br Conclusions br Acknowledgements br Introduction Glucose m

Conclusions
Acknowledgements
Introduction Glucose metabolism is vital to prepare uterine epithelium and stroma for embryo implantation and for the differentiation of the functionalis layer to support the developing conceptus [[1], [2], [3], [4]]. Due to its polar nature and hydrophilic condition, glucose is not able to pass through the lipid bilayer and has to be transported via specific integral proteins to reach the cytoplasm [5]. These carrier proteins are known as glucose transporters and are divided into two groups. The first group is formed by the Na+/Glucose co-transporters protein family (SGLTs) and the second group consist of the members of GLUT proteins family, which act through facilitated diffusion [5]. Focusing on GLUT proteins (GLUTs) family, they are molecules composed by about 500 aminoacidic residues and are classified according to the transported hexose [6]. Thus far, a total of 14 GLUTs have been described in the literature. However, only few have been determined to be present in the female reproductive tract; namely GLUT1, 3, 4 and 8 [[1], [2], [3],[7], [8], [9], [10], [11]]; and placental structures; namely GLUT1, 3, 4, 8 and 12 [[12], [13], [14], [15], [16], [17], [18], [19]]. To date, GLUT1 and 3 are the most described facilitative glucose transporters in both male and female reproductive tracts of several species. GLUT1 is the most ubiquitous facilitating glucose transporter [20] and is responsible for the glucose basal uptake and storage in all eukaryotic crizotinib [21]. It has been described to be present in rat and human endometrium [1,22] and placenta in humans, marmoset monkeys, rats [12], cats, minks and dogs [18]. On the other hand, GLUT3 shows a high affinity for glucose and a much lower affinity for other monosaccharides, such as mannose, xylose or galactose [23]. The GLUT3 transporter is very abundant in tissues that present an intensive glucose metabolism, such as brain, testis and placenta [[24], [25], [26], [27]]. Previous studies have demonstrated that steroid hormones are involved in the regulation of glucose metabolism via modulating the expression of GLUTs. In effect, progesterone up-regulates the expression of GLUT1 in human and murine endometrium [1,4], and down-regulates that of GLUT3 in rat uterus and mouse placenta and decidua [7,22]. This relationship between serum progesterone levels and two of the most important hexose transporters highlights the importance that a fine regulation of glucose uptake and, hence utilization, has for the proper maintenance of pregnancy. Nonetheless, pregnancy presents many differences between species in aspects as relevant as length, number of foetuses and type of placentation [28]. These differences could underlie species-specific adaptations in mechanisms such as the aforementioned progesterone-related control of hexoses during pregnancy. In this regard, it is reasonable to hypothesise that the described relationship between progesterone levels and GLUT1 and GLUT3 expression during pregnancy in mice and humans [1,4,7,22] could not be the same in other species with very different pregnancy conditions.
Materials and methods
Results
Discussion The results shown in this manuscript are the first reference about the concomitant presence of both GLUT1 and GLUT3 hexose transporters in both uterine and placental-transference tissues of queens during pregnancy, since GLUT1, but not GLUT3, has been already described in cats [18]. More importantly, our results also indicate the existence of a clear relationship between serum progesterone levels and GLUT3 expression, but not GLUT1, in both uterus and placental-transference area during the first half of pregnancy. These results match with previous reports showing the presence of GLUT1 in the uterus and placental transference zone in other mammalian species, such as rodents, human, minks, dog and sheep [16,18,22,34]. Likewise, a relationship between maternal serum progesterone levels and the utero-placental expression of GLUT1 and GLUT3 has also been found in rodents and humans [4,7,16,22]. However, there are striking differences between our study and these previous reports in other species. Centring on uterine samples, our results indicate that while the presence of GLUT3 in the endothelium, but not that of GLUT1, is related with the start of pregnancy, the expression of both GLUTs in other uterine locations does not rely upon pregnancy onset. Although GLUT3 is more specific for glucose transport than GLUT1, the affinity of both transporters for glucose is practically the same [34,35]. Thus, the modulation of the precise rhythm of glucose transport in the utero-placental system during early pregnancy would not require the presence of two glucose transporters with similar efficiency. This would imply that GLUT3 could play other roles than being just a reinforcement for glucose transport during the early stages of pregnancy in queens. Placental function and foetal development depend on maternal endometrial vascular remodelling [36,37]. Thus, the implementation of an optimal endometrial vascularization plays an important role in embryo implantation [38]. At this respect, the pregnancy-related presence of GLUT3 in the endometrial endothelium suggests that this hexose transporter might be involved in this remodelling process. Meanwhile, there are other putative roles for feline uterine/placental GLUT3 in the early stages of pregnancy than acting on remodelling of endometrial vascularization. On this respect, a relationship between GLUT3 expression in human trophoblast and the activity of mTORC1 protein has been described [39]. This is important, since mTORC1 is involved in a transduction signalling pathway sensing nutrients in the placenta and regulating protein synthesis in embryo and foetus [40]. Thus, a progesterone-related modulation of GLUT3 in the early phases of pregnancy in queens could be also related with the control of embryo/early foetus through a GLUT3/mTORC1-regulated pathway. Therefore, the progesterone-linked regulation of GLUT3 endometrial expression in the early phases of gestation would suggest that this specific hexose transporter is also involved in the implantation of feline conceptus.