Branched-chain amino acids (BCAA), besides making up 46% of the daily requirement for essential amino acids in man, may have important roles in metabolic regulation. These include protein turnover in muscle, release of alanine and glutamine by peripheral tissues, glucose oxidation and brain synthesis of neurotransmitters. Our studies and those of others have shown that BCAA metabolism, in turn, is regulated by dietary and nutritional factors. For example, starvation increases, while dieting on a hypocaloric carbohydrate diet decreases, catabolism of BCAA. Although there has been progress toward identification of the dietary and metabolic factors which alter BCAA metabolism and the mechanisms of these alterations, a number of fundamental questions remain either unresolved or unexplored. For example, why does carbohydrate spare catabolism of BCAA in brief starvation while fat does not? To answer this and other related questions, using humans and rats as experimental models, the following 8 interrelated research projects are proposed: 1. Effects of carbohydrate versus fat on BCAA metabolism in prolonged versus brief starvation (man). 2. Effect of carbohydrate versus fat on BCAA metabolism in the fed state (man). 3. BCAA metabolism in diabetes (man). 4. Mechanism of alteration in BCAA metabolism by dietary carbohydrate and fat (rats). 5. Mechanism of alteration in BCAA metabolism in hyper- and hypothyroidism (rats). 6. Effect of carnitine on oxidation of BCAA in vitro and in vivo (rats). 7. Metabolism of BCAA when lipid synthesis is inhibited (rats). 8. Effect of starvation, diabetes and clofibrate treatment on metabolism of isovalerate (rats). Our overall hypothesis is that the catabolism of BCAA is regulated by the state of energy metabolism and, moreover, these two metabolic processes are interconnected by a variety of chemical signals among which concentrations of leucine, ketone bodies and ATP are the most predominant. Finally, clinical observations in diseases which selectively affect oxidation of BCAA indicate that a precise regulation of BCAA catabolism is necessary to avoid deleterious effects of either impaired or enhanced oxidation of these amino acids. The studies proposed in the application are aimed at answering fundamental questions regarding this regulation. The information sought by the proposed studies may contribute to a better understanding of pathogenesis and treatment of common metabolic disorders such as obesity, undernutrition, diabetes, thyroid disorders, and liver disease.
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