During pregnancy, the placentae of ungulate mammals (e.g., cows, sheep, and pigs) convert glucose into fructose, which is the most abundant hexose sugar in fetal fluids and blood. However, the role of fructose, the most enigmatic component of carbohydrate metabolism in fetal-placental tissues, is largely ignored because it is not metabolized via the glycolytic pathway or the Krebs cycle as an energy source. Here we provided evidence for biological functions of fructose that affect proliferative behavior of the conceptus trophectoderm/chorion via activation of the Akt-TSC2-MTOR signaling cascade. The phosphorylation for activation of this cascade is mediated by O-linked glycosylation with UDP-N-acetylglucosamine, a primary product of the hexosamine biosynthesis pathway. These results reveal novel functional roles of fructose in promoting embryonic/fetal growth and development during pregnancy, and also provide new insight into understanding the relationship between excessive fructose intake and metabolic disorders.