Researchers at Institute of Science Tokyo published a study in Molecular Psychiatry on September 12, 2026, revealing that high-fat diets reduce nuclear protein PQBP1 expression in the cerebral cortex. This reduction disrupts alternative RNA splicing, triggering synaptic abnormalities and cognitive impairment in mice, which researchers successfully reversed using pioglitazone or gene therapy.
High-Fat Diets Drop PQBP1 Levels and Impair Cognition
- What scientists discovered: Consuming a calorie-rich, high-fat diet drops the levels of a specific protein called PQBP1 in the brain’s cerebral cortex.
- Why it alters brain function: Lower PQBP1 messes up alternative RNA splicing—the cellular process cells use to build proteins for neuron communication—leading directly to synaptic dysfunction.
- How it can be fixed: Treating mice with the diabetes medication pioglitazone or using targeted gene therapy successfully restored PQBP1 levels and reversed cognitive deficits.
Molecular Disruption in the Cerebral Cortex
While calorie-rich diets are well-documented contributors to obesity and metabolic disorders such as diabetes, growing clinical evidence indicates effects on central nervous system function. Studies link high-calorie nutrition to diminished cognitive performance and elevated neurodegenerative risks, including Alzheimer’s disease. Despite these epidemiological trends, the precise cellular cascades connecting metabolic overconsumption to neuronal decline have remained poorly understood.
Previous research primarily implicated systemic inflammation and insulin resistance. However, the exact neuronal changes underlying diet-associated cognitive impairment required deeper mechanistic evaluation. To address this knowledge gap, a collaborative research team investigated the physiological impacts of high-fat nutrition using murine models. Led by Specially Appointed Professor Hitoshi Okazawa and Project Associate Professor Hikari Tanaka from the Center for Brain Integration Research at the Institute of Science Tokyo, alongside Specially Appointed Professor Masanobu Kano of Teikyo University and Professor Albert R. La Spada of the University of California Irvine, the group set out to map the missing molecular links.
The investigators focused on PQBP1, a regulatory protein governing alternative RNA splicing. Alternative splicing is a biological mechanism allowing a single gene to encode multiple distinct transcripts and protein isoforms. Following a high-fat dietary regimen, researchers observed a reduction of PQBP1 levels specifically within the cerebral cortex, the anatomical brain region governing higher cognitive processes. The study links this localized reduction to suppressed PPARγ-mediated transcription of the PQBP1 gene, pointing to insulin-related signaling pathways as a potential upstream driver.
Splicing Aberrations Trigger Structural Abnormalities in Synapses
To determine how diminished PQBP1 levels translate to cellular damage, the team performed comprehensive RNA-sequencing analyses. They compared alternative RNA splicing profiles in mice maintained on a high-fat diet for one to six weeks against mice engineered with neuron-specific PQBP1 deficiencies. The analysis identified overlapping splicing aberrations affecting specific target genes critical for synaptic function and neuronal communication.
Abnormal alterations in these targeted splicing transcripts directly triggered structural and functional abnormalities within cerebral synapses. This breakdown in neuronal architecture manifested as measurable cognitive impairment in the experimental subjects. “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,” stated Professor Okazawa, according to Mirage News.
| Experimental Intervention | Targeted Mechanism | Observed Outcome |
|---|---|---|
| High-Fat Diet (1–6 Weeks) | Suppressed PPARγ-mediated transcription; reduced PQBP1 | Altered alternative RNA splicing, synaptic defects, cognitive impairment |
| Pioglitazone Treatment | Activates PPARγ, recovers PQBP1 protein levels | Rectified RNA splicing, restored synaptic and cognitive outcomes |
| AAV-PQBP1 Gene Therapy | Directly restores PQBP1 expression in neurons | Rescued synaptic structure and reversed cognitive deficits |
Therapeutic Reversal via Diabetes Pharmacology
Crucially, the research team tested whether these diet-induced neurological deficits could be halted or reversed. In mice subjected to a high-fat diet, administration of pioglitazone—a medication used in diabetes management that activates the PPARγ receptor—successfully recovered PQBP1 levels. This pharmacological intervention rectified abnormal RNA splicing in key synapse-related genes, yielding tangible improvements in synaptic plasticity and cognitive test outcomes.
Complementing the pharmacological approach, targeted gene therapy utilizing adeno-associated virus (AAV) vectors to restore PQBP1 expression similarly rescued synaptic and cognitive deficits. Restoring specific downstream target genes independently produced beneficial therapeutic effects. “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,” Professor Okazawa noted.
Future Research Targets Therapeutic Strategies for Humans
Future investigations will focus on deepening the scientific community’s understanding of how nutritional intake influences central nervous system regulation, paving the way toward clinically viable therapeutic strategies for humans.
References
- Okazawa, H., Tanaka, H., Kano, M., La Spada, A.R., et al. (2026). High-fat diet-induced reduction of PQBP1 causes synaptic and cognitive impairment via alternative splicing disruption. Molecular Psychiatry.
- Institute of Science Tokyo. (2026). High-Calorie Diet Linked to Cognitive Impairment. Published via Mirage News.
