BACKGROUND: Placental metabolic dysfunction is associated with pregnancy complications, including preeclampsia, gestational diabetes mellitus, and fetal growth restriction. However, little is known about how the metabolic processes regulate placental development and trophoblast differentiation. The adipokine chemerin, whose serum level is elevated during pregnancy, regulates the placental lipid metabolism and may influence placental development and trophoblast differentiation. RESULTS: In this study, we observed the increased chemerin expression in the serum and placenta of the pregnant mice. Chemerin is highly expressed in the extraembryonic primary parietal trophoblast giant cells and the ectoplacental cone (EPC) trophoblast cells. Excessive chemerin treatment in mice results in increased placental lipid accumulation, promotes the expansion of glycogen trophoblast cell (GlyT) and syncytiotrophoblast, and restricts the growth of spongiotrophoblast (SpT) and sinusoidal trophoblast giant cell (S-TGC). Chemerin deficiency led to increased expression of placental fatty acid oxidation enzymes and disrupted the proliferation of SpT and S-TGC in the labyrinth. Furthermore, we utilized the fatty acid oxidation inhibitor etomoxir and demonstrated that blocking fatty acid oxidation hinders the proliferation of SpT and S-TGC in the labyrinth. CONCLUSIONS: Our study demonstrated that chemerin-related lipid metabolism is crucial for EPC trophoblast differentiation during placental development, providing evidence that chemerin determines the growth of SpT and S-TGC through fatty acid oxidation. These findings also imply a possible pathological mechanism for pregnancy complications associated with chemerin.