Brain sugar levels act as signal for myelin growth, study finds

The amount of sugar in the brain plays a key role in governing the activity of oligodendrocytes, the brain cells responsible for making the protective myelin coating around nerve fibers, according to a study done in mice and cell models. The findings could have important implications for understanding diseases such as multiple sclerosis (MS), which is characterized by inflammation that damages myelin in the brain and spinal cord.

Researchers found that molecules derived from sugar are essential for the growth of immature cells that can develop into oligodendrocytes. When these cells can’t rely on sugar, they can make functional myelin using alternative metabolic sources, notably ketone bodies produced when the body burns fat.

In fact, myelin production was decreased in a genetically engineered mouse model in which oligodendrocytes could not use sugar, but these deficits were restored by feeding the mice a ketogenic diet — a high-fat, low-sugar diet designed to get the body to burn fat instead of sugar for energy.

“Our findings show that glucose is not just fuel for the brain, it’s also a signal for the cells to divide,” Sami Sauma, PhD, co-author of the study and postdoctoral research associate at the City University of New York (CUNY) Advanced Science Research Center, said in a university news story. “We found that when glucose levels are high in a particular brain region, progenitors use it to drive proliferation. As glucose levels shift, the same cells switch gears and begin maturing. It’s a beautifully coordinated metabolic system that helps shape brain development.”

The study, “Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation,” was published in Nature Neuroscience.

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Molecular mechanics

Myelin is a fatty substance that helps protect nerve fibers and helps them send efficient electrical signals. In MS, damage to myelin disrupts nerve signaling, ultimately leading to MS symptoms. Oligodendrocytes can help repair damaged myelin, but myelin repair mechanisms are usually defective in MS for reasons that aren’t fully understood.

Oligodendrocyte progenitor cells (OPCs) are immature cells that are able to grow into mature, myelin-making oligodendrocytes. During brain development, OPCs either divide to make more OPCs or mature into myelin-producing oligodendrocytes.

The team conducted a detailed series of experiments aiming to understand the molecular mechanisms that control whether OPCs divide or mature.

By analyzing developing mouse brains, the researchers found that OPC activity showed a striking correlation with glucose (sugar) levels. In brain regions with high glucose levels, OPCs were mostly dividing to make more OPCs. But in regions with lower glucose levels, the cells were more likely to be maturing. This suggested that the cells were responding to glucose levels to regulate their activity.

Cells can use glucose for energy, but they can also break this sugar down to make other molecules, including one called acetyl-CoA. Acetyl-CoA is an important ingredient used in myelin production, and it is also essential for histone acetylation, which is a biochemical process that cells use to increase the activity of certain genes.

The researchers found that OPCs rely on acetyl-CoA derived from glucose in order to perform histone acetylation that turns on the genes that let them divide to make more OPCs.

Building on this finding, the researchers engineered mice whose OPCs lacked the enzyme ATP-citrate lyase (ACLY), which is needed to convert glucose into acetyl-CoA. In these mice, OPCs couldn’t rely on glucose to grow, and as a result, oligodendrocyte counts were abnormally low, and myelin production was decreased in early development.

However, as the mice grew, myelin production increased to levels typically seen in healthy mice, which suggests the OPCs were still able to grow into functional oligodendrocytes that could make myelin. Because acetyl-CoA is needed to make myelin, and these cells were making myelin even when they couldn’t get acetyl-CoA by breaking down glucose, the cells must have been sourcing this molecule from elsewhere.

In further tests, the researchers found that OPCs used acetyl-CoA generated by the breakdown of ketone bodies. Building on this finding, they fed a ketogenic diet to mice lacking the ACLY enzyme, which helped normalize myelin production during early development.

“Although OPCs depend on [acetyl-CoA derived from glucose] for histone acetylation and proliferation, [oligodendrocytes] are less discriminatory as to the source of [acetyl-CoA needed for] myelin synthesis,” the scientists wrote.

The researchers hope this new understanding of the biochemistry that controls myelin-making cells will pave the way toward better understanding and treatments for diseases like MS.

“This study reveals that the same cell lineage interprets different metabolic signals at distinct stages of development,” said Patrizia Casaccia, MD, PhD, study co-author and director of the neuroscience initiative at the CUNY research center. “By understanding how glucose and alternative energy sources regulate proliferation and myelin formation, we are uncovering new metabolic strategies that could be harnessed to protect myelin in the developing brain and even promote repair in disease states.”