Epidemiological studies have traced the causes of obesity into intrauterine fetal development. The strong association between increased obesity prevalence and high or low birth weight has further reinforced the paradigm of developmental origins of obesity. Therefore, elucidating the mechanisms that link fetal growth and maternal metabolism will have a significant impact on obesity research. Adiponectin is an adipocyte- secreted hormone. Our studies from the previous funding cycle demonstrated that both maternal and fetal adiponectin enhance fetal fat accumulation but through different mechanisms. Fetal adiponectin enhances fat development by increasing de novo lipogenesis, while maternal adiponectin increases fetal adiposity by reducing lean tissue mass. Using a series of mouse models, our studies demonstrated that maternal adiponectin, but not fetal adiponectin, inhibits fetal growth. To our surprise, unlike virgin adiponectin gene knockout (Adipoq-/-) mice, pregnant Adipoq-/- mice exhibited glucose intolerance and hyperlipidemia, indicating that maternal adiponectin plays an important role in regulating maternal metabolic adaptation to pregnancy. Furthermore, our studies revealed that maternal adiponectin increases IGFBP-1 expression in trophoblast cells and fetal blood IGFBP-1 protein levels. It is known that IGFBP-1 is the predominant binding protein of IGF-1 in fetuses. IGFBP-1 inhibits IGF-1 bioavailability and suppresses fetal growth. Using the Cre-loxp technique, we created placenta-specific adiponectin receptor 1 (AdipoR1) or AdipoR2 gene knockout mice. Our preliminary studies showed that, similar to maternal adiponectin deficiency, knocking out placental AdipoR1 significantly increased fetal weight. Together, these data lead us to hypothesize that maternal adiponectin inhibits fetal growth through modulating maternal metabolism, fetal nutrient supply and fetal IGF-1 endocrine system.
Three specific aims are proposed to test this hypothesis. By restoring maternal metabolism in Adipoq-/- dams and directly measuring placental nutrient transport rates, Specific Aim 1 will investigate the role of fetal nutrient supply in maternal adiponectin-inhibited fetal growth.
In Specific Aim 2, we will expose IGFBP-1-/- and WT embryos to maternal hyperadiponectinemia, and then determine the role of the IGFBP-1/IGF-1 system in maternal adiponectin-regulated fetal growth. Studies of Aim 3 will clarify the protein expression pattern of adiponectin receptors in syncytiotrophblast cells and study how adiponectin signaling selectively mediates the regulatory effects of maternal but not fetal adiponectin. The anticipated success of this project will provide a novel mechanism that links maternal metabolism to the fetal endocrine system and fetal growth. Therefore, this project will have a significant impact on the research of developmental origins of obesity.
