Weill Cornell Medicine Study Reveals Brain's Ability to Utilize Fat for Energy

In a groundbreaking study published in *Nature Metabolism* on July 1, 2025, researchers at Weill Cornell Medicine have demonstrated that brain cells can utilize fat droplets as an energy source, challenging long-held beliefs about the brain's metabolic processes. This research, led by Dr. Timothy A. Ryan, a professor of biochemistry and anesthesiology at Weill Cornell Medicine, shows that electrical activity in synapses—the junctions where neurons communicate—can trigger the breakdown of lipid droplets, allowing neurons to convert fat into fatty acids. These fatty acids are then sent to the mitochondria, the powerhouse of the cell, to produce adenosine triphosphate (ATP), the energy currency of cells.

Historically, glucose has been viewed as the primary fuel for brain function, leading to the assumption that fat is not utilized by the brain. "We have long believed that the brain doesn't burn fat, but our findings suggest otherwise," stated Dr. Ryan. The study's lead author, Dr. Mukesh Kumar, a postdoctoral associate in biochemistry, emphasized the relevance of this discovery, noting that fat may serve as an energy substrate for the brain during periods when glucose is scarce.

The research team focused on the DDHD2 gene, which encodes a lipase that aids in fat breakdown. Mutations in this gene are associated with hereditary spastic paraplegia, a neurological disorder that affects motor function and cognitive abilities. Previous studies have indicated that blocking this enzyme leads to an accumulation of triglycerides in the brain, suggesting a potential link between lipid metabolism and neurological health.

The study's findings were corroborated through experiments involving mice lacking the DDHD2 gene, which showed that neurons could utilize lipid droplets for energy when glucose was not available. Dr. Ryan noted, "The neuronal activity directly influences lipid usage; when neurons are active, they consume fat. When they are at rest, this process is significantly reduced."

Further investigations involved blocking the enzyme carnitine palmitoyltransferase 1 (CPT1), which facilitates the transportation of fatty acids into mitochondria. This intervention resulted in the mice entering a torpor-like state, indicating a critical dependence on lipid metabolism for brain function. Dr. Ryan stated, "This response demonstrates a continuous need for the brain to access these lipid droplets for energy."

The implications of this research are substantial, particularly regarding neurodegenerative diseases. Fluctuations in glucose levels are common in aging and neurological disorders, and the ability of the brain to utilize fatty acids from lipid droplets might offer a compensatory mechanism. Dr. Kumar remarked, "The accumulation of fat droplets in neurons could be linked to conditions such as Parkinson's disease, warranting further investigation."

The research received support from the National Institute of Neurological Disorders and Stroke and the National Cancer Institute, among other funding sources. As we move forward, understanding the interplay between glucose and lipids in the brain may unlock new avenues for addressing neurodegeneration. Dr. Ryan concluded, "By delving deeper into these molecular mechanisms, we aim to find protective strategies for brain health."

This study not only enhances our understanding of brain metabolism but also opens new pathways for potential therapeutic interventions in neurodegenerative diseases, emphasizing the importance of lipid metabolism in maintaining cognitive function and overall brain health.