Abstract
BackgroundMaternal 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.MethodsFemale 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.ResultsWhen 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).ConclusionsConsumption 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0115-9) contains supplementary material, which is available to authorized users.
Highlights
Maternal obesity may program the fetus and increase the susceptibility of the offspring to adult diseases
High calorie diet alters maternal liver lipid profiles: no effect of metformin Livers obtained from the HCAL-fed dams showed a 40 % increase in total triglyceride-associated fatty acid (FA) vs. control dam livers, irrespective of metformin treatment (Fig. 1a, p < 0.05)
Maternal livers showed numerous HCAL-diet related changes in their FA profiles; HCAL-exposed livers had significantly higher saturated fatty acids (SFAs) (Fig. 1b, p < 0.05) and monounsaturated fatty acids (MUFAs) (Fig. 1c, p < 0.001) and lower polyunsaturated fatty acids (PUFAs) (Fig. 1d, p < 0.001), as well as a 3-fold lower expression of anti-inflammatory n3 FAs compared to control-fed dams (Fig. 1e, p < 0.001)
Summary
Maternal obesity may program the fetus and increase the susceptibility of the offspring to adult diseases. 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. Maternal obesity and aberrant glucose and lipid metabolism may program the fetus for hepatic lipid dysfunction and may increase the susceptibility of the offspring to adult diseases/ conditions, including metabolic syndrome-like phenotype and poor vascular health [14,15,16,17]. Because metformin crosses the placenta [22, 23] and could impact both maternal and fetal metabolism, we investigated the effects of prenatal metformin administration on maternal and fetal lipid metabolism and hepatic inflammation using a rat model of diet-induced obesity and metabolic syndrome during pregnancy
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