Gestational metabolic syndrome (GMS) not only causes maternal morbidities during pregnancy and after childbirth, but also predisposes offspring to long-term adverse health issues. Bile acids have now emerged as key regulatory factors in metabolism, but their role in mediating metabolic adaptations during pregnancy has not been understood completely. In this study, we investigated bile acids mediated lipid metabolism in a new rat GMS model which recapitulates major symptoms of human GMS, including elevated blood pressure, glucose intolerance, obesity and disrupted lipid metabolism, in response to a high fat diet in combination of drinking water with fructose (HFC feed) for only five weeks. We hypothesized that bile acids profile and downstream signaling in the placenta were altered by GMS, disrupting lipid metabolism in trophoblast cells. In Study One, we performed untargeted and targeted metabolomics analyses on the placentas for male and female fetuses at gestational day 20.5 in the control diet and HCF groups. In Study Two, we investigated placental expression of genes related to bile acids production (CYP7A1, CYP27A1, and CYP8B1) by Western blotting analysis. In Study Three, we explored the regulatory role of chenodeoxycholic acid (CDCA) and its receptor Takeda G protein-coupled receptor 5 (TGR5) on expression and/or activities of LPL (major lipase in the placenta ) and angiopoietin-like proteins (ANGTPL) 3, 4, 8 (inhibiting LPL activity), and formation of lipid droplets in human trophoblast cell line JEG-3, after administration of BAR501(TGR5 agonist), SBI-115 (TGR5 antagonist) and gene knockdown. All quantitative data were analyzed by ANOVA or Student’s t-test, to show the effects of feed, sex or cell treatments (n=3-5). The main findings include: 1) The concentrations of total cholesterol, triglyceride, and free fatty acids in the placentas of both male and female fetuses were highly elevated in the HCF group, with more remarkable increase in the placentas of male fetuses compared to those in female fetuses in the HCF group; 2) Several bile acids in placental tissues in the HCF group demonstrated sex difference, and CDCA levels were increased only in the placentas of male fetuses in the HCF group; 3) Unlike the placentas for female fetuses, the protein abundance of CYP7A1 was significantly elevated in the placentas of male fetuses, that of CYP8B1 was decreased and that of CYP27A1 was unaltered; 4) CDCA increased the protein abundance of ANGPTL4, reduced LPL activity and increased lipid droplets in JEG-3 cells, in a dose-dependent manner; 5) BAR501 significantly increased the protein abundance of ANGPTL4 and lipid droplets, while SBI-115 did not alter the protein abundance of ANGPTL4 but blocked CDCA induced lipid accumulation. These results indicate that GMS alters placental lipid metabolism in a sex-specific manner and CDCA/TGR5/ANGPTL4/LPL axis may play an important role in regulating the placental lipid metabolism in human trophoblast cells. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Lv et al. (Fri,) studied this question.