METABOLISM IN THE NONHUMAN PRIMATE AND OVINE FETUS

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The accrual of fetal energy stores is a necessary preparation for extrauterine life, but the mechanisms responsible for this accrual are not well understood. The thesis of this proposal is that placental substrate transport and metabolism, and placental hormone secretion, program the fetal milieu for glycogenesis and lipogenesis. We will study placental function, substrate availability, and placental lactogen action, in order to relate clearly the placentally-controlled fetal milieu to the development of fetal energy stores. Glycogenesis directly from glucose, from precursors derived during intrahepatic glycolysis, and from circulating precursors will be quantitated in fetal sheep and baboons. The time course of development of the gluconeogenic path to glycogenesis will be correlated with accrual of glycogen in the fetal/neonatal rat. The hypothesis that lactate and glutamine, produced by placental metabolism from glucose and glutamate respectively, are glycogenic precursors through the indirect (gluconeogenic route), and that the availability of these circulating precursors enhances fetal glycogenesis will be tested. Whether ovine placental lactogen (rat hepatocyte) enhances indirect glycogenesis, and whether human placental lactogen has similar effects (baboon fetal hepatocyte) will be determined. The precursors for lipogenesis will be examined. The hypothesis that lactate and glutamine enhance fetal lipogenesis and diminish lipolysis will be tested in vitro (rat, baboon hepatocyte/baboon adipocyte). The effect of human placental lactogen on fetal lipogenesis/lipolysis will be assessed in vitro. Total lipogenesis and lipogenesis from ketone bodies will be measured in the baboon fetus. Transfer and metabolism of ketone bodies and glutamate will be quantitated in the perfused, term human placenta, in order to confirm the nature of their transplacental passage and metabolism. These studies have direct bearing on the well-being of the human neonate, since acquisition of fetal energy stores is essential for survival during delivery and during the time between loss of the umbilical energy supply and commencement of oral intake. An understanding of the physiologic mechanisms involved in fetal energy storage will permit rational management and understanding of the growth-retarded neonate, and the infant of the diabetic woman. It will help us to understand the effects of fasting ketosis and of maternal nutritional oversupply upon the fetus.