The mitochondrial carnitine palmitoyltransferase system CPT (composed of CPT 1 and CPTII and a translocase) plays a pivotal role in the regulation of fatty acid metabolism in mammalian tissues. It has received increasing attention as a potential site for pharmacologic interventions in hyperglycemic states and is now recognized as a locus for human mutation, some with serious consequences. Unraveling the details of this complex transport mechanism has moved rapidly in recent years. For example, the amino acids sequences of all three CPT isozymes are now known i.e. CPTII and the two so far malonyl-COA-regulated isoforms of CPT-I (L) live and (M) muscle) from both rat and human; the chromosome location of all three CPT genes; that heart expresses both type of CPT I; that the M variant dominates in rat and human white fat cells as well as in developing rat sperm; and that CPT system appears to be an important element in pancreatic beta-cell function. The investigators now wish to elucidate the structures of the capital CPT 1 genes, how they are regulated, how inhibitors interact with the CPT 1 proteins, why proteins L and M- CPT 1 display such very different properties, the impact on various metabolic processes of tissue-specific CPT 1 knock out, and the genetic basis of CPT 1 deficiency. Also to be studied is the question of whether the fat dissipating action of the newly discovered hormone, leptin, involves alterations in CPT 1 activity and/or fatty acid flux through this step in selected body sites. Finally, the investigators shall begin to explore the role of CPT 1 in sperm development and function, and how CPT 1 inhibitors might impact at this level. The proposed experiments will answer many important questions in the expanding realm of CPT regulatory effects in the intact organism. Of particular importance, the information gained should provide greater insight into the role of abnormal fatty acid metabolism in the etiology of beta cell dysfunction and insulin resistance that characterize obesity and Type II diabetes syndromes, disorders that are reaching epidemic proportions in the United States.
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