Maternal Overweight Induced by a Diet with High Content of Saturated Fat Activates Placental mTOR and eIF2alpha Signaling and Increases Fetal Growth in Rats1

Abstract

The mammalian target of rapamycin (mTOR) and the eukaryotic initiation factor 2 (eIF2) signaling pathways control protein synthesis in response to nutrient availability. Moreover, mTOR is a positive regulator of placental nutrient transport and is involved in the regulation of fetal growth. We hypothesized that maternal overweight, induced by a diet with high saturated fat content, i) up-regulates placental mTOR activity and nutrient transport, resulting in fetal overgrowth; ii) inhibits phosphorylation of eIF2 at its alpha subunit (eIF2alpha); and iii) leads to placental inflammation. Albino Wistar female rats were fed a control or high-saturated-fat (HF) diet for 7 wk before mating and during pregnancy. At gestational day 21, the HF diet significantly increased maternal and fetal triglyceride, leptin, and insulin (but not glucose) levels and maternal and fetal weights, and placental weights trended to increase. Phosphorylated 4EBP1 (T37/46 and S65) was significantly higher, and phosphorylated rpS6 (S235/236) tended to increase, in the placentas of dams fed an HF diet, indicating an activation of mTOR complex 1 (mTORC1). Phosphorylation of AMPK and eIF2alpha was reduced in the HF diet group compared to the control. The expression and activity of placental nutrient transporters and lipoprotein lipase (LPL), as well as the activation of inflammatory pathways, were not altered by the maternal diet. We conclude that maternal overweight induced by an HF diet stimulates mTORC1 activity and decreases eIF2alpha phosphorylation in rat placentas. We speculate that these changes may up-regulate protein synthesis and contribute to placental and fetal overgrowth.

Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth

“…mTORC1 is a key positive regulator of placental amino acid transport (24,25), and placental mTORC1 signaling has been reported to be activated in obese women (6) and rodents fed a high-fat diet (40). Consistent with these reports, placental mTORC1 activity was elevated in obese dams and mTORC1 signaling returned to control levels by ADN infusion.…”

The Role of Placental Nutrient Sensing in Maternal-Fetal Resource Allocation1

“…In the placenta, the AAR pathway has been reported to be activated in a rat model of maternal protein restriction [95]. In addition, phosphorylation of eIF2a is increased in placentas from growth-restricted fetuses [96], whereas in pregnant rats fed with a high-fat diet leading to fetal overgrowth, eIF2a phosphorylation is decreased [97]. Interestingly, in pregnancies at high altitude, which are associated with chronic maternal hypobaric hypoxia and low birth weight, there is increased phosphorylation of eIF2a, indicative of inhibition of protein synthesis [98].…”

“…Moreover, AMPK activation inhibits ATP-consuming anabolic pathways, including protein synthesis, in order to maintain cellular energy balance and homeostasis. Placental AMPK phosphorylation has been reported to be increased in sheep subjected to 50% calorie restriction [100] and decreased in overnourished, obese pregnant ewes [101], high-fat diet-fed pregnant rats [97], and obese women giving birth to large babies [89]. In contrast, placental AMPK activity is unaltered in response to maternal protein restriction in the rat [62].…”

“…Placental mTORC1 activity is inhibited in human IUGR [96,114] and activated in placentas of large babies born to obese mothers [97]. Furthermore, placental mTORC1 activity has been reported to be decreased in hyperthermia-induced IUGR in the sheep [117] and in response to a maternal low-protein diet in the rat [62] and maternal calorie restriction in the baboon [27].…”

The Impact of Traditional Food and Lifestyle Behavior on Epigenetic Burden of Chronic Disease

“…Human/ cohort study Childhood obesity [206][207][208][209][210][211] Increased DNA methylation of the CASP10, CDKN1C, EPHA1, HLADOB3, IRF5, MMP9, MPL, NID1, retinoid X receptor-α, IGF2/ H19, and POMC, and lower methylation of LINE1 in children are strongly associated with childhood obesity Hypo-and hypermethylation and gene expression changes of the TACSTD2 gene at birth associated with childhood obesity Rat Maternal high fat diet prior to, and during pregnancy and lactation [127,131,172,176,178,179,[182][183][184][185]187,189,194,199] Higher placental weight, birth weight, and blood glucose at birth Increased expression (mRNA) of hepatic lipogenesis, oxidative stress, and inflammatory genes Decreased hepatic expression (mRNA) of Pon1, Pon2, Pon3, and Sod1, Gpx1…”