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Fatty acids increase toll‐like receptor‐4 gene expression, protein content in a saturation‐dependent manner in C2C12 skeletal muscle cells

Growing evidence suggests that obesity, and associated metabolic dysregulation, occurs in concert with chronic low‐grade inflammation. Our laboratory has reported that toll‐like receptor‐4 (TLR4) expression, an inflammatory mediator, is elevated in the skeletal muscle of obese humans and associated with reduced fatty acid oxidation and increased lipid synthesis. The purpose of this study was to examine the role of saturated vs. monounsaturated fatty acids on TLR4 transcription and function. Our hypothesis was that saturated fatty acids would sensitize the TLR4 pathway via increased receptor content. To this end, skeletal muscle cells were incubated in the presence of varying ratios of palmitate (16:0) and oleate (18:1) to examine the effects of fatty acid saturation on TLR4. Fatty acid exposure resulted in a significant and stepwise increase in TLR4 mRNA and protein content with increasing palmitate concentration. To determine if the fatty acid effect on TLR4 was translated into a functional consequence, we measured the effect of TLR4 activation on substrate metabolism. As the degree of fatty acid saturation was increased in the media, the effect of TLR4 activation on glucose and fat oxidation was exacerbated. In conclusion, exposure to a lipotoxic environment sensitizes the TLR4 pathway in skeletal muscle and suggests that this is accomplished via a mechanism that is fatty acid saturation specific.