High-fat diet impairs memory formation by reducing autophagy

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Modern lifestyles and dietary changes have significantly increased the consumption of high-fat foods, contributing to a steep rise in the prevalence of obesity, diabetes, and metabolic disorders. Furthermore, a high-fat diet is linked to cognitive impairments and neurodegeneration and has been shown to worsen the pathology of Alzheimer disease in mouse models. Yet, the underlying mechanisms remain largely elusive.

Autophagy, a crucial cellular recycling process, helps maintain neuronal health. Recent studies have shown that impaired autophagy contributes to neurodegeneration and cognitive decline. But is autophagy linked to high-fat diet-induced cognitive deficits?

To address this question, researchers from Chiba University, Japan, examined the effects of the high-fat diet on autophagy and memory formation using Drosophila, the humble fruit fly, as a model system. Rodent studies have focused mainly on specific regions of the brain, leaving the broader impact of high-fat diets on the nervous system unexplored. To bridge this gap, the researchers used Drosophila, given its ease of genetic manipulation, short lifespan, conserved metabolic and neural pathways with mammals, and well-validated memory assessments.

Associate Professor Ayako Tonoki and her team, including doctoral students Tong Yue, Minrui Jiang, and Kotomi Onuki from the Graduate School of Medical and Pharmaceutical Sciences, along with Professor Motoyuki Itoh from the Graduate School of Pharmaceutical Sciences, Chiba University, Japan, recently published their findings in Volume 21, Issue 8 of the journal PLOS Genetics on August 18, 2025. “Our findings suggest that diet-induced cognitive decline is not irreversible and may be improved by lifestyle interventions that promote autophagy, such as exercise or intermittent fasting. This research may raise public awareness about the cognitive risks of high-fat diet and provide new insights into potential preventive strategies against metabolic and neurodegenerative disorders,” explains Dr. Tonoki.

The researchers maintained the flies on a normal diet or an high-fat diet for 7 days and examined their lipid—triacylglycerol (TAG) and circulating glucose levels. Notably, high-fat diet-fed flies had significantly higher levels of TAG and glucose as well as higher intestinal lipid accumulation, suggesting that high-fat diet altered glucose and lipid metabolism.

Next, the researchers examined the effects of high-fat diet on memory formation by conditioning the flies to various odors and assessing their short-term (3 minutes following exposure), intermediate-term (3 hours following exposure), and long-term (24 hours following exposure) memory (STM, ITM, and LTM, respectively). Specific odor tubes were paired with an electric shock apparatus for behavioral reinforcement. Notably, high-fat diet-fed flies exhibited impaired ITM and LTM, while STM remained unaffected.

To elucidate the role of autophagy in high-fat diet-induced memory impairment, the researchers quantified the levels of autophagy-related proteins. They found that the levels of Ref(2)p—a protein normally degraded by autophagy—were significantly increased in high-fat diet-fed flies. At the same time, the Atg8a-II/I ratio, a marker of autophagosome (recycling vesicles) formation, was markedly lower, indicating autophagic dysfunction. Further, temporary suppression of the autophagy protein Atg1 in adult neurons selectively reduced ITM without affecting STM, consistent with the effects observed under high-fat diet feeding, suggesting that a temporary reduction in neuronal autophagic activity during adulthood is sufficient to cause memory decline. Conversely, boosting autophagy by overexpressing Atg1, suppressing the autophagy inhibitor Rubicon, or treating with the autophagy inducer rapamycin ameliorated memory deficits in high-fat diet-fed flies. These findings suggest that high-fat diet-induced memory deficits can be reversed by enhancing autophagic activity.

To better understand how high-fat diet disrupts autophagy, the researchers examined the final stage of autophagy—the fusion of autophagosomes and lysosomes into autolysosomes, where cellular contents are degraded and recycled. Notably, high-fat diet-fed flies showed abundant autophagosomes and lysosomes, but no change in autolysosome numbers, indicating that the high-fat diet-induced impairment in autophagy was likely due to the defective fusion of autophagosomes and lysosomes. Interestingly, gene expression analysis revealed that lysosome signaling-related genes were significantly downregulated in high-fat diet-fed flies. Finally, inhibition of lysosomal function markedly reduced ITM.

Overall, these findings provide novel insights into how high-fat diet induces memory deficits through autophagic and lysosomal impairment. Addressing the cognitive risks associated with high-fat diet can aid in the early prevention of neurodegenerative diseases.

Dr. Tonoki concludes by saying, “This research advances our understanding of how dietary habits influence brain health. Our findings may also accelerate the identification of autophagy-enhancing interventions—including specific nutrients and therapeutic agents—to combat diet-induced cognitive decline and preserve cognition in the aging population.”

Source: News Release
Chiba University
September 17, 2025