br Acknowledgements This work was supported by

Acknowledgements This work was supported by the National Institutes of Health [grant number GM024417].
Introduction In mammals, glucose is the major energy substrate supporting conceptus development after SR 49059 formation [1,2]. While the equine morula uses similar amounts of pyruvate and glucose, glucose uptake increases rapidly during blastocyst expansion such that glucose is the preferred energy substrate thereafter [3]. In sheep and pigs, uterine luminal fluid (ULF) glucose concentrations increase during early pregnancy [4,5], presumably to support conceptus development. In horses, total recoverable glucose in ULF is unaffected by pregnancy status or time after ovulation (5–6 mg [4]) and glucose concentrations in day 11–27 equine yolk-sac fluid are relatively low and stable (0.1–2.7 mM [6,7]). During the same period however, the concentration of fructose, synthesized from glucose by the conceptus, increases markedly in both the ULF (5–60 mg [4]) and yolk-sac fluid (4–62 mM [6,7]). Conceptus fructose production is assumed to depend on maternal glucose transported across the endometrium and conceptus membranes, a process that could be performed by members of two glucose transporter families; the facilitative transporters (solute carriers 2; SLC2A) and the sodium-dependent transporters (solute carriers 5; SLC5A [1,8,9]). Glucose transporter expression in the endometrium and early conceptus is species-specific (See Supp. Table 1 for details), and differences may relate to implantation type and duration of the pre-implantation period. SLC2A1 (also known as GLUT1 or GT1) supports maintenance glucose uptake in most cell types and is the most abundant glucose transporter in the endometrial stroma of species with invasive implantation, and the endometrial epithelium of species with non-invasive implantation [10,11]. SLC2A1 is also expressed on the apical membrane of trophectoderm cells in the early conceptus [1,10]. SLC2A2 (GLUT2) is present in the basolateral membrane of trophectoderm cells, but not in the endometrium [1,12]. However, given its insulin-dependence, high Km and low affinity for glucose, SLCA2 is unlikely to support glucose uptake from the low glucose environment of the ULF [1]. Conversely, SLC2A3 (GLUT3 or GT3) is a low Km, high affinity transporter that would support glucose transport from the ULF. Moreover, SLC2A3 is present in the apical membrane of trophectoderm cells [1] and, since SLC2A3 ablation (by antisense oligonucleotide treatment) inhibits murine blastocyst formation, is known to be required for embryo development [13]. SLC2A4 (GLUT4) and SLC2A8 (GLUT8) are both highly efficient insulin-responsive transporters present in rabbit conceptuses [14]. SLC2A5 (GLUT5) is a low Km, high affinity fructose transporter not detected in human endometrium nor human or mouse embryos [15], but present in ruminant conceptuses and endometrium [[16], [17], [18]]. SLC5A1 (SGLT1) and SLC5A11 (SGLT6) are sodium-dependent transporters that transport glucose against a concentration gradient; they were not detected in mouse or human embryos and endometrium [1], but are expressed in ruminant endometrium and conceptuses [5,16,17]. SLC5A9 (SGLT4) and SLC5A10 (SGLT5) are sodium-dependent transporters that have not been detected in the uterus or conceptus of any species. In various species, maternal progesterone (P4) and conceptus secreted factors such as interferon-tau (IFNτ), prostaglandins (PGs) and estrogens (E2) regulate endometrial expression of certain glucose transporters, and thereby ULF glucose concentrations [5,15,17,19]. In murine and human endometrial stromal cells, SLC2A1 expression and glucose uptake are up-regulated by P4 and down-regulated by E2 [15]. In sheep, maternal progesterone and conceptus IFNτ and PGs (PGF2α, PGE2 and PGI2) stimulate endometrial glucose transporter expression (SLC2A1, SLC2A4, SLC2A5, SLC5A1 and SLC5A11) [5,17], and INFτ promotes uterine luminal glucose accumulation [17]. Similarly, conceptus E2 upregulates SLC5A1 expression in porcine endometrium [19]. In short, the conceptus actively stimulates endometrial expression of specific glucose transporters, and increases ULF glucose availability [17].