The thrust of this proposal is to elucidate the regulation and interaction of carbohydrate and lipid metabolism in the liver and non-hepatic tissues, especially heart and skeletal muscle. Developments over the last grant period have cast doubt on traditional concepts of glucose homeostasis. In addition, intriguing aspects of the regulatory role of malonyl-CoA in fatty acid metabolism have come to light. Accordingly, two broad lines of investigation will be carried out. The first involves a study of the regulatory events initiating the conversion of catabolic metabolism to anabolic metabolism when fasted animals are refed. Three main questions will be posed: (1) what controls glucose-6-phosphate flow into glycogen or plasma glucose in fasting and its reversal? (2) What dictates whether glycogen is formed directly or indirectly (via lactate) from glucose? (3) What controls fructose-2, 6-bisphosphate levels in the liver after refeeding? The second series of experiments addresses the regulatory interaction between malonyl-CoA and carnitine palmitoyl-transferase I (CPT I), the rate limiting enzyme for fatty acid oxidation and ketogenesis. Again, three major questions will be asked: (1) is malonyl-CoA a physiologic regulator of fatty acid metabolism in non-hepatic tissues? (2) Are CPT I and CPT II different enzymes? (3) How does malonyl-CoA inhibit CPT I? Answers to these questions are important for an understanding of normal fuel metabolism and its derangements in disease states - particularly uncontrolled diabetes.
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