The hormone adiponectin has been shown to be important in maintaining insulin sensitivity throughout the body, while potential effects on the placenta have not been assessed. Pregnancy constitutes a unique physiological environment in which metabolism has a profound effect on the health of both the mother as well as the developing fetus. It is imperative that a delicate balance in glucose delivery be maintained between maternal tissues and the fetal/placental unit. Adiponectin's role in regulating peripheral insulin responsiveness suggests it may be a factor in maintaining this balance during gestation as well. Examination of human cytotrophoblast cells revealed that mRNA for both adiponectin receptors, adipoR1 and adipoR2, are abundantly expressed at term. We were however, unable to reliably detect mRNA for adiponectin in primary cytotrophoblasts. Expression of both receptors was maintained following induction of syncytium formation by exogenous EGF treatment. Treatment of cytotrophoblasts with adiponectin resulted in a significant drop, as assessed by quantitative RT-PCR, in expression for a number of genes involved in the endocrine function of the placenta, including the chorionic gonadotropin subunits, placental lactogen, and some steroidogenic enzymes. Immunofluorescent staining for connexin 43 and desmoplakin in primary trophoblasts revealed that adiponectin does not inhibit syncytialization of trophoblast cells in culture. Taken together, these data describe a novel role for maternal adiponectin in regulating the placental environment. Determination of the effects of such adipokines on the maternal-fetal interface is increasingly important, as the incidence of pregnancies complicated by gestational diabetes remains a significant health problem in developed countries.