Investigating the Potential of Long-Chain Polyunsaturated Fatty Acids and Exercise on Mitigating Skeletal Muscle Inflammation in Obesity

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Hutchinson, Amber
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University of Guelph

Chronic low-grade inflammation causally links obesity to the development of insulin resistance and type 2 diabetes, a disease that affects 462 million individuals world-wide. This thesis utilized both in vivo, ex vivo and in vitro methodologies to study whether n-6 and n-3 polyunsaturated fatty acids (PUFA) and exercise can mitigate obesity-induced skeletal muscle dysfunction with a particular focus on macrophage-myocyte crosstalk. Using an in vitro model designed to recapitulate the inflammatory microenvironment characteristic of obese macrophage-myocyte crosstalk, we showed that both the n-6 PUFA, arachidonic acid, and the n-3 PUFA, docosahexaenoic acid, reduced macrophage production of inflammatory cytokines which in turn promoted improved myocyte metabolic function. In an in vivo high fat diet-induced obese rodent model, we showed that dietary n-3 PUFA blunted skeletal muscle CD4+ and CD8+ T cell accumulation at 12 weeks. Subsequently, using an in vitro co-culture model with splenic-derived CD11b+ macrophages and L6 myocytes to recapitulate obese skeletal muscle stimulated with or without lipopolysaccharide, we showed that short-term (2 week) n-6 and n-3 PUFA reduced and long-term (12 week) n-6 PUFA promoted, inflammatory macrophage-myocyte crosstalk. Finally, we sought to understand how n-3 PUFA and/or moderate exercise (treadmill training 5 days/week for 3 weeks) mitigate the effects of simultaneously consuming a high fat diet on skeletal muscle inflammation. Using an ex vivo model, we demonstrated that n-3 PUFA improved, while exercise reduced, AT-myocyte inflammatory crosstalk suggesting that a high fat diet may inhibit the effects of exercise on skeletal muscle and AT inflammation to worsen insulin resistance. Overall, these studies were the first to investigate the effects of n-6 and n-3 PUFA on obesity-induced skeletal muscle immune cell infiltration and subsequent inflammatory macrophage-myocyte crosstalk. This thesis provides support for n-3 PUFA and short-term n-6 PUFA consumption as dietary strategies to mitigate obesity-associated skeletal muscle inflammation by reducing both immune cell infiltration and subsequent inflammatory macrophage-myocyte crosstalk thereby improving skeletal muscle function.

Obesity, Skeletal muscle, Immune cells, Macrophages, Inflammation, Fatty acids, Insulin, Exercise
Hutchinson, A. L., von Holt, R. K., Wellings, H. R., Monk, J. M., & Robinson, L. E. (2022). Effect of long-chain n-3 polyunsaturated fatty acids and obesity-associated metabolic dysfunction in adipose tissue and skeletal muscle. In: Fish Oil: Nutrition, Consumption and Health. Sandeep Kumar (Ed.) Nova Science Publishers Inc., Hauppauge, NY, USA. In Press