Maternal High-Fat Diet Impairs Placental Fatty Acid β-Oxidation and Metabolic Homeostasis in the Offspring

Abstract

Maternal overnutrition can affect fetal growth and development, thus increasing susceptibility to obesity and diabetes in later life of the offspring. Placenta is the central organ connecting the developing fetus with the maternal environment. It is indicated placental fatty acid metabolism plays an essential role in affecting the outcome of the pregnancy and fetus. However, the role of placental fatty acid β-oxidation (FAO) in maternal overnutrition affecting glucose metabolism in the offspring remains unclear. In this study, C57BL/6J female mice were fed with normal chow or high-fat diet before and during pregnancy and lactation. The placenta and fetal liver were collected at gestation day 18.5, and the offspring's liver was collected at weaning. FAO-related genes and AMP-activated protein kinase (AMPK) signaling pathway were examined both in the placenta and in the human JEG-3 trophoblast cells. FAO-related genes were further examined in the liver of the fetuses and in the offspring at weaning. We found that dams fed with high-fat diet showed higher fasting blood glucose, impaired glucose tolerance at gestation day 14.5 and higher serum total cholesterol (T-CHO) at gestation day 18.5. The placental weight and lipid deposition were significantly increased in maternal high-fat diet group. At weaning, the offspring mice of high-fat diet group exhibited higher body weight, impaired glucose tolerance, insulin resistance and increased serum T-CHO, compared with control group. We further found that maternal high-fat diet downregulated mRNA and protein expressions of carnitine palmitoyltransferase 2 (CPT2), a key enzyme in FAO, by suppressing the AMPK/Sirt1/PGC1α signaling pathway in the placenta. In JEG-3 cells, protein expressions of CPT2 and CPT1b were both downregulated by suppressing the AMPK/Sirt1/PGC1α signaling pathway under glucolipotoxic condition, but were later restored by the AMPK agonist 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR). However, there was no difference in CPT2 and CPT1 gene expression in the liver of fetuses and offspring at weaning age. In conclusion, maternal high-fat diet can impair gene expression involved in FAO in the placenta by downregulating the AMPK signaling pathway, and can cause glucose and lipid dysfunction of offspring at weaning, indicating that placental FAO may play a crucial role in regulating maternal overnutrition and metabolic health in the offspring.

The dynamic effects of maternal high-calorie diet on glycolipid metabolism and gut microbiota from weaning to adulthood in offspring mice

“…Our previous results demonstrated that a maternal HF diet led to higher blood glucose, glucose intolerance, and hypercholesteremia in dams during gestation ( 5 ). In the present study, the HF-fed dams exhibited glucose intolerance after lactation.…”

“…Early-life adverse environmental factors are linked to the development of diabetes and obesity ( 1 ). Accumulating evidence pointed out that maternal overnutrition not only caused metabolic disturbance in dams but also determined susceptibility to obesity and diabetes in the offspring ( 5 , 28 ). Growing evidence suggests an important role of dysbiosis of offspring microbiome influenced by maternal overnutrition in glycolipid disorders of offspring at weaning ( 6 , 28 , 40 ).…”

Molecular pathways and nutrigenomic review of insulin resistance development in gestational diabetes mellitus

“…Thus, controlling fat intake is fundamental in the GDM management. Fatty acid metabolism is mediated by beta-oxidation and ketogenesis and may have effects on gene expression in pancreatic beta cells and other cells ( 140 ). A study established that CPT I activity is key in the control of fatty acid oxidation ( 141 ).…”

Placental adaptations supporting fetal growth during normal and adverse gestational environments

“…In pregnant ewes, over‐feeding can also result in reduced cotyledon vascular density and a slowing of fetal growth towards term (Ma et al., 2010 ; Zhu et al., 2009 ). Placental thickness is also reduced in rats fed high‐fat diets (Song et al., 2017 ) and there are reports of disorganized labyrinthine zone structure in high‐fat‐fed mice (Zhang et al., 2022 ), even if fetal development may not always be impaired. Alterations in placental weight and labyrinthine zone morphology with an obesogenic diet can be linked to reduced neonatal viability (Lean et al., 2022 ).…”