Previous pulse-labeling experiments with rodents and more recent clinical studies provide compelling support that decidual cells of the endometrium derive from highly proliferating ESCs 
. From a metabolic perspective, a high rate of cellular proliferation requires a substantial increase in both glucose uptake and utilization not only to provide bioenergy but to furnish metabolic intermediates (amino acids, fatty acids, and nucleotides) to double biomass so that two daughter cells are generated following mitosis 
. To fulfill the bioenergetic and biosynthetic demands of increased cell proliferation, the rate of glycolysis from glucose to lactate (the glycolytic flux) must be increased to rapidly furnish ATP and the necessary glycolytic intermediates to support anabolic reactions which lead to cell growth to enable mitosis. Therefore, as long as glucose is abundant, acceleration of the rate of glycolysis can provide levels of ATP and metabolic intermediates that exceed those generated by oxidative phosphorylation. Despite growing support for a critical role for enhanced glucose use in endometrial decidualization 
, the key regulatory signals that direct the metabolic fate of this carbon source during the early proliferative stages of decidualization are unclear. From a clinical standpoint, identification of these regulatory signals may provide molecular insight into the etiopathogenesis of common gynecological disorders that are causally linked with impaired metabolic homeostasis as well as furnish novel targets for the clinical diagnosis and/or treatment of these co-morbidities.
We demonstrate here that SRC-2 is indispensable for the E2/P4-induced proliferation of ESCs that precedes their differentiation to decidual cells. Because early expansion of the decidual cell population is considered a key cellular event that enables deep invasion into a hypoxic environment and further development of the conceptus within the endometrium 
, our findings highlight a critical role for endometrial SRC-2 during the early steps that lead to the establishment of the maternofetal interface. For quiescent ESCs to proliferate, we reveal that SRC-2 plays a pivotal role in accelerating the glycolytic flux within predecidual cells by sustaining the induction level of PFKFB3 expression in response to E2/P4 exposure. As an inducible homodimeric enzyme, PFKFB3 converts fructose-6-phosphate to fructose-2, 6-bisphosphate 
, a signaling molecule which relieves the tonic inhibitory effects of ATP on phosphofructokinase-1 (PFK-1), a major rate-limiting glycolytic enzyme. With unrestricted acceleration of the glycolytic flux through the PFK-1 checkpoint, anabolic pathways such as the pentose phosphate pathway can be utilized to support rapid ESC proliferation and decidualization 
. Interestingly, P4 has been reported to induce PFKFB3 in human breast cancer cells 
, suggesting that PFKFB3 may mediate P4 mitogenic effects both in normal and abnormal physiologic contexts. Indeed, PFKFB3 is induced by a myriad of mitogenic, inflammatory, and hypoxic stimuli and is constitutively expressed in a number of leukemias and solid tumors 
. Although PFKFB3 has been shown to be expressed in human placenta 
, whether deregulation of this regulatory kinase can lead to proliferative disorders of the endometrium such as endometriosis, hyperplasia, or cancer constitutes an important question for future investigation.
Modulation of the ESC glycolytic flux by SRC-2 is in keeping with an expanding role for this coregulator in glucose metabolism 
. A member of the p160/SRC family of pleiotropic coregulators of glucose, fatty acid, and protein metabolism 
, SRC-2 has been shown to be critical for hepatic glucose release during periods of caloric restriction 
. During persistent periods of energy insufficiency, a critical role for SRC-2 is to release glucose from residual hepatic glycogen stores to maintain survival of the individual. During periods of glucose abundance, however, we show here that SRC-2 is crucial for rapid utilization of this energy source for endometrial decidualization, an essential reproductive process for the perpetuation of the species.
In conclusion, we demonstrate that SRC-2 is essential for the metabolic reprogramming of the predecidual ESC into a proliferative phenotype, an essential early step toward endometrial decidualization. Our findings not only offer an important conceptual advance in our understanding of endometrial SRC-2 in peri-implantation biology but may well provide mechanistic underpinnings to explain the role of this coregulator in other areas of endometrial physiology (i.e.
preterm labor 
) as well as in endometrial pathophysiologies in women diagnosed with leiomyoma or polycystic ovary syndrome 
. Finally, our new findings furnish the pretext for considering SRC-2 and its metabolic targets in the future design of new clinical approaches to more effectively diagnose and/or treat a non-receptive uterus in women with recurrent implantation failure or early pregnancy loss.