Brain Cells Can Burn Fat for Energy
Brain cells can break down fat to generate energy, a surprising finding that challenges the belief neurons rely solely on glucose.
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Researchers at Weill Cornell Medicine have discovered that brain cells can break down fat stores to fuel their activity, challenging the view that neurons rely exclusively on glucose for energy. The study, published July 1 in Nature Metabolism, shows that electrical activity at synapses – the contact points between neurons – can trigger the use of lipid droplets as an alternative energy source.
Lipid droplets
Lipid droplets are intracellular structures that store neutral lipids, such as triglycerides.
Synapse
A synapse is the junction between two neurons where electrical or chemical signals are transmitted.
The findings suggest that fat may have an underappreciated role in brain metabolism, especially under conditions where glucose availability is limited.
Revisiting brain energy metabolism
The work focused on a gene called DDHD2, which encodes an enzyme involved in fat breakdown. Mutations in this gene are known to cause a form of hereditary spastic paraplegia, a condition that affects motor function and cognition. Previous studies in mice lacking DDHD2 have shown abnormal accumulation of triglycerides, the storage form of fat, in brain tissue.
In the current study, researchers asked whether these lipid droplets serve as an energy reserve. Using mice that lacked DDHD2, they found that neurons could break down triglycerides into fatty acids and send them to mitochondria to generate ATP – the cell’s main energy currency.
Mitochondria
Mitochondria are membrane-bound organelles often described as the powerhouses of the cell.
Importantly, this fat-burning process depended on synaptic activity. When neurons were active, fat was used; when they were not, the process stopped.
Fat metabolism essential for brain function
To test whether fat metabolism was necessary for brain function, the researchers used a compound to block carnitine palmitoyltransferase 1 (CPT1), an enzyme that transports fatty acids into mitochondria. Inhibiting CPT1 in mice caused a rapid drop in body temperature and heart rate – a state known as torpor – suggesting that the brain's use of fat is critical for maintaining systemic physiological balance.
These findings highlight a direct link between neuronal activity and fat metabolism, and indicate that fat stores may serve as a buffer during times of high energy demand or limited glucose supply.
Looking ahead
The results raise questions about how lipid metabolism may contribute to neurodegenerative diseases. While the brain typically uses glucose, fluctuations in glucose levels can occur with age or illness. Fatty acids derived from lipid droplets might help sustain energy production in these conditions.
Accumulation of lipid droplets has been observed in diseases such as Parkinson’s, but their role remains unclear. Future research will aim to clarify how glucose and lipid metabolism interact in the brain, and whether targeting fat metabolism could influence disease progression.
Reference: Kumar M, Wu Y, Knapp J, et al. Triglycerides are an important fuel reserve for synapse function in the brain. Nat Metab. 2025. doi: 10.1038/s42255-025-01321-x
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