MECHANISMS FOR FETAL HEPATIC PROGRAMMING IN THE NON-HUMAN PRIMATE (NHP)

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DESCRIPTION (provided by applicant): The current childhood obesity epidemic, coupled with the increasing prevalence of maternal obesity raise the distressing concern that maternal obesity, independent of diabetes, may be contributing to fetal programming of obesity and its co-morbidities. Evidence from human and animal studies suggests that individuals exposed to a high nutrient supply during fetal life have a high risk of becoming obese children and adults. It is clear that children born to diabetic mothers have increased adiposity and are insulin resistant. Associations between childhood obesity and maternal obesity without diabetes or weight gain during pregnancy have been suggested, but are less clear. In collaboration with the Oregon Health and Sciences University, we have developed a nonhuman primate (NHP) model of high fat/calorie diet-induced maternal obesity/diabetes in order to determine the immediate and long-term effects on body weight homeostasis in the offspring. Pilot data obtained by our group in the fetal liver of NHP exposed to chronic (2-3 yr) maternal high fat diet show a novel transcriptional regulatory pattern (increased HNF4a, PEPCK, Heat Shock Protein Genes) that underlies two potentially important abnormalities: hepatic steatosis and premature gluconeogenesis. In addition, microarray and histological evidence suggests fetal livers from mothers fed a high fat diet develop a pattern of chronic inflammation, associated with oxidative stress and non-alcoholic steatohepatitis (NASH). The major goal(s) of this program is to collaborate with investigators at the Oregon National Primate Research Center to 1. Identify how high fat feeding during pregnancy triggers dysregulation of key aspects in hepatic fuel sensing network during fetal life. 2. Determine the impact of these changes on insulin resistance and obesity during post-natal life. 3. Determine if switching obese/diabetic mothers to a low fat/calorie diet during pregnancy alone can prevent the development of metabolic abnormalities in the fetus. The public health consequences of the hypothesis that fuel-mediated programming may be driven by maternal overnutrition and obesity are enormous. These studies will provide critical insights into the fundamental molecular mechanisms underlying susceptibility to pediatric and adult metabolic disease not possible in other animal models, and will lay important groundwork for future studies aimed at developing safe and effective therapeutic approaches to halting juvenile obesity and its devastating co-morbidities.