Mouse study reveals molecular link between high-fat diets and impaired brain function
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The molecular mechanisms linking a high-calorie diet to cognitive impairment remain unclear. Researchers at the Institute of Science Tokyo, Japan, investigated this association in mice, finding that the diet reduced expression of the nuclear protein PQBP1, disrupting the alternative splicing of genes involved in synaptic function. This was associated with synaptic abnormalities and cognitive impairment.
Treatment with pioglitazone or AAV-PQBP1 to restore PQBP1 levels improved synaptic and cognitive outcomes in mice, highlighting PQBP1-dependent RNA splicing as a potential therapeutic target.
The missing link between diet and cognition
Calorie-rich diets are well known to contribute to obesity and metabolic disorders such as diabetes. Growing evidence suggests that they can also affect brain function. Studies have linked high-calorie diets to poor cognitive performance and an increased risk of neurodegenerative conditions like Alzheimer's disease.
However, the precise molecular mechanisms linking a high-calorie diet to impaired cognitive function remain unclear. Previous research has implicated processes such as inflammation and insulin resistance, but understanding of the neuronal changes underlying diet-associated cognitive impairment remains limited.
To address this gap, a research team led by specially appointed professor Hitoshi Okazawa along with project associate professor Hikari Tanaka from the Center for Brain Integration Research, Institute of Science Tokyo (Science Tokyo), Japan, investigated how a high-fat diet affects brain function in mice.
The team collaborated with specially appointed professor Masanobu Kano of the Advanced Comprehensive Research Organization, Teikyo University, Japan (also professor emeritus at The University of Tokyo, Japan) and professor Albert R. La Spada of the University of California, Irvine, in the U.S.
Their study, published in Molecular Psychiatry on Sept. 12, 2026, reveals a molecular pathway linking a high-fat diet to altered synaptic function and cognitive impairment.
Reduced PQBP1 disrupts synaptic gene splicing
The team focused on PQBP1, a protein that regulates alternative RNA splicing. Alternative RNA splicing is a process that enables a single gene to produce different RNA transcripts and, potentially, different protein isoforms.
After feeding mice a high-fat diet, the researchers observed reduced PQBP1 levels in the cerebral cortex, a brain region that supports cognitive functions. The study links this reduction to suppressed PPARγ-mediated transcription of the PQBP1 gene and implicates insulin-related signaling as a potential upstream mechanism.
Next, the researchers examined how reduced PQBP1 levels affect neurons. Using RNA sequencing–based analyses, they compared alternative RNA splicing in mice fed a high-fat diet for one or six weeks with that in mice lacking PQBP1 in neurons. They identified shared splicing changes affecting specific genes involved in synaptic function.
Further experiments revealed that abnormal alternative RNA splicing of these PQBP1 target genes leads to abnormalities in synaptic structure and function, alongside cognitive impairment. Together, these findings implicate PQBP1-dependent alternative RNA splicing as a key link between a high-fat diet and impaired neuronal communication.
"Our findings reveal a molecular pathway linking a high-calorie diet to cognitive impairment. Reduced PQBP1 expression alters the alternative splicing of synapse-related genes, contributing to synaptic dysfunction," explains Okazawa.
Restoring PQBP1 improves outcomes in mice
The researchers also tested whether these effects could be reversed. In mice fed a high-fat diet, treatment with pioglitazone, a drug used for diabetes management that activates PPARγ, restored PQBP1 levels, rectified abnormal RNA splicing in key synapse-related genes and improved synaptic and cognitive outcomes. Gene therapy to restore PQBP1 also rescued synaptic and cognitive deficits. Furthermore, restoring specific downstream genes also produced beneficial effects.
Overall, this study clarifies how a high-fat diet can impair brain function through altered gene regulation and synaptic communication. The findings provide a foundation for exploring new strategies to counter diet-associated cognitive impairment and highlight PQBP1-dependent RNA splicing as a potential therapeutic target.
"By uncovering how diet-related changes in PQBP1 affect RNA splicing and synaptic function, our study highlights a potential new direction for developing interventions targeting conditions involving cognitive dysfunction," says Okazawa. Further research will deepen our understanding of how diet affects brain function and potentially help translate these findings into therapeutic strategies.
Publication details
Yong Huang et al., PQBP1-dependent alternative RNA splicing underlies high calorie diet-induced cognitive impairment, Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03868-x
Journal information: Molecular Psychiatry
Key medical concepts
Alternative SplicingCognitive DysfunctionDiet, High-FatPioglitazone
Clinical categories
NeurologyHealthy living Provided by Institute of Science Tokyo Who's behind this story?
Swati Mestri
Swati Mestri holds a bachelor's degree in Electronics Engineering and has worked as a content editor since 2019. She has experience editing research documents across technology, health care, and materials science, and has a particular interest in technology and space. Full profile →
Robert Egan
Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →
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