Liver Prlr signaling in metabolic adaptation to pregnancy - Abstract: Pregnancy is characterized by maternal insulin resistance secondary to maternal weight gain, especially in the 3rd trimester. Such physiological response serves to spare blood glucose for the fetus. To compensate for maternal insulin resistance, the body must undergo adaptive changes in energy metabolism to maintain euglycemia during pregnancy. Maladaptation of maternal metabolism to pregnancy is causative for gestational diabetes mellitus (GDM), a disease that affects up to 11% of all pregnancies. Critical for metabolic adaptation to pregnancy is prolactin, a pituitary hormone whose production increases with the progression of pregnancy. Prolactin acts as a lactogenic hormone to stimulate breast tissue growth and milk production. Apart from its essential in lactation, prolactin signaling via prolactin receptor (Prlr) regulates maternal metabolism. Women harboring genetic PRLR variants are associated with heightened risk of GDM. Prlr is expressed in the liver, but its liver-specific role in regulating maternal metabolism is unknown. This begs the question as to how the liver undergoes the adaptative changes in hepatic metabolism in the face of maternal insulin resistance to maintain normal energy homeostasis during pregnancy. To fill in the knowledge gap, we will conduct an in-depth characterization of hepatic Prlr signaling and determine its contribution to maternal metabolism. We generated hepatocyte-specific Prlr-knockout (Prlr-KO) mice. We found that virgin Prlr-KO mice maintained normal metabolism, but pregnant Prlr-KO mice developed GDM, as manifested by glucose intolerance at gestational day 15.5, a time that is equivalent to the 3rd trimester in humans. The severity of GDM in Prlr-KO mice was compounded by multiparity, advanced gestational age or increased maternal adiposity, three independent risk factors for GDM in women. Our data illustrate an unprecedented role of hepatic Prlr signaling in regulating maternal metabolism. Hepatic Prlr deficiency is sufficient for causing metabolic maladaptation to pregnancy, resulting in GDM. To decipher the underlying mechanism, we will delineate hepatic Prlr signaling and characterize hepatic Prlr targets, whose functions are instrumental for regulating hepatic metabolism in response to gestation. We will determine the mechanism by which hepatic Prlr depletion impairs maternal metabolism, contributing to GDM. Moreover, we will conduct ex vivo studies in primary human hepatocytes to validate the clinical significance of hepatic Prlr signaling in regulating maternal metabolism in response to prolactin. We expect to elucidate the adaptive mechanism by which the liver evolves to integrate prolactin signaling with glucose and lipid metabolism during pregnancy. Our data will gain new mechanistic insights into the etiology of GDM and uncover potential new targets for GDM.
