At birth a newborn lamb responds to cold by inducing shivering and nonshivering thermogenesis, increasing heat production three- to five- fold. If a fetal sheep is cooled in utero, however, the response is minimal. Even if additional O2 and catecholamines are provided to simulate birth conditions, the response remains quiescent. Thermogenic responses increase and approach newborn levels only after occlusion of the umbilical cord. The means by which cord occlusion facilitates thermogenesis is unknown. One viable possibility is that an inhibitor, perhaps of placental origin, suppresses thermogenesis before birth. Upon its removal thermogenesis begins under the stimulation of elevated catecholamines. We have considered several candidates for the proposed inhibitor and have designed experiments to test each of them. The hypotheses are as follows: 1) Adenosine of placental origin tonically inhibits lipolysis in utero. Removal of the placenta allows thermogenesis to begin. 2) A circulating eicosanoid, possibly PGE2, tonically suppresses thermogenesis in utero. Diminishing concentrations after birth allow thermogenesis to begin. 3) Growth hormone tonically suppresses thermogenesis before birth. Again, diminishing concentrations allow thermogenesis. To test these hypotheses a series of studies are proposed using the chronically-prepared, unanesthetized fetal sheep as an animal model. Birth will be simulated in utero by cooling the amniotic fluid, ventilating the fetal lungs with O2, and snaring the umbilical cord. The compounds of interest and their antagonists will be given. Fetal responses will be assessed by changes in plasma glycerol and free fatty acid concentration, changes in brown fat temperature, and specific binding of radiolabeled guanosine diphosphate, GDP (an index of uncoupling protein activity in brown fat). Whole-body responses will be characterized by measurements of O2 consumption and core body temperature. An additional line of work will test whether nonshivering thermogenesis occurs in tissues other than brown fat. Specific tissues will be tested using vasoactive agents and blockers of Ca2+ flux. Our goal is to continue to investigate the signals that activate and control thermogenic responses in the fetal and newborn sheep. These studies are directly relevant to treatment of hypothermia in the newborn human and, more generally, to the control of metabolism and growth.
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