Neurons can tap into fat for fuel

August 5, 2025

Neurons can tap into fat for fuel

At a Glance

Researchers found that neurons in the brain can use fat droplets as a source of energy.
The new insights into brain metabolism have important implications for understanding brain health and suggest new ways to protect neurons

IImmunoflurescence image showing bright dots throughout neurons.

Your brain needs lots of energy to function. Without the fuel it needs, the brain is also prone to breaking down. While other energy-demanding parts of the body store energy in the form of lipid, or fat, droplets, the brain has long been thought to rely solely on sugar (glucose). One reason is that the healthy brain doesn’t have any visible fat stores.

Recently, this view has been called into question. One study found that loss of a single gene called DDHD2 leads to a complex subtype of hereditary spastic paraplegia (HSP), a group of rare and progressive inherited disorders that cause weakness and stiffness of the legs. The subtype also includes intellectual disability and other problems in the central nervous system. It turns out DDHD2 encodes an enzyme in neurons that breaks down triglyceride lipids into fatty acids. When this enzyme doesn’t work properly, lipids build up in the cells.

In a new study, researchers led by Drs. Timothy A. Ryan and Mukesh Kumar at Weill Cornell Medicine explored the role of lipids and DDHD2 in the brain. Their findings were reported in Nature Metabolism on July 1, 2025.

The team first wanted to locate DDHD2 within the brain. Studies in mice showed the enzyme throughout the hippocampus, a brain area essential for learning and memory. In the rat hippocampus, high amounts of DDHD2 could be found at synapses, the junctions between neurons. Brain cells other than neurons didn’t have as much DDHD2. The findings suggested that DDHD2 might play an important role in fueling essential synapses between neurons.

When researchers blocked DDHD2 in mice, lipid levels at synapses increased. This suggests that when the brain is functioning normally, triglycerides are made and used continuously. Such turnover would explain why the healthy brain doesn’t have visible lipid stores.

Using isolated neurons, the researchers found that when glucose levels were low, fatty acids from lipid droplets drove energy production in mitochondria. Mitochondria serve as energy factories inside cells. This process occurred when the neurons were actively firing, but not when they were at rest.

Overall, the findings show how neurons in the brain can use lipid droplets for energy. The results suggest that fats have an unexpectedly important role for supporting healthy brain metabolism and normal brain function. Problems in lipid metabolism could also underlie neurodegenerative conditions, including Parkinson’s disease, in ways that now warrant further study.

“We don't know where this research will go in terms of neurodegenerative conditions, but some evidence suggests that accumulation of fat droplets in the neurons may occur in Parkinson’s disease,” Kumar explains.

More study will be needed to understand the interplay between glucose and lipid breakdown in the healthy, aging, and diseased human brain. “By learning more about these molecular details, we hope to ultimately unlock explanations for neurodegeneration, which would give us opportunities for finding ways to protect the brain,” Ryan says.

—by Kendall K. Morgan, Ph.D.

References

. Kumar M, Wu Y, Knapp J, Pontius CL, Park D, Witte RE, McAllister R, Gupta K, Rajagopalan KN, De Camilli P, Ryan TA. Nature Metabolism. 2025 Jul 1. doi: 10.1038/s42255-025-01321-x. Epub ahead of print. PMID: 40595405.

Funding

��Ӱҵ’s National Institute of Neurological Disorders and Stroke (NINDS) and National Cancer Institute (NCI); Aligning Science Across Parkinson’s.

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