinflammatory cytokines. Moreover, tested PUFAs reversed palmitate down-regulated of phosphorylation of AMP-activated protein kinase(AMPK) and AS160 ,which were associated with regulation of glucose transporter 4 translocation and increase of muscle cells glucose uptake in basal state. Furthermore, tested PUFAs significantly reversed down-regulation of insulin-induced Akt phosphorylation by palmitate. These findings suggest that palmitate would be through activation of ERK1/2/PKC-θ/NF-κB to induce inflammatory responses and impair insulin signaling. PUFAs including DHA, EPA and AA could inhibit palmitate induced inflammation and insulin resistance.
