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

J Clin Invest. 2009 Feb;119(2):323-35. doi: 10.1172/JCI32661. Epub 2009 Jan 19.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytokines / blood
  • Dietary Fats / adverse effects*
  • Fatty Liver / etiology*
  • Female
  • Fetal Development
  • Fetus / metabolism*
  • Gluconeogenesis
  • Glucose Tolerance Test
  • Insulin Resistance
  • Leptin / blood
  • Liver / metabolism*
  • Macaca
  • Male
  • Maternal Nutritional Physiological Phenomena
  • Obesity / complications
  • Oxidative Stress
  • Pregnancy
  • Triglycerides / metabolism


  • Cytokines
  • Dietary Fats
  • Leptin
  • Triglycerides