Metabolic Adaptation in the Postnatal Rat -- Epidermal Growth Factor

Hoath, Steven

Abstract

In newborn mammals, neurosympathetic induction of thermogenin gene expression in brown adipose tissue (BAT) results in closure of an important sensorimotor control loop regulating postnatal energy metabolism. The ability to increase oxygen consumption following environmental cold stress is called the metabolic response to cold (MRC). This important postnatal survival mechanism is compromised in low birth weight infants. This proposal tests the hypothesis that intrauterine growth retardation (IUGR) due to placental insufficiency in the rat will accelerate neurosympathetic development leading to precocious postnatal induction of thermogenin gene expression and early onset of the MRC. Primary focus will be placed on the critical first 72 hours after birth. The long-range hypothesis will also be tested that IUGR will result in metabolically """"""""imprinted"""""""" adults with high resting metabolic rates. To test these hypotheses, real time in vivo systems for measuring respiratory gas exchange in the intact animal will be coupled with infrared imaging of interscapular (BAT) temperature fields. These systems will yield dynamic physiological data which will be complemented with direct biochemical measures of homeothermic ability (BAT thermogenin mRNA and protein, serum and tissue glycerol and free fatty acids). These studies will delineate BAT-dependent mechanisms by which IUGR alters the timing, magnitude, and long-term control of postnatal heat production. In the second half of this proposal we will investigate the role of epidermal growth factor (EGF) as a novel molecular regulator of BAT growth and differentiation. Using the EGF functions as a thermoregulatory molecule in the perinatal rat and a specific mitogen for BAT (but not for liver or kidney). The role of prostaglandins will be examined as a mechanistic basis for the unique metabolic effects of EGF (reduction in body temperature, decrease in systemic oxygen consumption, rapid decline in serum glycerol and triglycerides). BAT thermogenin message and protein and tissue DNA content will be measured following EGF exposure and longterm metabolic imprinting studies in adults will be performed as with the IUGR animals. In summary, the regulation of BAT growth, differentiation, and gene expression will be studied in two well characterized perinatal rat models of somatic growth retardation. This program will yield new metabolic and thermoregulatory data in the rat relevant to perinatal growth control, neonatal imprinting, and the mechanism of action of an important mammalian growth factor (EGF).