Glucose is widely known as the simple sugar molecule that powers our bodies’ cells. Now, a new study reveals that it also plays a far more critical role in guiding embryonic development (embryogenesis) than scientists previously thought. The findings could offer new insights into how developmental disorders such as congenital heart defects and limb malformations arise due to problems during the early stages of embryo development.
Decades of research have shown that mechanisms such as gene regulation and cellular signaling are major drivers of embryogenesis, but given its highly intricate nature, researchers felt certain that other mechanisms must be at work. However, the other regulators were unclear. Recently, a team led by Berna Sozen, PhD, assistant professor of genetics at Yale School of Medicine, discovered that glucose metabolism is one such regulator, playing a key role beyond its known function of energy production in steering embryonic development. The researchers published their findings in Nature on October 16.
“This study shows that metabolism is not just working in the background, but actively guiding our life,” says Sozen, who was the study’s principal investigator. “With these findings, we gained a new understanding of how a single nutrient [glucose] is utilized in distinct ways to guide the development of different parts of the mammalian organism.”
The theory that metabolism drives embryogenesis dates back to 1915 in a paper by University of Chicago zoologist Charles Manning Child based on his experiments with flatworms. However, these findings coincided with the explosion of revolutionary developments in molecular genetics, says Sozen, and “the theory was eclipsed.”
But over the past few years, there has been growing interest among researchers about the role of metabolism beyond fueling the body. Emerging research has started to show that metabolism also helps regulate processes such as tissue development, stem cell differentiation, and cancer. Thus, Sozen’s team grew interested in how metabolism comes together with other developmental processes in a living organism in utero. These findings could help explain why a mother's glucose metabolism is integral to ensuring that the embryo receives the necessary resources and signals for healthy development.
Glucose takes center stage in embryogenesis
In their latest study, Sozen’s team used fluorescent imaging to visualize where glucose uptake occurred within live mouse embryos developing in an incubator. They discovered that glucose uptake was specific to certain portions of the embryo at certain points in development. Specifically, they discovered two distinct waves of glucose metabolism during gastrulation, the process in which the cells of the epiblast [an early embryonic layer] migrate and rearrange to form three germ layers—ectoderm, mesoderm, and endoderm—which give rise to the body’s tissues and organs.
As the cells of the epiblast began gastrulation, researchers found, to their surprise, that glucose uptake peaked in cells at the posterior side of the embryo. “Researchers have believed that embryos utilize glucose uniformly in every developing cell,” says Sozen. “But we saw that embryos instead take in glucose in a compartmentalized way.” Then, the team observed a second wave of glucose uptake as cells migrated to form the mesoderm.
To better understand the mechanism and functions of metabolism, the team then used chemical inhibitors to block different stages of the process, and also deprived embryos of certain nutrients such as glucose. They then observed how the embryos responded. During the first wave of metabolism, their experiments suggested, the cells process glucose through a route called the Hexosamine Biosynthetic Pathway. This helps determine the “cell fate,” or future roles of cells in the epiblast. During the second wave, cells processed glucose through a different pathway called glycolysis. This time, glucose metabolism helped drive the cellular migration. “The cells are using a single nutrient, but there are two different pathways it goes through,” says Sozen.
Furthermore, these experiments revealed that metabolism drives these processes through communication with cell signals and genetic factors—two other key players in embryonic development. “At the mechanistic level, we observed glucose bioproducts are key to activate cellular signaling programs. This gives us a bigger picture of how embryogenesis occurs," says Sozen. “For an organism to grow, it needs the integration and coordination of multiple regulatory mechanisms.”
New insights for developmental disorders and more
This study, Sozen says, challenges the previously held view of metabolism as primarily a background process during embryonic development. Rather, she says, in synergy with gene regulation and cell signaling, it plays an integral role in guiding cell fate in a developing organism. Studying how these essential components work together will help researchers better understand why processes sometimes go awry and how developmental disorders arise. “If we only try to tackle developmental disorders by studying their genetic mechanisms, that might not be enough to find a solution for them,” says Sozen. “If we think about these other regulators such as metabolism, we will have a better chance at battling these kinds of conditions.”
These processes are also tightly related to regeneration, Sozen adds. Thus, studying the various mechanisms of embryogenesis could also help scientists better understand how regeneration of tissues happens and offer insights into regenerative medicine.
After glucose is metabolized, it becomes broken down into many different bioproducts. In future studies, Sozen’s team is interested in exploring how some of these bioproducts might play a role in epigenetic regulation (control of gene activity without changing the DNA sequence). Her lab also plans to investigate the mechanisms underlying how a mother’s diet during pregnancy may impact embryonic development. “If we can understand more precisely how nutrients are linking with genetic or epigenetic regulations, we can start understanding pregnancy-related conditions as well.”