Brain cells can burn fat to fuel activity

While glucose, or sugar, is a well-known fuel for the brain, Weill Cornell Medicine researchers have demonstrated that electrical activity in synapses—the junctions between neurons where communication occurs—can lead to the use of lipid or fat droplets as an energy source.

The study, published July 1 in Nature Metabolism, challenges "the long-standing dogma that the brain doesn't burn fat," said principal investigator Dr. Timothy A. Ryan, professor of biochemistry and of biochemistry in anesthesiology, and the Tri-Institutional Professor in the Department of Biochemistry at Weill Cornell Medicine. 

The paper's lead author, Dr. Mukesh Kumar, a postdoctoral associate in biochemistry at Weill Cornell Medicine who has been studying the cell biology of fat droplets, suggested that 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 research team was particularly intrigued by the DDHD2 gene, which encodes a lipase, or enzyme that helps break down fat. Mutations in DDHD2 are linked to a type of hereditary spastic paraplegia, a neurological condition that causes progressive stiffness and weakness in the legs, in addition to cognitive deficits.

Prior research by other investigators has demonstrated that blocking this enzyme in mice causes a build-up of triglycerides—or fat droplets that store energy—throughout the brain.  "To me, this was evidence that maybe the reason we claim the brain doesn't burn fat is because we never see the fat stores," Dr. Ryan said. 

Research demonstrates lipids have an important role

The current study explored whether the lipid droplets that build up in the absence of DDHD2 are used as fuel by the brain, particularly when glucose isn't present, Dr. Ryan said.

Dr. Kumar found that when a synapse contains a lipid droplet filled with triglycerides in mice without DDHD2, neurons can break down this fat into fatty acids and send it to the mitochondria—the cell's energy factories—so they can produce adenosine triphosphate (ATP), the energy the cell needs to function.

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. If the neuron is busy, it drives this consumption. If it's at rest, the process isn't happening."  

Dr. Timothy A. Ryan, professor of biochemistry and of biochemistry in anesthesiology

In another study, researchers injected a small molecule into mice to block the enzyme carnitine palmitoyltransferase 1 (CPT1), which helps transport fatty acids into the mitochondria for energy production. Blocking CPT1 prevented the brain from using fat droplets, which then led to torpor, a hibernation-like state, in which the body temperature rapidly plummets and the heartbeat slows. "This response convinced us that that there's an ongoing need for the brain to use these lipid droplets," Dr. Ryan said.

Implications for future research

This research may encourage the further investigation of neurodegenerative conditions and the role of lipids in the brain. 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, Dr. Kumar said. "We don't know where this research will go in terms of neurodegenerative conditions, but some evidence suggests that accumulation of fat droplets in the neurons may occur in Parkinson's disease," he said.

Researchers also need to better understand the interplay between glucose and lipids in the brain, Dr. Ryan said. "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 research was supported in part by the National Institute of Neurological Disorders and Stroke and the National Cancer Institute, both part of the National Institutes of Health, through grant numbers NS036942, NS11739 and F31CA278383. Additional support was provided by Aligning Science Across Parkinson's through grant number ASAP-000580.