Harris Kemoy, Desai Neeraj, Gupta Madhu, Xue Xiangying, Chatterjee Prodyot K, Rochelson Burton, Metz Christine N
Hofstra Northwell School of Medicine, Department of OB/GYN, Division of Maternal-Fetal Medicine, Manhasset, NY USA ; Present Address: Jamaica Hospital Medical Center, Medisys Health Network, Jamaica, NY USA.
Hofstra Northwell School of Medicine, Department of OB/GYN, Division of Maternal-Fetal Medicine, Manhasset, NY USA ; Winnie Palmer Hospital-Orlando Health, Orlando, FL USA.
Nutr Metab (Lond). 2016 Aug 22;13(1):55. doi: 10.1186/s12986-016-0115-9. eCollection 2016.
Maternal obesity may program the fetus and increase the susceptibility of the offspring to adult diseases. Metformin crosses the placenta and has been associated with decreased inflammation and reversal of fatty liver in obese leptin-deficient mice. We investigated the effects of metformin on maternal and fetal lipid metabolism and hepatic inflammation using a rat model of diet-induced obesity during pregnancy.
Female Wistar rats (6-7 weeks old) were fed normal or high calorie diets for 5 weeks. After mating with normal-diet fed males, half of the high calorie-fed dams received metformin (300 mg/kg, daily); dams (8 per group) continued diets through gestational day 19. Maternal and fetal livers and fetal brains were analyzed for fatty acids and for fatty acid metabolism-related gene expression. Data were analyzed by ANOVA followed by Dunnett's post hoc testing.
When compared to control-lean maternal livers, obesogenic-diet-exposed maternal livers showed significantly higher saturated fatty acids (14:0 and 16:0) and monounsaturated fatty acids (16:1n7 and 18:1n9) and lower polyunsaturated (18:2n6 and 20:4n6 [arachidonic acid]) and anti-inflammatory n3 polyunsaturated fatty acids (18:3n3 and 22:6n3 [docosahexaenoic acid]) (p < 0.05). Metformin did not affect diet-induced changes in maternal livers. Fetal livers exposed to the high calorie diet showed significantly increased saturated fatty acids (18:0) and monounsaturated fatty acids (18:1n9 and 18:1n7) and decreased polyunsaturated fatty acids (18:2n6, 20:4n6 and 22:6n3) and anti-inflammatory n3 polyunsaturated fatty acids, along with increased gene expression of fatty acid metabolism markers (Fasn, D5d, D6d, Scd1, Lxrα). Metformin significantly attenuated diet-induced inflammation and 18:1n9 and 22:6n3 in fetal livers, as well as n3 fatty acids (p < 0.05). Prenatal obesogenic diet exposure significantly increased fetal liver IFNγ levels (p < 0.05), which was reversed by maternal metformin treatment (p < 0.05).
Consumption of a high calorie diet significantly affected maternal and fetal fatty acid metabolism. It reduced anti-inflammatory polyunsaturated fatty acids in maternal and fetal livers, altered gene expression of fatty acid metabolism markers, and induced inflammation in the fetal livers. Prenatal metformin attenuated some diet-induced fatty acid changes and inflammation in the fetal livers without affecting maternal livers, suggesting that maternal metformin may impact fetal/neonatal fatty acid/lipid metabolism.
母亲肥胖可能会对胎儿产生影响，并增加后代患成人疾病的易感性。二甲双胍可穿过胎盘，且与肥胖的瘦素缺乏小鼠体内炎症减轻及脂肪肝逆转有关。我们使用孕期饮食诱导肥胖的大鼠模型，研究了二甲双胍对母体和胎儿脂质代谢及肝脏炎症的影响。
将6至7周龄的雌性Wistar大鼠喂食正常或高热量饮食5周。与喂食正常饮食的雄性大鼠交配后，一半高热量饮食喂养的母鼠接受二甲双胍（300毫克/千克，每日）；母鼠（每组8只）在妊娠第19天前持续喂食相应饮食。对母体和胎儿的肝脏以及胎儿的大脑进行脂肪酸和脂肪酸代谢相关基因表达分析。数据采用方差分析，随后进行Dunnett事后检验。
与对照瘦型母体肝脏相比，暴露于致肥胖饮食的母体肝脏中饱和脂肪酸（14:0和16:0）和单不饱和脂肪酸（16:1n7和18:1n9）显著更高，而多不饱和脂肪酸（18:2n6和20:4n6[花生四烯酸]）和抗炎n3多不饱和脂肪酸（18:3n3和22:6n3[二十二碳六烯酸]）更低（p<0.05）。二甲双胍未影响饮食诱导的母体肝脏变化。暴露于高热量饮食的胎儿肝脏中饱和脂肪酸（18:0）和单不饱和脂肪酸（18:1n9和18:1n7）显著增加，多不饱和脂肪酸（18:2n6、20:4n6和22:6n3）和抗炎n3多不饱和脂肪酸减少，同时脂肪酸代谢标志物（Fasn、D5d、D6d、Scd1、Lxrα）的基因表达增加。二甲双胍显著减轻了饮食诱导的胎儿肝脏炎症以及18:1n9和22:6n3，以及n3脂肪酸（p<0.05）。产前暴露于致肥胖饮食显著增加了胎儿肝脏IFNγ水平（p<0.05），而母体二甲双胍治疗可使其逆转（p<0.05）。
食用高热量饮食显著影响母体和胎儿的脂肪酸代谢。它降低了母体和胎儿肝脏中的抗炎多不饱和脂肪酸，改变了脂肪酸代谢标志物的基因表达，并诱导了胎儿肝脏的炎症。产前使用二甲双胍减轻了一些饮食诱导的胎儿肝脏脂肪酸变化和炎症，而不影响母体肝脏，这表明母体二甲双胍可能会影响胎儿/新生儿的脂肪酸/脂质代谢。
