Maternal High-Fat Feeding Increases Placental Lipoprotein Lipase Activity by Reducing SIRT1 Expression in Mice

Abstract

This study investigated how maternal overnutrition and obesity regulate expression and activation of proteins that facilitate lipid transport in the placenta. To create a maternal overnutrition and obesity model, primiparous C57BL/6 mice were fed a high-fat (HF) diet throughout gestation. Fetuses from HF-fed dams had significantly increased serum levels of free fatty acid and body fat. Despite no significant difference in placental weight, lipoprotein lipase (LPL) protein levels and activity were remarkably elevated in placentas from HF-fed dams. Increased triglyceride content and mRNA levels of CD36, VLDLr, FABP3, FABPpm, and GPAT2 and -3 were also found in placentas from HF-fed dams. Although both peroxisome proliferator–activated receptor-γ (PPARγ) and CCAAT/enhancer binding protein-α protein levels were significantly increased in placentas of the HF group, only PPARγ exhibited a stimulative effect on LPL expression in cultured JEG-3 human trophoblasts. Maternal HF feeding remarkably decreased SIRT1 expression in placentas. Through use of an SIRT1 activator and inhibitor and cultured trophoblasts, an inhibitory effect of SIRT1 on LPL expression was demonstrated. We also found that SIRT1 suppresses PPARγ expression in trophoblasts. Most importantly, inhibition of PPARγ abolished the SIRT1-mediated regulatory effect on LPL expression. Together, these results indicate that maternal overnutrition induces LPL expression in trophoblasts by reducing the inhibitory effect of SIRT1 on PPARγ.

Choline prevents fetal overgrowth and normalizes placental fatty acid and glucose metabolism in a mouse model of maternal obesity

“…CD36 showed an increase in mRNA but not protein abundance when comparing the HFCO with the NFCO placentas. Placental LPL and GLUT3 levels were reported to increase during HF feeding at late gestation [9, 10] but were not altered at E12.5 in this study. Interestingly, Fatp4 mRNA levels were elevated in the HFCS group versus the other 3 groups.…”

“…Specifically, maternal obesity upregulated glucose transporters (GLUT) 1 and 3, which are two major glucose transporters expressed in cytotrophoblasts that promote facilitated diffusion of glucose across the placenta, and thus may increase glucose accretion by the fetus [9]. Maternal obesity also results in excess fetal adiposity in both rodents and humans [10, 11]. The fetus acquires lipids mostly from maternal circulation through placental fatty acid transport due to limited de novo lipogenesis [12].…”

“…Fatty acid transport in the placenta is initiated with the action of lipases which release fatty acids from triglycerides, phospholipids, and lipoproteins. Thereafter the free fatty acids are transported by fatty acid binding proteins (FABPs), fatty acid transporters (FATPs) 1–4, and fatty acid translocase (CD36) to the fetus [10]. Maternal obesity is associated with upregulation of the fatty acid transport related proteins and marked increases in triglyceride content in the placenta [10, 13].…”

Sirtuins—mediators of maternal obesity‐induced complications in offspring?

“…Given the increased availabilities of glucose and lipid in obese individuals that during pregnancy are prioritized for fetal usage (7), the fetus tends to undergo overnutrition‐related metabolic programming at early developmental periods, which may confer additional risks to appetite dysregulation and metabolic disorders later in life (59). Strikingly, SIRT1/3 appears to be involved in all of these mechanisms (13, 53, 60).…”

“…Supporting this hypothesis, an in vivo study has demonstrated that sodium‐coupled neutral amino acid transporter (SNAT)1 and SNAT2 mRNA expression were up‐regulated by increased IL‐6 concentrations in cultured human primary trophoblast cells (70). Because SIRT1 exerts anti‐inflammatory effects (71), and its placental expression has been shown to be down‐regulated by LPS and proinflammatory cytokines TNF‐α and IL‐1b (64), possible SIRT1 deficiency due to maternal obesity may facilitate nutrient flow from the maternal blood to the fetus (60) (Fig. 2 B ).…”