Faculty Collaboration Database

O-GlcNAc transferase contributes to sex-specific placental deregulation in gestational diabetes. Placenta 2023 Jan;131:1-12

Date

11/29/2022

Pubmed ID

36442303

Pubmed Central ID

PMC9839643

DOI

10.1016/j.placenta.2022.11.006

Scopus ID

2-s2.0-85142764152 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

INTRODUCTION: Gestational diabetes (GDM) is traditionally thought to emerge from placental endocrine dysregulations, but recent evidence suggests that fetal sex can also impact GDM development. Understanding the molecular mechanisms through which sex modulates placenta physiology can help identify novel molecular targets for future clinical care. Thus, we investigated the nutrient-sensing O-GlcNAc pathway as a potential mediator of sex-specific placenta dysfunction in GDM.

METHODS: Expression levels of O-GlcNAc enzymes were measured in male and female (n = 9+/gender) human placentas based on the maternal diagnosis of GDM. We then simulated the observed differences in both BeWo cells and human syncytiotrophoblasts primary cells (SCT) from male and female origins (n = 6/gender). RNA sequencing and targeted qPCR were performed to characterize the subsequent changes in the placenta transcriptome related to gestational diabetes.

RESULTS: O-GlcNAc transferase (OGT) expression was significantly reduced only in male placenta collected from mothers with GDM compared to healthy controls. Similar downregulation of OGT in trophoblast-like BeWo male cells demonstrated significant gene expression deregulations that overlapped with known GDM-related genes. Notably, placental growth hormone (GH) production was significantly elevated, while compensatory factors against GH-related insulin resistance were diminished. Inflammatory and immunologic factors with toxic effects on pancreatic β cell mass were also increased, altogether leaning toward a decompensatory diabetic profile. Similar changes in hormone expression were confirmed in male human primary SCTs transfected with siOGT. However, down-regulating OGT in female primary SCTs did not impact hormone production.

CONCLUSION: Our study demonstrated the significant deregulation of placental OGT levels in mothers with GDM carrying a male fetus. When simulated in vitro, such deregulation impacted hormonal production in BeWo trophoblast cells and primary SCTs purified from male placentas. Interestingly, female placentas were only modestly impacted by OGT downregulation, suggesting that the sex-specific presentation observed in gestational diabetes could be related to O-GlcNAc-mediated regulation of placental hormone production.

Author List

Cui Y, Cruz M, Palatnik A, Olivier-Van Stichelen S

Authors

Meredith Cruz MD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Stephanie Olivier-Van Stichelen PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin
Anna Palatnik MD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Diabetes, Gestational
Female
Humans
Insulin
Male
N-Acetylglucosaminyltransferases
Placenta
Pregnancy