Nutrient and Hormonal Regulation of Systemic Lipid and Glucose Handling
Nutrient uptake into skeletal muscle involves the redistribution of specific transport proteins to the plasma membrane, events that are tightly regulated by various cellular signals, including the hormone insulin. However, a dysregulatation in nutrient homeostasis causes insulin resistance, a process related to attenuated skeletal muscle glucose transporter (GLUT4), and exaggerated redistribution of fatty acid transporters (i.e. FAT/CD36), at the plasma membrane. Therefore, this thesis investigated the hormonal regulation of nutrient uptake, as well as the ability of prior exercise training to combat high fat diet induced metabolic perturbations. Study one examined post-prandial control of GLUT4 subcellular localization in muscle. This study demonstrated that a mixed carbohydrate- and fat-containing meal increased circulating GIP and improved whole body glucose clearance. Moreover, in skeletal muscle, GIP directly stimulated glucose uptake and increased plasmalemmal GLUT4 independent of insulin, highlighting a novel mechanism for GIP. Hyperinsulinemia has been proposed to result in FAT/CD36 redistribution to the plasma membrane, influencing ectopic lipid accumulation and insulin resistance. However, study two demonstrated that although a pharmacological dose of insulin is sufficient to cause fatty acid transporter plasmalemmal accumulation, this relocation is brief and cannot explain the responses observed post-prandially or during a high-fat challenge. Rather, acute and chronic translocation of fat transporters was matched to increased circulating free fatty acids, suggesting lipids may regulate fatty acid transporter subcellular location. Adipose tissue metabolism is known to influence whole body insulin sensitivity, and is responsive to exercise training. Therefore, in the third study I utilized prior exercise training to examine the protective effects on high fat diet-induced insulin resistance, and potential mechanisms in diverse tissues. I determined that prior training blunted high fat diet-induced weight gain and glucose intolerance independently of food intake and cage activity, responses associated with increased mitochondrial enzyme content in white adipose tissue and increased UCP-1 content in brown adipose tissue. Together, this thesis adds to our understanding of the signals mediating nutrient transporter cycling in skeletal muscle, potentially providing new targets for the treatment of insulin resistance. Additionally, this thesis further emphasizes the importance of regular exercise on metabolic health, specifically in the face of nutrient over-consumption.