Study Reveals Role of Lipids in Brain Metabolism and Energy Use

In a groundbreaking study published on July 1, 2023, in *Nature Metabolism*, researchers from Weill Cornell Medicine have challenged the long-held belief that glucose is the sole energy source for the brain. The study, led by Dr. Timothy A. Ryan, Professor of Biochemistry, and Dr. Mukesh Kumar, a postdoctoral associate in biochemistry, reveals that electrical activity in synapses can facilitate the use of lipid droplets, or fats, as an alternative energy source. This discovery not only redefines our understanding of brain metabolism but also opens new avenues for investigating neurodegenerative conditions.

Historically, it has been accepted that the brain primarily relies on glucose for energy, a notion that has guided research into metabolic disorders and neurodegeneration. According to Dr. Ryan, "the brain doesn't burn fat" has been a prevailing dogma in neuroscience. However, the new findings suggest that lipid droplets, typically associated with energy storage rather than energy consumption, can indeed be utilized by neurons when glucose is scarce.

The research team focused on the DDHD2 gene, which encodes a lipase enzyme responsible for breaking down fats. Mutations in this gene are linked to hereditary spastic paraplegia, a condition characterized by progressive weakness and stiffness in the legs and cognitive deficits. Previous studies highlighted that blocking this enzyme in mouse models leads to the accumulation of triglycerides in the brain, hinting at a potential metabolic pathway that had been overlooked. As stated by Dr. Kumar, "It makes sense that fat may play a role as an energy source in the brain like it does with other metabolically demanding tissues, such as muscle."

The study demonstrated that when lipid droplets filled with triglycerides are present in synapses, neurons can convert these fats into fatty acids, which are then transported to mitochondria for energy production. Dr. Ryan remarked, "If the neuron is busy, it drives this consumption. If it's at rest, the process isn't happening." This finding underscores the importance of neuronal electrical activity in regulating metabolic processes.

Further experimentation revealed that inhibiting the enzyme carnitine palmitoyltransferase 1 (CPT1), which facilitates the transport of fatty acids into mitochondria, resulted in a state of torpor in mice. This hibernation-like condition, characterized by a rapid decrease in body temperature and heart rate, provided additional evidence of the brain's dependency on lipid metabolism for energy, particularly under stress or low glucose availability.

The implications of this research extend to the understanding of neurodegenerative diseases. Fluctuations in glucose levels are common in aging and various neurological disorders. Dr. Kumar noted, "Fatty acids broken down from lipid droplets may help to maintain the brain's energy, especially in conditions where glucose is compromised." This insight suggests that lipid metabolism could be a critical factor in the progression of diseases such as Parkinson's, where fat droplet accumulation is observed.

As the research progresses, the team aims to explore the interplay between glucose and lipids in the brain further. Dr. Ryan stated, "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."

This pivotal study not only reshapes the understanding of brain metabolism but also emphasizes the need for further investigation into lipid's roles in cognitive function and neurological health. The findings may pave the way for novel therapeutic strategies targeting lipid metabolism in neurodegenerative diseases, potentially transforming how these conditions are approached in clinical settings.