Mechanisms mediating beneficial effects of Eicosapentaenoic Acid (EPA) in insulin resistance and obesity: Studies in muscle

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2013-08

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Abstract

Obesity is a major epidemic problem in the US and worldwide. It is associated with several other chronic diseases such as type-2 diabetes mellitus, insulin resistance, cardiovascular disease and some types of cancers [1-4]. Major contributors to the obesity epidemics include sedentary lifestyle and lack of physical activity, increased consumption of energy dense foods as well as genetic and other environmental factors [1, 2]. Omega-3 polyunsaturated fatty acids (PUFA) are known to confer multiple health benefits such as, improvements in blood pressure and cardiovascular health and alleviation of symptoms associated with anti-inflammatory diseases such as rheumatoid arthritis [5, 6].
Previous research from Dr. Moustaid-Moussa’s lab showed that feeding mice high-fat (HF) diets enriched with the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) decreased inflammation, adiposity and insulin resistance compared to mice fed only the high fat diet. Skeletal muscle is well known for its key role metabolic homeostasis. Accordingly, we sought to investigate mechanisms by which EPA ameliorates glucose tolerance, lipid metabolism and inflammation. Specifically, we investigated effects of EPA on skeletal muscle taken from mice fed high fat diets with or without EPA. In addition, we used C2C12 cells, a skeletal muscle model that is used to study myocytes differentiation and metabolism in vitro, to further dissect the mechanisms mediating EPA on skeletal muscle. Metabolomic, gene and protein expression approaches were used to determine the role of EPA in skeletal muscle. In vivo, our analyses showed that fatty acid and amino acid profiles were altered by the EPA diet. Both saturated fatty acids and docosahexaenoate (DHA, a polyunsaturated fatty acid downstream of EPA) were elevated in muscle from the EPA group. Furthermore, essential amino acids for muscle protein synthesis and growth, namely branched chain amino acids (BCAAs) were increased by the EPA diet. However, no significant changes were observed in fatty acid oxidation between HF and HF-EPA fed animals. In vitro, preliminary data showed that treating C2C12 cells with EPA tended to increase the expression of genes involved in both fatty acid synthesis and oxidation. In conclusion, EPA didn’t significantly affect fatty acid oxidation but increased de novo lipogenesis and BCAA synthesis in vivo. By contrast, EPA treatment increased both fatty acid synthesis and oxidation in vitro. However, additional experiments are needed to confirm these findings and gain further insight into mechanisms by which EPA prevents high fat diet-induced obesity, inflammation and insulin resistance in both animal models and human subjects.

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Keywords

Obesity, Insulin resistance, Skeletal muscle, Eicosapentaenoic acid (EPA)

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