Summary: Researchers have long sought to understand why myelin—the insulating sheath that enables fast nerve signaling—forms at different times across brain regions. A new study from CUNY reveals that glucose acts not only as fuel but also as a developmental signal. High local glucose encourages progenitor cells to divide, while lower glucose prompts them to stop proliferating and begin maturing into myelin-producing cells. This metabolic switch helps coordinate when and where the brain’s wiring is assembled.
During development, fluctuating glucose levels act like a traffic light for oligodendrocyte progenitor cells (OPCs): plentiful glucose favors expansion of the progenitor pool; falling glucose levels trigger differentiation into oligodendrocytes that form the myelin membrane. This coordinated metabolic signaling ensures myelination proceeds in a precise spatial and temporal pattern.
Key Facts
- The glucose signal: In the developing brain, regions with higher glucose levels serve as hotspots where Oligodendrocyte Progenitor Cells (OPCs) proliferate rapidly. As glucose decreases locally, OPCs receive a cue to exit the cell cycle and begin differentiating into myelin-forming oligodendrocytes.
- The ACLY enzyme: The enzyme ATP-citrate lyase (ACLY) converts glucose-derived citrate into acetyl-CoA inside the nucleus. Nuclear acetyl-CoA fuels histone acetylation, activating genes that drive OPC proliferation.
- Metabolic switch: Mature oligodendrocytes no longer depend on nuclear, glucose-derived acetyl-CoA to make myelin. Instead, they use extranuclear acetyl-CoA produced from alternative fuels—such as ketone bodies—to build myelin membranes.
- Ketogenic rescue: Mice engineered to lack ACLY in OPCs showed fewer progenitors and transient reductions in myelin. When these mice were fed a ketogenic diet—raising circulating ketone levels—the myelination deficit was improved, indicating an alternative metabolic route can compensate.
- Critical windows: The developmental period modeled in mice corresponds to roughly 32–40 weeks of human gestation, a vulnerable window for premature infants. Understanding how metabolic signals influence OPC behavior could inform strategies to protect or support white matter development in preterm babies.
Source: CUNY
Researchers at the Advanced Science Research Center at the CUNY Graduate Center (CUNY ASRC) identified a direct connection between local brain glucose levels and the timing of myelination—the process by which oligodendrocytes wrap axons in insulating membrane.
The study, published in Nature Neuroscience, shows that OPCs sense glucose and use that information to decide whether to proliferate or differentiate. Mapping glucose across developing mouse brains with advanced imaging at the CUNY ASRC MALDI Imaging Core revealed clear spatial and temporal glucose gradients. Regions with higher glucose had more proliferating OPCs and higher histone acetylation, while lower-glucose regions contained OPCs that were beginning to mature.
Lead author Sami Sauma explains that glucose functions beyond energy supply: “When glucose is abundant in a brain region, progenitors harness it to expand. As glucose declines, those same cells switch gears and mature. It’s a coordinated metabolic program that shapes brain development.”
Central to this mechanism is ACLY, which links glucose metabolism to gene regulation. Deleting ACLY specifically in OPCs reduced nuclear acetyl-CoA and histone acetylation, impairing OPC proliferation and producing a temporary hypomyelination in mice due to a smaller progenitor pool. Importantly, OPCs retained the capacity to differentiate because mature oligodendrocytes can obtain acetyl-CoA from extranuclear sources and other substrates.
The authors showed that elevating ketone availability through a ketogenic diet helped bypass the blockade caused by ACLY loss, improving myelin production. This demonstrates that distinct metabolic pathways operate at different stages of the oligodendrocyte lineage: ACLY-dependent nuclear acetyl-CoA supports proliferation, while alternative, extranuclear pathways supply acetyl-CoA for membrane synthesis in mature cells.
These findings have potential clinical relevance. The developmental window examined corresponds to a period when preterm infants are at heightened risk for white matter injury. Metabolic support targeted to preserve OPC populations or to provide alternative fuels could help protect or restore myelination. Beyond neonatal care, the work points to metabolic interventions as a possible avenue to promote myelin repair in diseases involving demyelination.
Funding: Supported by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.
Key Questions Answered:
A: No. “Low sugar” in this research refers to localized, naturally occurring metabolic shifts inside developing brain regions. The study investigates how cells sense glucose and use that signal during development, not general dietary advice. The brain needs a steady glucose supply to function.
A: The study shows ketones can substitute as a fuel for myelin production when the glucose-ACLY pathway is disrupted, which is encouraging. However, translating that into clinical treatment for conditions such as multiple sclerosis will require substantial additional research and controlled clinical trials.
A: This research suggests a major contributing factor: spatial and temporal gradients of glucose. By mapping those gradients, the team found that glucose availability effectively schedules where progenitors expand and where differentiation begins, helping prioritize wiring across regions.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context provided by staff.
About this neuroscience research news
Author: Shawn Rhea
Source: CUNY
Contact: Shawn Rhea – CUNY
Image: Image credited to Sami Sauma
Original Research: Closed access. “Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation” by Sami Sauma, Stephanie Stransky, Ipek Selcen, Simone Sidoli, Rinat Abzalimov, Ye He & Patrizia Casaccia. Nature Neuroscience. DOI: 10.1038/s41593-026-02263-7
Abstract
Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation
How postnatal oligodendrocyte progenitor cells (OPCs) decide to survive, proliferate or differentiate has been unclear. This study presents evidence that temporal and region-specific fluctuations in glucose, aligned with changes in vascularization, shape OPC population dynamics.
Regions with higher glucose levels showed increased OPC proliferation and histone acetylation, mediated by ATP-citrate lyase (ACLY), which converts glucose-derived citrate to acetyl-CoA. Mice with Acly deletion in OPCs displayed transient hypomyelination driven by reduced OPC numbers; however, differentiation into oligodendrocytes proceeded because enzymes that generate extranuclear acetyl-CoA from other substrates were upregulated.
Thus, OPC proliferation depends on ACLY-dependent nuclear acetyl-CoA derived from glucose, while mature oligodendrocytes rely on extranuclear acetyl-CoA from alternative metabolic sources to form myelin. These results indicate a metabolic layer of regulation controlling oligodendrocyte lineage cell population dynamics.