(provided by applicant: An association between birthweight and later risk for developing coronary heart disease has been shown for both small (SGA) and large (LGA) for gestational age newborns. However, most clinical and basic sciences studies have concentrated on effects of low birthweight. Maternal obesity and gestational diabetes (GDM) are the main determinants of LGA newborns. Of these conditions, maternal obesity has received little attention as a potential prenatal insult leading to fetal programming. The goal of this proposal is to develop an animal model of maternal obesity that will allow study of the mechanisms by which fetal adaptations to maternal obesity and/or being born LGA increase the risk for developing cardiovascular diseases. Our global hypothesis is that the offspring of obese mothers have permanent alterations in adipose tissue that predispose them to develop abnormalities in endothelial function/vascular reactivity and hypertension and in adult life. Therefore, we propose that: 1) The maternal environment of the obese pregnant female elicits fetal adaptations which have long-term effects on the offspring's adipose tissue regulation and function;2) The adipose tissue in the offspring of obese mothers has alterations in hormonal (adiponectin, leptin, resistin) and cytokine (TNF?, IL-6 and CRP) production and secretion;3) Alterations in adipose tissue production and/or secretion of hormones and cytokines play a central role in the development of vascular reactivity abnormalities and hypertension. We will test these hypotheses with the following specific aims: Specific Aim 1: To establish an animal model of maternal obesity (overfeeding) in sheep fed a complete balanced diet. Specific Aim 2: To determine if offspring of obese sheep develop alterations in endothelial function/vascular reactivity and/or hypertension. Specific Aim 3: To determine if the offspring of obese sheep exhibit insulin resistance and alterations in adipose tissue hormone and cytokine expression and secretion. PUBLIC HEALTH RELEVANCE: Our proposal will provide an opportunity to study the effect of maternal obesity in an animal model in which much is already known about adipocyte function, and in which the endocrine environment both before and after birth is similar to that of human infants. One of the unique features of our proposal is the study of maternal obesity as a pregestational/gestational continuum, the most common clinical presentation of maternal obesity. The data gathered will serve as the basis for a new application (R01) directed toward identifying the underlying mechanisms for the abnormalities present in the offspring. Future experiments will be conducted at different stages of development to determine the longitudinal nature of any deleterious effects of increased adiposity.

R21HL089840

2008-07-01

2011-06-30