high-Fat Diet Linked to Memory Impairment in Fruit Flies,Reversible Through Autophagy Enhancement
New research published in PLoS Genetics demonstrates a link between a high-fat diet (HFD) and impaired intermediate- and long-term memory in fruit flies (Drosophila melanogaster),with the underlying mechanism appearing to be a disruption in the cellular process of autophagy. Importantly, the study suggests this memory impairment is not permanent and can be improved by interventions that boost autophagy.
Researchers led by Dr. Tonoki observed that flies fed an HFD for seven days exhibited significantly elevated levels of lipid-triacylglycerol (TAG) and circulating glucose, alongside increased lipid accumulation in the intestines. This indicates the HFD altered the flies’ metabolic processes related to glucose and lipid management.
To assess the impact on cognitive function, the team tested the flies’ memory formation using odor-conditioning paired with mild electric shock.While short-term memory (STM) remained unaffected, intermediate-term memory (ITM) and long-term memory (LTM) were significantly impaired in flies consuming the HFD.
Further investigation revealed a correlation between the HFD and autophagic dysfunction. Levels of Ref(2)p, a protein normally broken down by autophagy, were elevated in HFD-fed flies. Together, the ratio of Atg8a-II/I – a marker indicating autophagosome formation – was reduced, suggesting a decline in autophagic activity.
To confirm autophagy’s role, researchers selectively suppressed the autophagy protein Atg1 in adult neurons, which resulted in ITM impairment mirroring the effects of the HFD. Conversely, enhancing autophagy through overexpression of Atg1, suppression of the autophagy inhibitor Rubicon, or treatment with the autophagy inducer rapamycin, reversed the memory deficits observed in the HFD-fed flies.
The study pinpointed a specific point of failure within the autophagy process: the fusion of autophagosomes and lysosomes into autolysosomes, where cellular waste is degraded. HFD-fed flies showed an abundance of both autophagosomes and lysosomes, but no corresponding increase in autolysosome numbers, indicating a blockage in the final stage of autophagy.gene expression analysis revealed downregulation of genes related to lysosome signaling. Further supporting this, inhibiting lysosomal function also reduced ITM.
“This research advances our understanding of how dietary habits influence brain health,” explains Dr. Tonoki. “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.” The researchers emphasize that the cognitive risks associated with HFD are potentially reversible and highlight the possibility of preventative strategies against metabolic and neurodegenerative disorders through lifestyle interventions promoting autophagy, such as exercise or intermittent fasting.
Source: Yue, T., et al. (2025). High-fat diet impairs intermediate-term memory by autophagic-lysosomal dysfunction in Drosophila. PLoS Genetics. doi.org/10.1371/journal.pgen.1011818.