Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates
Carrie E. McCurdy, … , Jacob E. Friedman, Kevin L. Grove
Carrie E. McCurdy, … , Jacob E. Friedman, Kevin L. Grove
Published January 19, 2009
Citation Information: J Clin Invest. 2009;119(2):323-335. https://doi.org/10.1172/JCI32661.
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Research Article Metabolism

Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates

Abstract

Maternal obesity is thought to increase the offspring’s risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.

Authors

Carrie E. McCurdy, Jacalyn M. Bishop, Sarah M. Williams, Bernadette E. Grayson, M. Susan Smith, Jacob E. Friedman, Kevin L. Grove

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Figure 6

Effects of increased maternal/fetal lipid supply on hepatic lipotoxicity in the fetus.

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Effects of increased maternal/fetal lipid supply on hepatic lipotoxicity...
An increase in the availability of lipids to the fetus during early development prior to adipose tissue accretion results in lipid accumulation in nonadipose fetal tissues, leading to toxic effects. In O-HFD fetal liver, there was a significant increase in fetal hepatic TG accumulation that correlated with increased JNK activation. Liver staining revealed substantial elevations in markers of oxidative stress and damage in O-HFD livers. It is likely that the elevated TG levels lead to macrophage infiltration and contribute to the liver inflammation. Liver TG accumulation and inflammation are important events underlying NAFLD. The elevation in liver stress activates heat shock proteins (HSPs), which have previously been shown to be involved in chromatin remodeling (epigenetic programming; ref. 98). Oxidative stress and JNK activation triggers transcription for genes involved in gluconeogenesis as well as inflammation. Upregulation of inflammatory cytokines likely contributes to the progression of NAFLD, while early activation of gluconeogenic genes, such as PCK1, in fetal liver may predispose offspring for increased hepatic gluconeogenesis and insulin resistance.