Antagonism of GPR4 with NE 52-QQ57 alleviates gestational diabetes mellitus-induced placental insults mediated by inhibiting NF-κB.

Abstract

Gestational diabetes mellitus (GDM) refers to a diabetic condition observed in pregnant women, significantly affecting both the health of the mother and the growth of the offspring. G protein-coupled receptor 4 (GPR4) is a receptor widely distributed across various tissues, but its role in GDM remains unclear. Our research aims to investigate the role of GPR4 in GDM and explore the potential therapeutic effects of its antagonist, NE 52-QQ57, in treating this condition. First, we found that GPR4 was expressed in placental tissues. Mice were divided into three groups: wild-type, db/+ pair-fed, and db/+ pair-fed + NE 52-QQ57. GPR4 expression was significantly higher in the db/+ pair-fed mice compared with wild-type mice. Markedly increased blood glucose and serum insulin levels were observed in GDM mice on gestational days (GD), accompanied by disrupted lipid profiles, all of which were significantly alleviated by NE 52-QQ57. Moreover, undesirable fetal outcomes, including increased fetal mortality, decreased fetal weight, reduced crown-rump length, and decreased placental weight, were observed in GDM mice, however, all were notably improved by NE 52-QQ57. Increased oxidative stress (OS) and the release of inflammatory cytokines were observed in GDM mice, but these were significantly reversed by NE 52-QQ57. Additionally, activated nuclear factor κ-B (NF-κB) signaling in placental tissues of GDM mice was significantly suppressed by NE 52-QQ57. Collectively, antagonism of GPR4 protected against GDM-induced placental damage in mice, confirming the critical role of GPR4 in the development of GDM.