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.

Impact of maternal obesity on offspring obesity and cardiometabolic disease risk

“…This has been associated with altered hepatic mitochondrial electron transport chain complex activity and with increased expression of genes involved in lipogenesis, oxidative stress and inflammation (Bruce et al 2009). An effect of maternal high-fat diet on offspring liver triglyceride content has also been shown in non-human primates in which the offspring of females maintained long-term on a high-fat diet had increased liver triglyceride content and evidence of increased hepatic oxidative stress whether or not their mothers had become obese, suggesting that programming of liver fat may be independent of maternal obesity, at least in this model (McCurdy et al 2009). The impact of maternal obesity in humans on offspring development of non-alcoholic fatty liver disease has not been studied, although preliminary evidence suggests that early feeding habits may impact on development of fatty liver disease in childhood suggesting a potential role for early life experience in development of this condition (Nobili et al 2009).…”

Nutritional developmental epigenomics: immediate and long-lasting effects

“…High fat consumption during pregnancy induces features of MetS including dyslipidaemia in adult offspring, independent of adult environmental factors (12)(13)(14) . A maternal high-fat diet (HFD) in nonhuman primates triggers lipid accumulation, inflammation and oxidative stress in the fetal liver (15) . These data indicate that the developing fetus is highly vulnerable to excess lipids.…”

124: Genomic variants associated with resistance to high fat diet induced obesity in a primate model

“…The impact of early in life high fat diet exposure are noteworthy and include non-alcoholic fatty liver disease (NAFLD) with lipid accumulation, pancreatic and immune modulatory dysfunction, thyroid hormone dysregulation, hypertension, and alterations in sirtuins and their regulated pathways 18,27,[50][51][52] . These further manifest as aberrant metabolic homeostasis and altered behaviors at both 1 and 3 years of age 30,31 , with early increased body mass trajectories.…”

“…To this end, we have spent nearly a decade establishing and characterizing the effect of obesity and chronic high fat dietary exposure on adult female dams and their offspring in Macaca fuscata (Japanese macaque) [18][19][20][21] . Specifically, we have demonstrated that a high fat diet (HFD) comprised of 36% calories from fat during gestation and lactation structures the offspring's epigenome, metabolome, and intestinal microbiome 18,19,[22][23][24][25][26][27] ; these molecular and metabolic perturbations are accompanied by persistent changes in offspring behavior and impairments in critical neural circuitry despite weaning to a healthy diet 28 . Of interest, we have consistently observed that HFD feeding for 1-5 years prior to pregnancy leads to insulin resistance and obesity in the majority, but not all, exposed dams 18,23,26,27,[29][30][31] .…”