Abstract
GLUT4 is involved in rapid glucose uptake among various kinds of cells to contribute to glucose homeostasis. Prior data have reported that aberrant glucose metabolism by GLUT4 dysfunction in the uterus could be responsible for infertility and increased miscarriage. However, the expression and precise functions of GLUT4 in the endometrium under physiological conditions remain unknown or controversial. In this study, we observed that GLUT4 exhibits a spatiotemporal expression in mouse uterus on pregnant days 1–4; its expression especially increased on pregnant day 4 during the window of implantation. We also determined that estrogen, in conjunction with progesterone, promotes the expression of GLUT4 in the endometrial epithelium in vivo or in vitro. GLUT4 is an important transporter that mediates glucose transport in endometrial epithelial cells (EECs) in vitro or in vivo. In vitro, glucose uptake decreased in mouse EECs when the cells were treated with GLUT4 small interfering RNA (siRNA). In vivo, the injection of GLUT4-siRNA into one side of the mouse uterine horns resulted in an increased glucose concentration in the uterine fluid on pregnant day 4, although it was still lower than in blood, and impaired endometrial receptivity by inhibiting pinopode formation and the expressions of leukemia inhibitory factor (LIF) and integrin ανβ3, finally affecting embryonic development and implantation. Overall, the obtained results indicate that GLUT4 in the endometrial epithelium affects embryo development by altering glucose concentration in the uterine fluid. It can also affect implantation by impairing endometrial receptivity due to dysfunction of GLUT4.
Highlights
Embryo implantation is a complex process in which the developing blastocyst adheres to and embeds into the receptive endometrium (Zhang et al, 2013; Kim and Kim, 2017), and these two events are precisely regulated by maternal hormones, in particular ovarian estrogen and progesterone (Cha et al, 2012; Kim and Kim, 2017)
The distribution of GLUT4 spread to the stroma, and its expression scope and intensity were obviously expanded on pregnant days 3–4, when the uterus was gradually entering the receptive status under the actions of increasing progesterone and a small amount of estrogen (Figure 1A)
GLUT4 protein expression and distribution were altered within the uterine tissues depending on days of mouse pregnancy, which suggests that GLUT4 expression varies temporally and spatially in response to the changes of ovarian hormones on pregnant days 1–4
Summary
Embryo implantation is a complex process in which the developing blastocyst adheres to and embeds into the receptive endometrium (Zhang et al, 2013; Kim and Kim, 2017), and these two events are precisely regulated by maternal hormones, in particular ovarian estrogen and progesterone (Cha et al, 2012; Kim and Kim, 2017). In this process, the uterine epithelium, especially the luminal epithelial (LE) cells, is the first site of contact between the maternal and fetal. Glucose uptake and utilization in the endometrial epithelium and its transportation between the uterine fluid and maternal blood circulation remain elusive
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