Disruption of O-Linked N-Acetylglucosamine Signaling in Placenta Induces Insulin Sensitivity in Female Offspring

Abstract

Placental dysfunction can lead to fetal growth restriction which is associated with perinatal morbidity and mortality. Fetal growth restriction increases the risk of obesity and diabetes later in life. Placental O-GlcNAc transferase (OGT) has been identified as a marker and a mediator of placental insufficiency in the setting of prenatal stress, however, its role in the fetal programming of metabolism and glucose homeostasis remains unknown. We aim to determine the long-term metabolic outcomes of offspring with a reduction in placental OGT. Mice with a partial reduction and a full knockout of placenta-specific OGT were generated utilizing the Cre-Lox system. Glucose homeostasis and metabolic parameters were assessed on a normal chow and a high-fat diet in both male and female adult offspring. A reduction in placental OGT did not demonstrate differences in the metabolic parameters or glucose homeostasis compared to the controls on a standard chow. The high-fat diet provided a metabolic challenge that revealed a decrease in body weight gain (p = 0.02) and an improved insulin tolerance (p = 0.03) for offspring with a partially reduced placental OGT but not when OGT was fully knocked out. Changes in body weight were not associated with changes in energy homeostasis. Offspring with a partial reduction in placental OGT demonstrated increased hepatic Akt phosphorylation in response to insulin treatment (p = 0.02). A partial reduction in placental OGT was protective from weight gain and insulin intolerance when faced with the metabolic challenge of a high-fat diet. This appears to be, in part, due to increased hepatic insulin signaling. The findings of this study contribute to the greater understanding of fetal metabolic programming and the effect of placental OGT on peripheral insulin sensitivity and provides a target for future investigation and clinical applications.

O-GlcNAc transferase contributes to sex-specific placental deregulation in gestational diabetes

“…Previous studies have investigated the role of O -GlcNAcylation in the placenta, using deletion models of Ogt in trophoblast lineage in murine models. Consequences of placental-specific Ogt deletion on metabolic homeostasis included increased responsivity of the hypothalamic-pituitary-adrenal stress axis in male offspring and increased insulin resistance to high-fat-diet in females 36,50 . However, while rodent models have enabled significant advances in understanding the role of O -GlcNAcylation in placenta function, it is an imperfect simulation of human placental biology and pathophysiology.…”

“…Particularly, during environmental stress from hyperglycemia, the extra copy of Ogt has been shown to offer increased plasticity in response in pregnant murine models (30). Finally, animal phenotypes resulting from O-GlcNAc modulation varied based on sex [29][30][31][32][33][34][35][36] , emphasizing the link between sexual dimorphism and O-GlcNAcylation.…”

O-GlcNAcylation: The Underestimated Emerging Regulators of Skeletal Muscle Physiology

“…Meanwhile, PPO is located at the carboxyl terminal of OGT and strongly interacts with PIP3, which promotes the recruitment of OGT to the membrane under insulin induction for catalyzing the dynamic O -GlcNAcylation of the insulin signaling pathway [ 95 ]. Targeting special localization of this interaction led to the alteration in the phosphorylation of pivotal insulin signal molecules and weakening of the insulin signal transduction [ 96 ]. This suggests the indispensable role of OGT in diabetic pathology.…”

Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

“…Therefore, in the present study, we aimed to understand whether specific placental loss of the insulin receptor has a lasting effect on the fetus, altering the birthweight and the long-term metabolic health trajectory of the mouse offspring. Mice with a genetic specific deletion of the insulin receptor in the placental trophoblast (Cyp19-cre; InsR f/f hereinafter, referred to as InsR KO placenta ) were generated using the cre/loxP system described further in the Methods section [23,[36][37][38]. Fetal and newborn body weight and pancreatic β-cell mass were assessed in littermate male and female offspring.…”