Insulin resistance is a hallmark feature of type 2 diabetes mellitus (DM) and is also present in many obese individuals and the majority of those with the metabolic syndrome. Fasting plasma free fatty acids (FFA) are frequently elevated in these subjects and significant controversy surrounds the role of hepatic FFA oxidation in the development of insulin resistance. Previous studies have been limited by the absence of a specific activator of this pathway. However, our preliminary data demonstrate that this issue can be addressed directly for the first time by overexpression of the enzyme carnitine palmitoyltransferase I (CPT I), a major intracellular regulator of beta-oxidation. This proposal has two primary goals. The first is to provide the applicant with the skills necessary to become an independent clinical investigator in the field of lipid metabolism and type 2 DM. Training aims; 1. To expand the candidate's theoretical background in the biochemistry of metabolic disorders. 2. To gain experience in the design and interpretation of metabolic studies. 3. To learn many of the practical techniques necessary to pursue a career in metabolic research. The second goal is to perform novel research into the role of L-CPT I in hepatic fatty acid metabolism, particularly as it relates to the development of insulin resistance, liver steatosis and type 2 DM.
Research aims :
In Aim 1, we will test the hypothesis that increased activity of L-CPT I in hepatocytes in vitro will promote fatty acid oxidation, while reducing acyl-CoA esterification, intracellular triglyceride (TG) accumulation and very low-density lipoprotein (VLDL) secretion.
In Aims 2, 3 and 4, CPT I will be overexpressed in vivo, in the liver of normal rats, high-fat fed obese/insulin resistant rats and ZDF obese/diabetic rats, respectively. Elevated hepatic L-CPT I is expected to have similar effects on lipid metabolism as proposed for in vitro studies. We hypothesize that such alterations will decrease or prevent lipid accumulation in the liver. This is expected to: (1) enhance insulin sensitivity in normal rats (Aim 2); (2) ameliorate the disregulation of liver fatty acid metabolism associated with the development of insulin resistance in the high-fat fed animals (Aim 3); and (3) prevent or reverse the abnormalities of fatty acid metabolism that accompany the fully diabetic phenotype in ZDF rats (Aim 4).
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