Objective ·To analyze the effects of maternal high-fat diet on placental phenotype, and investigate the role of placental microenvironment in the intergenerational transmission. Methods ·The 3-week-old C57BL/6J female mice were fed with either the high-fat diet (HFD group) or the control diet (CD group) for 5 weeks before mating and throughout gestation. Placentas and fetal liver tissues were collected from maternal mice after 20 d of gestation. The effects of maternal HFD on the placental inflammation and placental structure were investigated by hematoxylin-eosin staining (H-E staining), immunohistochemistry, Western blotting and RT-PCR. The lipid deposition levels in fetal livers were also detected. Body weight changes, fasting blood glucose and glucose tolerance levels of the 3-week-old weaned mice were also detected. Results ·The body weight of female mice in the HFD group increased significantly, and the liver triacylglycerol (TAG) and total cholesterol (TC) levels were higher than those in the CD group (all P<0.05). Compared to the CD group, the liver cells of fetus in the HFD group showed steatosis, lipid vacuoles of different sizes, and the content of TAG in the fetal livers in the HFD group increased, but the difference was not statistically significant (P>0.05). Compared to the CD group, the body weight, fasting blood glucose level and the area under the glucose tolerance curve of the 3-week-old weaned mice of the HFD group were increased significantly (all P<0.05). The immunohistochemical results showed that the levels of interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the placenta in the HFD group were significantly increased (both P<0.05), and the level of IL-1β did not change significantly. In addition, H-E staining of placentas showed that the area proportion of the labyrinth zone (the maternal-fetal exchange area) in the HFD group decreased significantly, which was statistically significant by ImageJ software (P<0.05). The intervascular membrane thickened, and the maternal blood sinuses were narrow. RT-PCR results showed the expressions of placental tight-junction-related protein Zo-1 (zonula occludens 1) and claudin were increased (both P<0.05). Conclusion ·Maternal high-fat diet may result in placental inflammation and abnormal structure, which may be related to glucose and lipid metabolism disorder in offspring.