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117 MATERNAL OVERNUTRITION CAUSES LIVER DISEASE IN THE NONHUMAN PRIMATE.
  1. A. K. Batra1,
  2. P. R. Levasseur1,
  3. A. L. Fletcher1,
  4. W. F. Grant1,
  5. X. Zhu1,
  6. D. L. Marks1
  1. 1Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, OR.

Abstract

Obesity in children is now epidemic in the United States. The increasing prevalence of maternal obesity raises the concern that maternal obesity, independent of diabetes, may be contributing to fetal programming of obesity and its comorbidities. The notion that maternal nutrition may lead to stress-like changes in gene expression, steatosis, and gluconeogenesis that underlie programming of adult disease is increasingly gaining acceptance. However, the mechanisms involved in generating such responses are not well characterized. 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. We have developed a nonhuman primate (NHP) model of high-fat/-calorie diet-induced maternal obesity/diabetes in which age (5-7 years at start) and weight (7-9 kg) matched Japanese macaques were assigned (fall 2002) to either a control diet group (13% of calories from fat) or a high-fat diet group (35.2% of calories from fat). Males were housed with each group and pregnancies were terminated by cesarean section early in the third trimester (gestational day 130). Our data demonstrate that maternal consumption of a high-fat diet results in changes in gene expression in the fetal livers in four categories of genes, including those involved in oxidative stress, inflammatory cytokine/signaling, lipid metabolism/transport, and the gluconeogenic pathway. There was a coordinated increase in genes involved in oxidative stress, specifically a family of heat shock proteins (HSP), including HSP90, HSP70, HSP40, and HSP27. We found significant up-regulation of 18 genes involved in the recruitment and activation of neutrophils and macrophages into injured liver as well as genes that are markers of early hepatic fibrosis. These include up-regulation of IL-13 (17-fold), lymphotoxin alpha (47-fold), IL-1β (6-fold), CCL2 (8-fold), and TNF-α (3-fold). We also found a significant up-regulation of genes involved in gluconeogenesis, such as phosphoenolpyruvate carboxykinase (PEPCK), fructose biphosphatase 1 (FBP1), glucose 6 phosphatase (G6Pase) and PGC1-α. Increased Oil Red-O staining suggested the presence of fatty liver disease in the livers of fetuses from mothers on a high-fat diet. Direct measure of liver triglycerides confirmed elevated levels of fatty acids. In summary, we hypothesize that diet-induced inflammation can have a permanent impact on metabolic programming of the liver in a way that favors hepatic insulin resistance and the development of nonalcoholic fatty liver disease in the NHP.

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