A weekend of burgers, fries and hot dogs will probably have you thinking more about your waistline than your brain, but a new study has found that just a few days on a high-fat Western diet is enough to rewire pathways in your memory hub, impairing cognitive function. The good news is that the damage can be undone.
Research led by scientists at the University of North Carolina's (UNC) School of Medicine has identified a previously unknown mechanism concerning a specific group of brain cells impacted by high-fat foods. These cells, known as cholecystokinin (CCK) interneurons, are specialist inhibitory cells that act like brakes in the brain’s memory hub, the hippocampus. Their job is to keep excitatory pyramidal neurons – the workhorses of memory encoding – firing in rhythm, editing and shaping their signals so that memories are stored properly. When pyramidal cells are too excitable, memory processing becomes noisy and disorganized. But when CCK interneurons go into overdrive, they can silence pyramidal cell activity, preventing the hippocampus from building and stabilizing new memories.
Scientists already knew that a high-fat diet (HFD) interfered with how the brain metabolizes its primary fuel, glucose (sugar). In this study, feeding mice a HFD for four days impaired that glucose availability in the brain, causing CCK interneurons to ramp up their firing. That shift alone was enough to interfere with memory performance in behavioral tests, even before the mice showed signs of weight gain or diabetes. So the problem wasn’t simply fat intake in itself, but the way the brain responded to it.
“We knew that diet and metabolism could affect brain health, but we didn’t expect to find such a specific and vulnerable group of brain cells, CCK interneurons in the hippocampus, that were directly disrupted by short-term high-fat diet exposure,” said Song, who is a member of the UNC Neuroscience Center. “What surprised us most was how quickly these cells changed their activity in response to reduced glucose availability, and how this shift alone was enough to impair memory."
The researchers then identified that a protein known as pyruvate kinase M2 (PKM2) played a key role in why the CCK interneurons became overexcited. Under normal circumstances, PKM2 helps regulate how neurons use glucose for energy, but when glucose is scarce, this balance shifts in a way that drives CCK interneurons into overactivity.
While the study was performed on mice, the changes in the brain were fast – just four days – and the researchers suggested that long-term exposure to a diet high in saturated fats, such as a lot of junk food, could lead to a higher risk of developing serious conditions like dementia and Alzheimer's disease.
However, an important part of the study was what happened after the HFD was discontinued. Restoring brain glucose levels calmed the overactive CCK interneurons, in turn regulating the function of those excitatory pyramidal neurons, and the short-term memory problems seen in the mice were resolved. What's more, intermittent fasting (which has been shown to alleviate some symptoms of Alzheimer's disease), following a period of eating a high-fat diet was also enough of an intervention to restore normal activity to the CCK interneurons.
“This work highlights how what we eat can rapidly affect brain health and how early interventions, whether through fasting or medicine, could protect memory and lower the risk of long-term cognitive problems linked to obesity and metabolic disorders,” said lead researcher Juan Song, PhD, professor of pharmacology at the UNC school of Medicine. “In the long run, such strategies could help reduce the growing burden of dementia and Alzheimer’s linked to metabolic disorders, offering more holistic care that addresses both body and brain.”
The team now plans to investigate whether such targeted therapies could benefit humans – and also if a high-fat diet is a factor in developing Alzheimer's disease.
The study was published in the journal Neuron.
