FETAL BRANCHED CHAIN AMINO ACID AND KETOACID METABOLISM

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Precise regulation of protein synthesis and protein breakdown is critical to maintaining normal rates of fetal protein assimilation. Although insulin is regarded as the primary fetal growth hormone our earlier investigations of fetal protein metabolism demonstrated that hyperinsulinemia in the fetus does not diminish protein breakdown. We hypothesize that IGF-I has this function in the fetus. We propose to investigate the role of insulin-like growth factors in the regulation of fetal protein kinetics utilizing the chronically catheterized fetal lamb. Tracer modeling of fetal protein kinetics, using labeled leucine and phenylalanine, will be used to determine in the whole fetal body and in the fetal hindlimb during fetal infusion of insulin-like growth factor I. The following specific aims will be investigated: 1. To assess the effect of the IGF-I on amino acid and protein metabolism in the late gestation fetus. Recombinant human IGF-l infusions will be performed, with simultaneous determination of rates of protein synthesis, breakdown, oxidation, and net accretion in the whole fetal body (by leucine kinetics) and in fetal hindlimb tissue, reflective of skeletal muscle, (by phenylalanine kinetics). We hypothesize that rhIGF-I will result in diminished protein breakdown. 2. To determine whether the changes seen in fetal leucine kinetics are independent of simultaneously induced changes in insulin and amino acid concentrations. Insulin, amino acids, and glucose will be co-infused with IGF-I into the fetus. Animals will be studied when fed and after a prolonged maternal fast. We hypothesize that changes in protein breakdown will be similar to animals studied without insulin and amino acids, but that protein synthetic rates and protein accretion will be increased. 3. To determine the dose response of changes in fetal leucine and phenylalanine kinetics to graded circulating IGF-I concentrations. Studies will be conducted in fed and fasted animals, and dose-response curves constructed. Total circulating IGF-I concentration, and concentrations of binding proteins will be determined. We hypothesize that the dose response for protein breakdown (IGF-I effect) will be similar in fed and fasted animals, but that amino acid accretion (substrate supply effect) will be increased to a greater extent in the fed animals. 4. To determine the relative importance of systemic vs. tissue limited changes in the IGF system. Specific tissues will be assayed for IGF-I and mRNA and protein and ICFBP 1-4 protein; fractional protein synthetic rates will be determined in the same tissues. We hypothesize that fractional synthetic rates will be decreased in tissues obtained from fasted animals, and will be associated with decreased message and protein for IGF-I. In addition, we hypothesize that alterations in tissue IGF-I expression will be correlated with differential responses in fractional protein synthetic rate among tissues to fasting induced substrate deprivation.