LONG TERM METABOLIC CONSEQUENCES OF EARLY NUTRITIONAL MODIFICATION

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Neonatal rats fed a high-carbohydrate (HC) milk formula using an artificial rearing system ("pup in a cup" model) during the suckling period experience hyperinsulinemia which persists in adult life and causes obesity. Animal (second generation) born to hyperinsulinemic/obese HC females also develop hyperinsulinemia and obesity. Glucose-stimulated insulin secretory response is altered in the pancreatic beta cells of HC animals of both generations. Our long-term goals are: (i) to investigate the molecular mechanisms responsible for alterations of specific gene transcription in beta cells of HC rat, and (ii) to investigate the molecular mechanisms responsible for alterations of specific gene transcription in beta cells of HC rat, and (ii) to study other strains with a different genetic background for their responses to this early nutritional intervention and the transmission of this "metabolic programming" to this progeny. The specific aims are: (i) to investigate the molecular mechanisms responsible for enhanced insulin gene transcription in islets of HC rats (experiencing diet-induced alterations) and the progeny of HC females, (ii) to investigate the molecular mechanisms responsible for increased transcription of the two genes (the acetyl-CoA carboxylase and pyruvate dehydrogenase alpha subunit genes) whose products are implicated to play regulatory roles in glucose-induced insulin secretion, and (iii) to investigate the maternal environmental factor(s) responsible for the development of hyperinsulinemia in the progeny born to hyperinsulinemic HC females. Islets will be isolated from HC rats as well as from rats red a milk-formula high in fat (HF) and also rats reared naturally (mother fed group, MF). Experimental approaches include: transcription run-on assay, gel mobility shift assay, modification of transcription factors by specific kinases and phosphatase, Northern blot analysis, enzyme activity assay, reciprocal embryo transfer between HC and MF females, dietary restriction to avoid the development of obesity, and measurement of specific hormones and growth factors in plasma from three different groups of animals at different ages. This unique rat model has the potential for providing new and significant insight into the molecular mechanisms responsible for the development of hyperinsulinemia due to early nutritional interventions and also on fetal pancreatic adaptations to chronic hyperinsulinemic environment.