EPIDERMAL GROWTH FACTOR, OBESITY & INSULIN RESISTANCE

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The long-term goal of this project is to determine how environmental exposures during development contribute to acquisition of obese or insulin resistant traits in the adult. If successful, it may be possible to devise strategies for early intervention which might prevent or at least forestall the onset of these disorders. The studies proposed in this application address the role of epidermal growth factor (EGF) secretion during intrauterine and postnatal life in development of an animal's susceptibility to become obese or insulin resistant as an adult. During intrauterine and early neonatal life EGF is largely of maternal origin. In pregnant animals circulating EGF is dependent upon synthesis and exocrine secretion from submandibular gland, while in the neonatal period EGF delivery to pups occurs via synthesis in mammary tissue and secretion into milk. In both circumstances, the ingested EGF is absorbed intact, though its systemic effects are not clearly defined. The potential importance of EGF for development in insulin resistance is suggested by observations from epidemiological studies linking insulin resistance in adults with impaired fetal growth and from animal studies demonstrating fetal growth retardation in conditions of EGF deficiency during pregnancy. In contrast, elevations of EGF content in milk as associated with a heightened propensity for animals to accumulate fat and become obese. Studies in this project will examine the environmental factors which influence EGF secretion by submandibular gland during pregnancy and determine if reduction in EGF release lead to decreased fetal growth and ultimately to insulin resistance in adult animals. Studies will also examine the role of milk-borne EGF in fostering adipose tissue development in neonatal animals. A principal tenet of this proposal is that early life events which predispose animals to become obese differ from those which promote subsequent development in insulin resistance.