| Obesity is now deemed to be the primary preventable cause of illness and premature death. Recent studies demonstrate that alterations in fatty acid metabolism contribute towards the pathology of many of the conditions associated with obesity, some of which include skeletal muscle insulin resistance, type 2 diabetes, and ischemic heart disease. It has been postulated that an impairment in skeletal muscle and cardiac fatty acid oxidation rates during obesity results in the intracellular accumulation of lipid metabolites such as diacylglycerol and ceramide, which contribute to the development of these obesity-associated diseases. With regards to ischemic heart disease, it has been proposed that inhibiting fatty acid oxidation during reperfusion can protect against the development of reperfusion injury by improving the efficiency of contractile function in the heart.;With regards to the development of cardiomyopathy during obesity, our results once again challenge current dogma and show that reduced myocardial fatty acid oxidation rates do not have negative consequences on contractile function, and can actually improve insulin-stimulated cardiac glucose utilization rates in MCD deficient mice. In addition, we show that the stimulation of glucose oxidation either directly, or secondary to an inhibition of fatty acid oxidation, reduces infarct size following in vivo ischemia/reperfusion.;Overall, the results of this thesis illustrate that modulating fatty acid metabolism (via either MCD or SPT 1 inhibition) is a promising target for the treatment of obesity-associated diseases.;This thesis addresses these proposals by using a number of genetic and pharmacological approaches to alter fatty acid metabolism. Our results challenge current dogma by demonstrating that treatments which lower fatty acid oxidation rates in the muscle (genetic deletion of malonyl CoA decarboxylase (MCD) in mice) actually protect against insulin resistance associated with both obesity and age. Furthermore, we follow up on these observations by showing differences between the inhibition of mitochondrial fatty acid uptake and mitochondrial fatty acid oxidation in providing protection against insulin resistance. In subsequent studies, we demonstrate that pharmacological inhibition of serine palmitoyl transferase 1 (SPT 1) prevents the obesity-induced rise m skeletal muscle ceramide content and reverses insulin resistance. |
