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The impact of lifestyle factors on whole-body lipid handling and skeletal muscle mitochondrial content and function

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Title: The impact of lifestyle factors on whole-body lipid handling and skeletal muscle mitochondrial content and function
Author: Matravadia, Sarthak
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Holloway, Graham PMutch, David M
Abstract: The worldwide incidence of obesity has reached pandemic proportions, and is associated with a high risk of developing type 2 diabetes (T2D). Distinct lifestyle choices including sedentary behavior and surplus caloric intake are recognized contributors to obesity development. Lifestyle interventions that target physical activity and dietary habits, including alterations in macronutrient composition, have been shown to improve health status. Importantly, lifestyle interventions are valuable approaches to study the intricate biochemical changes that occur in diverse metabolic tissues under healthy and pathological conditions. Studies in this thesis utilized exercise and dietary essential fatty acid (EFAs) interventions to advance our understanding of how lifestyle factors improve metabolic disturbances within major insulin responsive tissues (i.e., skeletal muscle, white adipose tissue (WAT), and liver) associated with obesity and T2D risk. Skeletal muscle is important given its mass and high capacity for insulin- stimulated glucose transport. Within skeletal muscle, whole-body insulin resistance (IR) has been strongly linked to mitochondrial dysfunction (i.e., reductions in content and/or function). This thesis investigated the posttranscriptional events during exercise-induced mitochondrial biogenesis in lean mice. Results demonstrated that increases in mitochondrial protein content following chronic exercise training occurred in a cellular environment promoting the destabilization of mRNA. These findings provide insight on the regulation of mitochondrial biogenesis in skeletal muscle. This thesis subsequently explored diets enriched with EFAs (α-linolenic (ALA) and linoleic (LA) acids), which prevented whole-body IR and preserved muscle-specific insulin signaling in obese rats; however, their divergent impacts on mitochondrial bioenergetics suggested the involvement of a different mechanism of action. Therefore, it was investigated if reactive lipid species (diacylglycerol (DAG) and ceramide) accumulation was reduced in major insulin-responsive tissues. However, results demonstrated unaltered DAG and ceramide levels in skeletal muscle, WAT and the liver. However, ALA and LA distinctly remodeled the FA composition of major lipid fractions (triglycerides, DAGs and phospholipids) within these diverse tissues, which may underline their protective effects. Together, these results extend our understanding of the biological effects of ALA and LA. Overall, this thesis highlights the therapeutic value of lifestyle factors and their wide-ranging effects in major insulin responsive tissues implicated in the pathogenesis of T2D.
Date: 2016-06
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