Studies show that when neurons fire, the brain uses fat for fuel

Scientists overturn basic assumptions about brain metabolism by discovering that neurons burn fat droplets when they are electroactive.

Weill Cornell Medicine researchers have found that synapses, the key junction conveyed by brain cells, break down stored lipids and convert them into fuel, challenging long-standing belief that the brain relies solely on glucose.

These findings, published in natural metabolism, reveal a previously unknown backup energy system that may help explain certain neurodegenerative diseases and may point to novel treatments for brain diseases.

Electric activity triggers fat burning

Weill Cornell Medicine and the study’s lead investigator, Dr. Timothy A. Ryan, explained that the study’s “long-term dogma of the brain not burning fat”. The findings come from the study of DDHD2, which produces an enzyme responsible for breaking down fat molecules.

When researchers blocked the enzyme in mice, triglycerides (droplets that store energy) took up the entire brain. This suggests that under normal circumstances, the brain actively consumes these fat stores, which contradicts decades of scientific consensus.

The team made amazing discoveries about when this fat burning occurs:

• Neurons only break down fat when electroactive
• Inactive neurons keep fat stores untouched
• This process converts triglycerides into fatty acids produced by mitochondrial energy
• Blocking fat metabolism can trigger torpor, a hibernating state

“The process of being able to use fat is controlled by the electrical activity of the neurons, and I was shocked by this discovery,” Ryan noted. “If the neuron is busy, it drives this consumption. If it is in a quiescent state, the process will not happen.”

Hidden energy system reveals

Dr. Mukesh Kumar, a postdoctoral researcher who studies fat droplet biology, suggests that brain fat metabolism has evolutionary significance. Just as muscles rely on fat to sustain energy during intense activity, the brain may need a similar backup fuel system during high nerve activity or glucose shortage.

The researchers conducted an obvious experiment by injecting mice into the molecule of CPT1, an enzyme necessary to transport fatty acids to cellular power plants called mitochondria. When fat is prevented from burning, the animals quickly enter Torpor, their body temperature drops and their heart rate slows down sharply.

“This response convinced us that the brain needed to use these lipid droplets,” Ryan observed. The Torpor response showed that fat metabolism is not only a supplement, but also plays a crucial role in maintaining normal brain function.

The finding helps explain why mutations in DDHD2 cause hereditary spastic paraplegia, a neurological disorder with progressive leg weaknesses and cognitive problems. Without the enzyme that functions to burn fat, neurons may struggle to meet energy needs during high activity.

Effects on neurodegeneration

This study opens interesting possibilities for understanding brain diseases. As people age or develop neurological conditions, the availability of glucose may be impaired. In these fragile times, newly discovered combustion systems may be crucial backups.

“Glucose fluctuations or low glucose levels may occur in aging or neurological disorders, but fatty acids broken down from lipid droplets may help maintain brain energy,” Kumar explained. The researchers noted that although the link to energy metabolism is not yet clear, fat droplet accumulation has been observed in Parkinson’s disease.

This metabolic flexibility could explain why some brain regions resist degeneration better than others, or why certain interventions that affect fat metabolism show promise in treating neurological disorders. The finding that electrical activity directly controls fat burning also suggests that neural stimulation therapy may work partly by optimizing energy metabolism.

Ryan highlighted the broader meaning: “By learning more about the details of these molecules, we hope that the explanation for neurodegeneration will eventually be unlocked, which will allow us to find ways to protect our brains.”

This study represents a fundamental shift in understanding brain energy science, revealing that our most complex organs maintain complex backup systems that ensure continuous function even when the primary fuel source flows.

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