Purpose The dramatic increase in childhood obesity greatly increases the risk of obesity and related health risks in adulthood. While this increase has been predominantly attributed to changes in nutrition and physical exercise in children, maternal health and diet during pregnancy are proving to be critical contributors as well. Concurrent with higher-fat diets in children, an increase in pediatric nonalcoholic fatty liver disease (NAFLD) has been shown. The purpose of these studies was to develop a non-human primate (NHP) model to investigate the contribution of chronic maternal high-fat diet on fetal metabolic systems and, in particular, the liver.
Methods Japanese macaques were placed on one of two diets; (1) control diet (CTR) - 13% of calories from fat and (2) high-fat diet - 35% of calories from fat for 3 years. Fetuses from these moms were obtained at gestational day 130 (full term = 175 days) each year of the diet and tissues were collected during necropsy.
Results The high-fat diet induced moderate maternal hyperinsulinemia and hyperleptinemia that increased over the 3 years. In addition, the fetuses displayed increased circulating free fatty acids and shifts in gene expression in liver and skeletal muscle indicating attempted adaptation to this high-fat environment. Fetuses from mothers on the high fat diet for 2-3 years showed changes in gene expression that suggest oxidative stress and insulin resistance. Furthermore, histological analysis of the liver showed increased staining for markers of oxidative stress as well as steatosis.
Conclusion Fetuses exposed to a high-fat maternal environment can initially generate an adaptive response; however, if the maternal condition persists, the fetus can develop metabolic sequelae. This maternal phenotype (overweight and on a high-fat diet) represents a large proportion of pregnancies within the United States and may be one of the most common health risks facing developing fetuses. These data suggest that increased maternal high fat consumption may underlie some of the metabolic disorders in children including the increased occurrence of NAFLD.
Acknowledgments NIH grants DK060685, DK060685S2, HD14643, HD18185, and RR00163.
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