LONG-TERM METABOLIC CONSEQUENCES OF EARLY NUTRITIONAL MODIFICATION

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Nutrition plays a very important role in the development and growth of mammals. The influence of nutritional modifications during early childhood on the etiology of obesity and obesity-related diabetes later in life is poorly understood. Our current studies are based on a hypothesis that the consumption of a formula high in carbohydrate calories alters the hormonal and metabolic responses not only in the immediate postnatal period but also alter in adulthood due to "imprinting". We have tested this hypothesis using rat pups reared artificially on a high-carbohydrate (HC) formula during the suckling period. This early nutritional intervention causes hyperinsulinemia and increases hepatic lipogenic capacity during the suckling period. Chronic hyperinsulinemia which persists int he postweaning period leads to the development of obesity later in adult life. We now propose to investigate the mechanisms responsible for early adaptive changes in cell proliferation (e.g. pancreatic islet cells and adipocytes) and metabolic adaptations ("imprinting") in hyperinsulinemic adult rats. Our four specific aims and approaches are: (i) to examine the "critical period" (duration) and "threshold" for the stimulus, we will vary the length of treatment and the concentration of carbohydrate in the (HC) formula, (ii) to investigate the mechanism(s) responsible for altered insulin secretion in pancreatic islet cells, we will use isolated perifused pancreatic islets, primary cultures of islets and cultured insulinoma RINm5F cells; and glucose-mediated responses will be studied at the level of the promoter region of the pyruvate dehydrogenase alpha subunit gene, (iii) to investigate the mechanisms responsible for altered metabolic responses in hyperinsulinemic rats, we plan to study insulin receptor autophosphorylation, phosphorylation of endogenous substrates (pp185) and Glut 4 transporter levels in target tissues, and (iv) to examine the effects of altered maternal metabolic milieu due to hyperinsulinemia and its effect on growth and "metabolic imprinting" in the progeny, we will investigate pregnant females (with early nutritional intervention in their infancy) and their progeny for long-term consequences. Our rat model has potential for providing new, significant insight into the impact of an early postnatal nutritional experience on the development of obesity later in life and also into a maternal non-genetic transfer of "metabolic imprinting" in the progeny.