Regulation of Facilitative Glucose Transporters and AKT/MAPK/PRKAA Signaling via Estradiol and Progesterone in the Mouse Uterine Epithelium1

Abstract

Adequate uterine glucose metabolism is an essential part of embryo implantation and the development of an adequate uterofetal environment. However, expression of facilitative glucose transporters (GLUTs [solute transporter family SLC2A]) and AKT/MAPK/PRKAA (PRKAA) signaling has not been described in the mouse uterine cells, to our knowledge. The objective of this study was to determine the hormonal regulation of SLC2A protein expression and AKT/MAPK/PRKAA signaling in the mouse uterine epithelial cells during estrous cycles and periimplantation periods. SLC2As 1, 4, 8, and 9B were highly expressed in the luminal and glandular epithelia of estrous stage. In metestrous and diestrous stages, expression of SLC2As 1, 4, 8, and 9B was lower than that in proestrous stage. Levels of activated phospho-AKT (p-AKT), p-MAPK3, and p-MAPK1 also varied during the estrous cycle. Estrogen and progesterone injection in an ovariectomized mouse (delayed implantation model) resulted in a decrease and an increase, respectively, in expression of GLUTs in the luminal epithelial cells of the uterus.

Warburg-like Glycolysis and Lactate Shuttle in Mouse Decidua during Early Pregnancy

“…Our study reveals that Hif1␣ protein is enhanced by progesterone in the stromal cells under normoxia condition, consistent with an earlier study indicating progesterone-dependent Hif1␣ induction in mouse uteri during early pregnancy (39). Furthermore, Pi3k-Akt signaling pathway is activated in mouse endometrium during decidualization (21,35). Thus we propose that mouse decidualizing cells are eventually adapted to aerobic glycolysis due to Hif1␣ activation under progesterone priming.…”

“…Several studies also imply that decidual signals improve glycolysis in human endometrial stromal cells, which are also cultured under normoxic conditions. Glut1 is strongly induced and plays important roles during human decidualization (8,35). Pdk4, which has a similar property as Pdk1, is also induced in human decidualizing cells (36).…”

Slc2a8 Deficiency in Mice Results in Reproductive and Growth Impairments1

“…Expression in the whole uterus, including the stroma, the decidua, and both the luminal and glandular epithelium, has been reported [20]. Although our lab has previously confirmed the necessity of SLC2A1 in uterine decidualization, mRNA expression of SLC2A8 is dramatically increased upon embryo implantation and decidualization in both mice and humans, indicating that it may play an important role in this process as well [19].…”

“…SLC2A8 is expressed in the tissues of the female reproductive tract, including the ovaries (and oocytes) and the uterus [19,20]. The histology of ovaries from Slc2a8 À/À mice was comparable to that of the Slc2a8 þ/þ mice ovaries, and all cell types were present (Fig.…”

“…It is possible that SLC2A8 is present in lysosomal membranes to transport and thus recycle glucose residues from degraded glycosylation sites on proteins targeted for autophagy or lysosomal degradation. This function may be critical in processes that require an abundance of glucose (and SLC2A8 is shown to be increased), such as uterine decidualization and fat differentiation [19,20,27,30,31], and thus lack of SLC2A8 expression globally accounts for abnormal decidualization and possibly subsequent placentation and fetal growth, as well as differentiation of adipose cells, thus accounting for elimination of lipid accumulation and fat pad mass in the knockout mice. Further studies, however, will need to be completed to fully understand the role of SLC2A8.…”