Brain Can Tap Stored Fat for Energy

For decades, neurons have generally been viewed as cells that depend overwhelmingly on glucose and related substrates for their energy needs. Research is now adding an important twist to that picture: neurons can also tap into their own stores of fat to help power their activity.

Scientists have found that tiny lipid droplets inside neurons can act as energy reserves. Fatty acids released from these droplets can enter mitochondria — the energy-producing structures inside cells — where they undergo beta-oxidation and contribute to ATP production.

A central player in this process is DDHD2, an enzyme involved in neuronal lipid metabolism. Research published in Nature Metabolism showed that fatty acids released through DDHD2 activity support mitochondrial energy production, particularly when neurons face increased energy demands.

The researchers reported that loss of Ddhd2 impaired mitochondrial respiration and ATP production in cultured neurons even as glycolysis increased. Long-chain saturated fatty acids normally released in an activity-dependent manner by the enzyme were reduced.

Experiments also showed that blocking the transport of fatty acids into mitochondria reduced mitochondrial respiration and energy production, further supporting the conclusion that neurons can burn endogenous fatty acids for fuel.

Earlier in-vivo work provided another striking clue. Acute inhibition of either DDHD2 or CPT1, a transporter needed for mitochondrial fatty-acid use, caused adult male mice to rapidly enter torpor — a low-energy, hibernation-like physiological state. The result suggested that continuous neuronal fat metabolism may be important for maintaining normal whole-body energy function.

The DDHD2 connection also has medical significance. Mutations in the DDHD2 gene cause a rare neurological condition known as hereditary spastic paraplegia type 54. Previous studies found that mice lacking DDHD2 accumulated triglycerides and large lipid droplets in neurons and developed motor and cognitive impairments.

Researchers have further estimated that roughly 20 per cent of basal neuronal energy in their experimental system could be supplied through the DDHD2-dependent fatty-acid oxidation pathway. The pathway appeared especially important when neuronal activity — and therefore energy demand — increased.

The discovery does not mean that glucose is unimportant to the brain. Glucose remains a major brain fuel, and the new findings instead show that neuronal energy metabolism is more flexible than previously appreciated.

Scientists say the work could improve understanding of how failures in lipid metabolism affect brain function and may eventually point toward therapeutic strategies for disorders linked to DDHD2. However, these findings are primarily based on cellular and animal experiments and do not imply that eating more dietary fat will directly improve brain energy or treat neurological disease.

Together, the studies reveal an unexpected metabolic reserve inside neurons: stored fat that can be mobilised when cells need energy. The finding reshapes scientists’ understanding of how active neurons meet their substantial energy demands.

What researchers discovered

•   Neurons can release fatty acids from intracellular lipid stores.
•   These fatty acids can enter mitochondria and contribute to ATP production through beta-oxidation.
•   DDHD2 plays an important role in releasing fatty acids used by neurons.
•   Loss or inhibition of DDHD2 leads to abnormal lipid accumulation and impaired neuronal energy production.
•   Blocking neuronal fatty-acid use triggered a torpor-like state in experimental mice.
•   The findings expand — rather than replace — the established role of glucose in brain metabolism.

Sources

Nature Metabolism (2025): “DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.”

Nature Metabolism (2025): “Triglycerides are an important fuel reserve for synapse function in the brain.”

US National Institutes of Health, NIH Research Matters (August 5, 2025): “Neurons can tap into fat for fuel.”