The Role of Kisspeptin in Metabolism Regulation

PROJECT SUMMARY/ABSTRACT Pregnancy is a physiological state of continuous and significant adaptation to changing maternal and fetal nutritional needs ensuring successful completion of pregnancy at term. To this end, as pregnancy progresses, the placenta produces multiple hormones that participate in modifying maternal metabolism to meet the metabolic needs of both fetus and mother. Of the placental hormones, circulating kisspeptin1 (Kiss1) levels progressively increase by several-hundred-fold during pregnancy. Although certain metabolic actions have been assigned to Kiss1, little is known about how Kiss1 contributes to the metabolic adaptations of pregnancy. In addition to developing insulin resistance, maternal hepatic glucose output (rate of appearance) increases as does the propensity to developing hypoglycemia and ketosis even after short periods of fasting. The mechanism underlying the tendency of the pregnant female to develop ketosis remains unknown. Further, insufficient glucose and nutrient supply to the fetus poses a significant health risk for the developing child. Based on our preliminary studies, we hypothesize that during gestation placenta-derived circulating Kiss1, activates its cognate G-protein coupled receptor Kiss1R on hepatocytes and signals via Gaq-inositol triphosphate receptors (IP3R) to activate AMPK (adenosine-monophosphate dependent kinase), lipolysis and ketogenesis. Absence of Kiss1R in hepatocytes of female mice during pregnancy leads to excessive lipid accumulation in maternal hepatocytes and to increased risk of hypoglycemia in the third trimester. Furthermore, our preliminary studies indicate that the pancreatic hormone glucagon stimulates hepatic Kiss1 production, whereby Kiss1 acts in the liver in an autocrine manner. Absent liver Kiss1R, glucagon-induced IP3 production as well as hepatic glucose output are blunted in fasting mice, suggesting that kisspeptin induction is an integral part of glucagon action in hepatocytes. These observations reveal a novel regulatory interplay between glucagon and Kiss1 in regulating hepatic metabolic pathways. We now seek to expand our novel and exciting findings specifically a) to understand the molecular mechanisms that shape maternal liver metabolism in gestation; b) to understand different Kiss1R-IP3R signaling pathways in regulating liver metabolism, and c) to understand the role of glucagon-stimulated kisspeptin production by the liver in modulating liver metabolism during gluconeogenesis. We will use complementary in vivo and in vitro approaches to elucidate these important signaling pathways in hepatocytes using newly generated unique mouse models as well as in vitro in human hepatocyte cell lines. Our studies will yield important insights into kisspeptin’s role in liver metabolism during eutherian pregnancy and into how kisspeptin and glucagon signaling interplay in hepatocytes to regulate metabolism. Further, our studies will dissect signaling pathways as potential therapeutic targets in metabolic liver disease and diabetes mellitus.