Summary: Researchers have long asked why myelin—the insulating sheath that speeds nerve signaling—appears at different times across brain regions. New work from CUNY shows that glucose acts not only as fuel but also as a developmental signal that tells progenitor cells whether to keep dividing or to begin maturing into myelin-forming cells.
High local glucose levels encourage stem-like oligodendrocyte progenitor cells (OPCs) to proliferate, while falling glucose levels cue them to exit the cell cycle and differentiate into oligodendrocytes that make myelin. This metabolic “gear shift” helps the brain build its wiring in the right sequence and location.
Key Facts
- Glucose as a developmental cue: During brain development, regions with elevated glucose serve as hotspots for OPC proliferation. When glucose decreases, OPCs receive a signal to stop dividing and begin the maturation process that produces myelin.
- ACLY translates the signal: The enzyme ATP-citrate lyase (ACLY) converts glucose-derived citrate into acetyl-CoA in the nucleus. That nuclear acetyl-CoA promotes histone acetylation and the activation of genes required for OPC proliferation.
- Metabolic switching for myelin assembly: After OPCs differentiate into oligodendrocytes, they no longer rely on nuclear glucose metabolism for growth. Instead, mature oligodendrocytes use extranuclear sources of acetyl-CoA—such as ketone bodies—to synthesize the lipid-rich myelin membrane.
- Dietary ketones can bypass the block: In mice genetically engineered to lack ACLY in OPCs, myelination was reduced because fewer progenitors were available. Feeding these mice a ketogenic diet, which raises ketone levels, partially restored myelin by providing an alternate source of acetyl-CoA.
- Timing matters for preterm infants: The developmental window modeled in mice corresponds roughly to 32–40 weeks of human gestation—a vulnerable period for premature infants. Understanding these metabolic signals could point to interventions that protect white matter during that critical window.
Source: CUNY
Researchers at the Advanced Science Research Center at the CUNY Graduate Center (CUNY ASRC) have identified a direct connection between local brain glucose levels and the timing of myelination — the process by which oligodendrocytes wrap axons with the insulating myelin membrane.
Their study, published in Nature Neuroscience, shows that OPCs sense regional and temporal changes in glucose and use that information to decide whether to proliferate or to differentiate. This mechanism helps explain why some brain regions myelinate earlier than others.
Oligodendrocytes arise from OPCs and assemble myelin, a membrane essential for rapid electrical signaling. Myelination starts before birth and continues into adulthood, enabling developmental milestones such as sitting, crawling, walking, and talking.
To track glucose across the developing brain, the team used high-resolution metabolic mapping at the CUNY ASRC MALDI Imaging Core Facility. They discovered clear spatial and temporal glucose gradients: regions with higher glucose showed more OPC division and greater histone acetylation, while regions with lower glucose contained OPCs beginning to mature.
“We found that glucose acts as more than energy—it functions as a cue for progenitor behavior,” said lead author Sami Sauma, a postdoctoral researcher with the CUNY ASRC Neuroscience Initiative. “When glucose is abundant, progenitors use it to support proliferation; as glucose declines, those same cells switch into a maturation program.”
Central to this process is ACLY. By producing nuclear acetyl-CoA from glucose-derived citrate, ACLY enables acetylation of histones and the activation of genes that promote OPC proliferation. Deleting ACLY in OPCs reduced their capacity to divide, creating a temporary shortfall in the progenitor pool and consequent hypomyelination.
Despite that deficit, OPCs without ACLY could still differentiate. The team found compensatory upregulation of enzymes that generate acetyl-CoA outside the nucleus from alternative substrates. Mature oligodendrocytes appear to depend on these extranuclear acetyl-CoA sources—such as ketone bodies—to synthesize the lipids required for myelin.
When ACLY-deficient mice were given a ketogenic diet, increasing circulating ketones, their myelin deficits improved, indicating that ketone-derived acetyl-CoA can bypass the nuclear glucose pathway during myelin synthesis.
“The same lineage interprets distinct metabolic cues at successive stages: glucose-driven nuclear metabolism fuels proliferation, and extranuclear metabolic pathways fuel myelin assembly,” said Patrizia Casaccia, founding director of the CUNY ASRC Neuroscience Initiative. “Understanding these switches reveals metabolic approaches that might protect or repair myelin in development and disease.”
Because the mouse developmental window corresponds to a late gestational period in humans, these findings have implications for premature infants at risk of white matter injury. They also suggest metabolic targets that could be explored for disorders with myelin loss, including multiple sclerosis, though clinical translation will require more research.
Overall, the study highlights metabolism as a powerful regulator of brain wiring: local glucose gradients and metabolic enzyme activity help orchestrate where and when myelin is produced.
Funding: The research was supported by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.
Key Questions Answered:
A: No. “Low sugar” here refers to localized, natural metabolic shifts inside developing brain regions, not overall dietary glucose. The study describes how cells sense and respond to local glucose differences. Pregnant people still need a steady supply of glucose for overall brain function.
A: The findings indicate ketones can substitute as a source of acetyl-CoA for myelin synthesis when the glucose-dependent pathway is impaired. While promising, especially for neonatal white matter injury, more preclinical and clinical studies are required before recommending ketogenic diets as standard therapy for demyelinating diseases.
A: This work shows that timed and regional glucose variations form gradients that help schedule OPC proliferation and differentiation. In effect, sugar distribution helps prioritize where and when the brain builds its insulating wiring.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience research news
Author: Shawn Rhea
Source: CUNY
Contact: Shawn Rhea – CUNY
Image: The image is 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. We propose that temporal and regional fluctuations in glucose, linked to changes in vascularization, modulate OPC population dynamics.
Regions with elevated glucose showed increased OPC proliferation and histone acetylation relative to low-glucose regions. This effect is mediated by ATP-citrate lyase (ACLY), which converts glucose-derived citrate into acetyl-CoA.
Mice with Acly deleted in OPCs displayed transient hypomyelination caused by reduced OPC numbers, while differentiation into oligodendrocytes continued because enzymes that generate extranuclear acetyl-CoA from alternative substrates were upregulated.
Thus, OPCs depend on ACLY-driven nuclear acetyl-CoA derived from glucose to regulate proliferation, whereas mature oligodendrocytes rely on extranuclear acetyl-CoA from other metabolic sources to form myelin. These results point to metabolic regulation of oligodendrocyte lineage dynamics.