The regulation of fetal growth is coordinated by a complex interaction of substrate supply and endocrine signals of fetal and placental origin: insulin and insulin-like growth factor 1 are believed to have the major regulatory roles. We have been investigating the regulatory roles of these hormones in the ovine fetus, particularly their regulation of proteolysis and amino acid catabolism. We have found that the fetus is resistant to insulin's effect to suppress proteolysis, but insulin is potent inhibitor of amino acid catabolism. IGF-1 inhibits proteolysis by 30%, but has a lessor effect on acid catabolism. The hypothesis of the present proposal is that during brief elevations of insulin and IGF-1, the hormones act in distinct but synergistic manners to promote tissue accretion, insulin by promoting carbohydrate utilization and suppressing amino acid catabolism, and IGF-1 by suppression proteolysis. Insulin acts to reduce amino acid catabolism, directly affecting the activity state of enzymes responsible for amino acid catabolism. IGF-1 acts independent of insulin to decrease proteolysis by suppressing the ubiquitin proteolytic system in the fetus. However, as the length of time in the elevation of plasma IGF-1 progresses, stimulation of protein synthesis becomes predominant, and suppression of proteolysis decreases. Finally, we hypothesize that circulating fetal IGF-1 acts primarily on fetal tissues, but also has effects on placental tissues to alter metabolism and/or transport. These hypotheses will be investigated through three specific aims. 1. To verify that the branched chain dehydrogenase complex in the fetus is a) regulated by the phosphorylation/dephosphorylation; and b) that insulin and insulin-like growth factor act by regulation of the activity state of the complex. 2. To investigate the mechanisms by which IGF-1 inhibits fetal proteolysis. The ubiquitin system will be investigated. We hypothesize the IGF-1 inhibits the ubiquitin system at the gene transcription level, thereby inhibiting fetal proteolysis. 3. To investigate the transplacental flux rates of important fetal substrates during infusion of IGF-1 and/or insulin. 4. To compare and contrast the acute versus chronic effects of increased plasma IGF-1 on fetal growth and protein kinetics. Investigations will be carried out in the chronically catheterized fetal lamb. IGF-1 and insulin will be infused singly and in combination, with detailed analysis of fetal protein kinetics and placental substrate transfer rates determined. In addition, hormonal regulation of the branched chain ketoacid decarboxylase complex and the ubiquitin proteolytic will be examined in detail at the cellular level. These studies will result in important new information system regarding the mechanisms of fetal protein accretion, which will be important in evaluations of the potential for IGF-1 and/or insulin therapy for intrauterine growth restriction or inadequate postnatal growth in premature infants.
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