A critical role for adiponectin‐mediated development of endometrial luminal epithelial cells during the peri‐implantation period of pregnancy

Abstract

Adiponectin is one of the adipokines in the collagen superfamily. It is secreted primarily by white adipocytes and influences reproductive processes including ovarian and uterine functions. Adiponectin regulates energy homeostasis, insulin sensitivity, and is anti-inflammatory in various tissues. Its receptors (ADIPOR1 and ADIPOR2) are widely expressed in mammalian tissues, including porcine conceptuses and endometrial during the estrous cycle and peri-implantation period of pregnancy. However, regulatory effects of adiponectin on endometrial epithelial cells are unknown. Therefore, we investigated the effects of parity on expression of ADIPOR1 and ADIPOR2 and the effects of adiponectin in the porcine endometrium during early pregnancy. Results of this study revealed robust expression of ADIPOR1 and ADIPOR2 in uterine luminal (LE) and glandular (GE) epithelia during early pregnancy and expression decreased as with increasing parity. For porcine luminal epithelial (pLE) cells, adiponectin enhanced proliferation, and increased phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, P38, and P90RSK in a time-dependent manner. Moreover, the abundance of adiponectin-activated signaling molecules were suppressed by pharmacological inhibitors including wortmannin, U0126, SP600125, and SB203580, respectively, in pLE cells. Furthermore, inhibition of each targeted signal transduction molecule influenced proliferation of adiponectin-stimulated pLE cells. In addition, adiponectin inhibited tunicamycin-induced endoplasmic reticulum (ER)-stress through effects on ER stress regulated proteins in pLE cells. Collectively, these results suggest that adiponectin affects development of porcine uterine epithelia and reproductive performance through modulation of PI3K/AKT and MAPK cell signaling pathways.

Transcriptomic Analysis of Porcine Endometrium during Implantation after In Vitro Stimulation by Adiponectin

“…On the other hand, the latest studies revealed that adiponectin significantly stimulated proliferation and suppressed apoptosis of porcine uterine luminal epithelial cells (LEc) which would enhance uterine receptivity for embryo implantation. The mentioned adiponectin-stimulated proliferation of LEc was related to activation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase signal transduction pathways [38]. This finding supports the hypothesis that adiponectin signalling is necessary for the establishment and maintenance of conceptus–uterine cross-talk during early pregnancy.…”

Brain‐derived neurotrophic factor improves proliferation of endometrial epithelial cells by inhibition of endoplasmic reticulum stress during early pregnancy

“…ER stress in adipose tissue of obese women with gestational diabetes mellitus results in an increase in interleukin‐1β, IRE1α, GRP78, and X‐box binding protein 1 (XBP1) (Liong & Lappas, ). We previously reported increased expression of UPR‐regulatory genes in response to tunicamycin treatment of pLE cells (Lim, Choi, Bae, Bazer, & Song, ). Based on those results, we confirmed effects of BDNF on the tunicamycin‐induced ER stress in pLE cells and demonstrated that tunicamycin induced death of pLE cells involved an increase in cells in the Sub‐G 1 phase of the cell cycle.…”

C‐C motif chemokine ligand 23 abolishes ER stress‐ and LPS‐induced reduction in proliferation of bovine endometrial epithelial cells

“…ER stress activates three highly conserved signaling cascades in the UPR stress sensors, including PERK that in turn phosphorylates eIF2α and ATF6α, which increase GRP78 to enhance folding capacity, and IRE1α which in turn activates X‐box binding protein 1 (Hetz, ). In domestic animals, tunicamycin‐induced ER stress decreases proliferation of porcine uterine luminal epithelial cells and increases the expression of ER stress response proteins implicated in implantation failure during early pregnancy (Lim, Bae, Bazer, & Song, ; Lim, Choi, Bae, Bazer, & Song, ). Moreover, ER stress signaling may be associated with mammary lipogenesis during lactation in dairy cows, with accumulation of PERK protein within the ER cisternae (Invernizzi, Naeem, & Loor, ).…”