Maternal betaine supplementation affects fetal growth and lipid metabolism of high-fat fed mice in a temporal-specific manner

Abstract

Background/objectivesMaternal obesity increases the risk of gestational diabetes mellitus (GDM), which results in fetal overgrowth and long-lasting metabolic dysfunctioning in the offspring. Previous studies show that maternal choline supplementation normalizes fetal growth and adiposity of progeny from obese mice. This study examines whether supplementation of betaine, a choline derivative, has positive effects on fetal metabolic outcomes in mouse progeny exposed to maternal obesity and GDM.MethodsC57BL/6J mice were fed either a high-fat (HF) diet or a control (normal-fat, NF) diet and received either 1% betaine (BS) or control untreated (BC) drinking water 4–6 weeks before timed-mating and throughout gestation. Maternal, placental, and fetal samples were collected for metabolite and gene-expression assays.ResultsAt E12.5, BS prevented fetal and placental overgrowth and downregulated glucose and fatty acid transporters (Glut1 and Fatp1) and the growth-promoting insulin-like growth factor 2 (Igf2) and its receptor Igf1r in the placenta of HF, glucose-intolerant dams (P < 0.05). However, these effects disappeared at E17.5. At E17.5, BS reduced fetal adiposity and prevented liver triglyceride overaccumulation in HF versus NF fetuses (P < 0.05). BS fetal livers had enhanced mRNA expression of microsomal triglyceride transfer protein (Mttp) (P < 0.01), which promotes VLDL synthesis and secretion. Although we previously reported that maternal choline supplementation downregulated mRNA expression of genes involved in de novo lipogenesis in fetal livers, such alterations were not observed with BS, suggesting differential effects of betaine and choline on fetal gene expression.ConclusionWe propose a temporal-specific mechanism by which maternal BS influences fetal growth and lipid metabolic outcomes of HF mice during prenatal development.

Maternal Choline and Betaine Supplementation Modifies the Placental Response to Hyperglycemia in Mice and Human Trophoblasts

“…We have previously shown that the HF-fed mice demonstrate impaired glucose tolerance during pregnancy, resembling the characteristics of GDM [ 23 , 24 , 25 ]. The HF-fed female mice also had higher weight gain and visceral fat weight than the NF-CO mice.…”

“…We confirmed the impaired glucose tolerance of HF mice via intraperitoneal glucose tolerance tests at E11.5 and E15.5. The glucose tolerance test (GTT) results were published in prior studies [ 23 , 24 , 25 ].…”

“…Our previous studies have demonstrated that high-fat feeding-induced GDM mice had higher fetal weight in mid-gestation and higher total body adiposity in latest gestation, while maternal choline and betaine supplementation in GDM mice mitigates these indices of fetal overgrowth and excess adiposity [ 23 , 24 , 25 ]. We further provide evidence to support the potential mechanism in which choline and betaine modify fetal growth in GDM mice via alterations in placental functioning, such as downregulating the placental growth promoter insulin-like growth factor 2 ( Igf2 ), suppressing the mechanistic target of rapamycin (mTOR) signaling or reducing macronutrient transporter expression [ 23 , 24 , 25 ]. Literature also suggests that maternal choline supplementation alters DNA methylation and angiogenesis in human and rodent placentas and/or trophoblasts [ 26 , 27 , 28 , 29 , 30 ].…”

Maternal betaine status, but not that of choline or methionine, is inversely associated with infant birth weight

“…The significant positive association between maternal betaine status and SGA risk, showed in GUSTO, was not found in our study; this can be explained by the limited power of the analysis resulted from the small number of SGA infants. Besides, a recent study showed that maternal betaine supplementation prevented fetal and placental overgrowth in high-fat-fed mice (27) . Maternal plasma betaine have been found to remain constant from twenty-two gestational weeks to the rest of pregnancy (28,29) , a stage covering the period of our blood sample collection.…”

Choline transport for phospholipid synthesis: An emerging role of choline transporter-like protein 1

“…60 Igf2 is an imprinted gene and maternal choline and betaine decreased the Igf2 expression and fetal adiposity. 61 On the other hand, gestational choline supply increases the histone methylation by simultaneously activating Kmt1c and Kmt1a methyltransferases and increasing the concentration of SAM. 62 Therefore, choline has a long-term epigenomic impacts on human health as presented in numerous benefits of prenatal choline supplementation on neurogenesis, gestational diabetes, and non-alcoholic liver disease.…”