Scientists have demonstrated that even two days on a Western-like high-fat diet reduce hippocampal glucose availability, which activates a subset of inhibitory neurons and causes memory problems in mice [1].
Is it OK to eat junk occasionally?
Metabolic disease and obesity are known to harm cognitive function and have been linked to neurodegenerative diseases such as Alzheimer’s [2], among numerous other health problems. However, many people tend to think that they can get away with temporarily switching to an unhealthy diet or even with constantly eating such a diet while maintaining a healthy weight.
Recent research shows that it’s not that simple: even short periods of a high-fat diet can cause issues, including a decline in cognitive function [3]. A new study from the University of North Carolina, published in Neuron, delves deeper into this phenomenon, yielding intriguing insights.
Memory impairments after just two days
The researchers set out to investigate the impact on healthy adult mice of a very short-term high-fat diet (stHFD) consisting of 58% fat, 25% carbohydrates, and 17% protein. According to the paper, this diet resembles Western diets rich in saturated fat.
Two days into the experiment, the researchers put the mice through a battery of cognitive tests and found that mice on this stHFD did noticeably worse on some of them, particularly on novel place recognition (NPR) and contextual fear conditioning (CFC), indicating “significant impairments in hippocampus-dependent spatial and contextual memory.” Importantly, body weight and blood glucose levels remained unchanged due to the short duration of the intervention.
The stHFD mice, however, were more physically active in the arena, traveling farther (and/or at higher speed) during the open-field session. This suggests that the poorer scores on the two cognitive tests were not due to the mice being lethargic or motor-impaired.
The neurons that didn’t get enough glucose
NPR is thought to depend on the function of the hippocampal region called the dentate gyrus, and the hippocampus is especially vulnerable to brief HFD. The team detected greatly increased activity of a subset of neurons called cholecystokinin-expressing interneurons (CCK-INs) in the dentate gyrus. Interneurons are local inhibitory neurons. Stimulating CCK-INs impaired memory in controls, while dampening their signals rescued memory deficits in stHFD mice.
Prior research has found that just three days of HFD downregulates GLUT1, the main endothelial glucose transporter, across the brain, including the hippocampus. With less GLUT1 at the blood-brain barrier, less glucose gets from capillaries into brain tissue, as if a faucet is turned down, so neuronal glucose availability drops even if blood glucose is normal.
The researchers confirmed that CCK-INs in the dentate gyrus sit farther from capillaries than granule neurons and hence have worse access to the reduced amount of glucose. CCK-INs are glucose-inhibited, which means that when glucose is low, their activity increases, inhibiting that of other local neurons. Giving stHFD mice extra glucose or putting them on a one-night fasting-refeeding protocol restored the activity of CCK-INs. Crucially, if the researchers forced CCK-INs to stay active by chemogenetic activation, the glucose/refeeding no longer improved memory.
PKM2 inhibition rescues memory
Investigating what intracellular switch links low glucose to CCK-IN hyperactivity, the team focused on a glycolytic enzyme, PKM2. stHFD elevated PKM2 signaling markers in CCK-INs, while knocking down PKM2 in these cells reduced their baseline activity and rescued NPR without changing intake/weight. Shikonin, a PKM2 inhibitor, also rescued NPR.
“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 Juan Song, PhD, principal investigator, professor of pharmacology at the UNC School of Medicine, and a senior author of the study. “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.”
Having discovered this pathway for diet-related memory deficiency, the team asked whether this can be applied beyond stHFD. In a “classic” scenario of obesity induced by 10 weeks of HFD, mice showed spatial-memory deficits, but chronic CCK-IN inhibition for the duration of HFD or long-term PKM2 knockdown reversed these effects.
“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 Song. “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.”
Literature
[1] Landry, T., Perrault, L., Melville, D., Chen, Z., Li, Y. D., Dong, P., … & Song, J. (2025). Targeting glucose-inhibited hippocampal CCK interneurons prevents cognitive impairment in diet-induced obesity. Neuron.
[2] Patel, V., & Edison, P. (2024). Cardiometabolic risk factors and neurodegeneration: a review of the mechanisms underlying diabetes, obesity and hypertension in Alzheimer’s disease. Journal of Neurology, Neurosurgery & Psychiatry, 95(6), 581-589.
[3] McLean, F. H., Grant, C., Morris, A. C., Horgan, G. W., Polanski, A. J., Allan, K., … & Williams, L. M. (2018). Rapid and reversible impairment of episodic memory by a high-fat diet in mice. Scientific reports, 8(1), 11976.
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