High NOV/CCN3 expression during high-fat diet pregnancy in mice affects GLUT3 expression and the mTOR pathway

We investigated the expression levels of nephroblastoma overexpressed [NOV or CCN3 (cellular communication network factor 3)] in the serum and placenta of pregnant women and of pregnant mice fed a high-fat diet (HFD), and its effect on placental glucose transporter 3 (GLUT3) expression, to examine its role in gestational diabetes mellitus (GDM). NOV/CCN3 expression was increased in the mouse serum during pregnancy. At gestational day 18, NOV/CCN3 protein expression was increased in the serum and placenta of the HFD mice compared with that of mice fed a normal diet. Compared with non-GDM patients, the patients with GDM had significantly increased serum NOV/CCN3 protein expression and placental NOV/CCN3 mRNA expression. Therefore, we hypothesized that NOV/CCN3 signaling may be involved in the pathogenesis of GDM. We administered NOV/CCN3 recombinant protein via intraperitoneal injections to pregnant mice fed HFD or normal diet. NOV/CCN3 overexpression led to glucose intolerance. Combined with the HFD, NOV/CCN3 exacerbated glucose intolerance and caused insulin resistance. NOV/CCN3 upregulates GLUT3 expression and affects the mammalian target of rapamycin (mTOR) pathway in the GDM environment in vivo and in vitro. In summary, our results demonstrate, for the first time, the molecular mechanism of NOV/CCN3 signaling in maternal metabolism to regulate glucose balance during pregnancy. NOV/CCN3 may be a potential target for detecting and treating GDM.NEW & NOTEWORTHY NOV/CCN3 regulates glucose homeostasis in mice during pregnancy. NOV/CCN3 upregulates GLUT3 expression and affects the mTOR pathway in the GDM environment in vivo and in vitro.