Brain Uses Fat for Fuel When Neurons Fire, Study Shows

Scientists have overturned a fundamental assumption about brain metabolism by discovering that neurons can burn fat droplets for energy when electrically active.

Researchers at Weill Cornell Medicine found that synapses—the critical junctions where brain cells communicate—can break down stored lipids and convert them to fuel, challenging the longstanding belief that the brain relies exclusively on glucose for energy.

The findings, published in Nature Metabolism, reveal a previously unknown backup energy system that may help explain certain neurodegenerative diseases and could point toward novel treatments for brain disorders.

Electrical Activity Triggers Fat Burning

“The long-standing dogma that the brain doesn’t burn fat” has been challenged by this research, explained Dr. Timothy A. Ryan, professor of biochemistry at Weill Cornell Medicine and the study’s principal investigator. The discovery emerged from investigating DDHD2, a gene that produces an enzyme responsible for breaking down fat molecules.

When researchers blocked this enzyme in mice, triglycerides—fat droplets that store energy—accumulated throughout the brain. This suggested that under normal circumstances, the brain actively consumes these fat stores, contradicting decades of scientific consensus.

The research team made a remarkable discovery about when this fat burning occurs:

• Neurons only break down fat droplets when electrically active
• Inactive neurons leave fat stores untouched
• The process converts triglycerides into fatty acids for mitochondrial energy production
• Blocking fat metabolism can trigger torpor, a hibernation-like state

“The process of being able to use the fat is controlled by the electrical activity of the neurons, and I was shocked by this finding,” Ryan noted. “If the neuron is busy, it drives this consumption. If it’s at rest, the process isn’t happening.”

A Hidden Energy System Revealed

Lead author Dr. Mukesh Kumar, a postdoctoral researcher studying fat droplet biology, proposed that brain fat metabolism makes evolutionary sense. Just as muscles rely on fat for sustained energy during intense activity, the brain may need similar backup fuel systems during periods of high neural activity or glucose shortage.

The researchers conducted a telling experiment by injecting mice with a molecule that blocks CPT1, an enzyme essential for transporting fatty acids into cellular power plants called mitochondria. When fat burning was prevented, the animals rapidly entered torpor—their body temperature plummeted and heart rates slowed dramatically.

“This response convinced us that that there’s an ongoing need for the brain to use these lipid droplets,” Ryan observed. The torpor response demonstrated that fat metabolism isn’t merely supplemental but plays an essential role in maintaining normal brain function.

The discovery helps explain why mutations in DDHD2 cause hereditary spastic paraplegia, a neurological condition featuring progressive leg weakness and cognitive problems. Without functional fat-burning enzymes, neurons may struggle to meet energy demands during periods of high activity.

Implications for Neurodegeneration

The research opens intriguing possibilities for understanding brain diseases. As people age or develop neurological conditions, glucose availability can become compromised. The newly discovered fat-burning system might serve as a crucial backup during these vulnerable periods.

“Glucose fluctuations or low levels of glucose can occur with aging or neurological disease, but fatty acids broken down from lipid droplets may help to maintain the brain’s energy,” Kumar explained. The researchers noted that fat droplet accumulation has been observed in Parkinson’s disease, though the connection to energy metabolism remains unclear.

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 therapies might work partly by optimizing energy metabolism.

Ryan emphasized the broader implications: “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.”

The research represents a fundamental shift in understanding brain energetics, revealing that our most complex organ maintains sophisticated backup systems to ensure continued function even when primary fuel sources falter.