The western style dietary pattern and inactive lifestyle have been shown to increase insulin resistance and to be a risk factor for developing metabolic syndrome and diabetes. It was reported that elevated plasma free fatty acid is response to the inflammation and insulin resistance in diabetic patients and nondiabetic subjects. Propionate (PrA) and butyrate (BuA) short chain fatty acids (SCFAs) are metabolic products of fiber by intestinal bacteria fermentation, SCFAs could regulate immune function and inflammation. Here, the effects of SCFAs on palmitate (PA) -induced inflammation and insulin resistance in C2C12 skeletal muscle cells were examined. Exposure of C2C12 cells to PA enhanced phosphylation of protein kinase c-θ, mitogen-activated protein kinase. Moreover, PA increased activity of transcription factor nuclear factor-κB and production of proinflammatory mediators, such as, cyclooxygenase-2, interleukin-6 and tumor necrosis factor-α. PrA and BuA reversed palmitate down-regulated of phosphorylation of AMP-activated protein kinase and Akt substrate of 160 kDa in basal state. PA-induced insulin resistance as the evidence by decrease phosphylation of Akt activation and glucose uptake in insulin stimulated C2C12 cells. Co-incubation of C2C12 cells with PA, PrA and BuA reversed PA induced inflammatory events and insulin resistance. These data demonstrated that SCFAs are effective in inhibition of PA-induced inflammation and insulin resistance in C2C12 skeletal muscle cells.