High-fat diet impairs mouse cognition through altered RNA splicing

A high-fat diet reduced expression of the nuclear protein PQBP1 in the cerebral cortex of mice, disrupting the alternative splicing of genes involved in synaptic communication and contributing to cognitive impairment. The experimental study, led by researchers at the Institute of Science Tokyo in Japan with collaborators at Teikyo University and the University of California, Irvine, was published in Molecular Psychiatry on September 12, 2026. It identifies a molecular pathway that may help explain how calorie-rich diets can affect brain function, although the findings do not establish a treatment or demonstrate clinical benefits in people.

The team first fed mice a high-fat diet and observed lower PQBP1 levels in the cerebral cortex, a brain region involved in cognitive functions. PQBP1 regulates alternative RNA splicing, a process that allows a single gene to generate different RNA transcripts and potentially different protein isoforms. The researchers linked the diet-associated reduction in PQBP1 to suppressed PPARγ-mediated transcription of the PQBP1 gene. They also implicated insulin-related signaling as a possible upstream mechanism, but the supplied study description does not establish whether that signaling change is a direct cause of the reduction.

To examine the cellular consequences, the scientists used RNA-sequencing-based analyses to compare splicing patterns in mice fed a high-fat diet for one or six weeks with those in mice lacking PQBP1 in neurons. Both conditions shared changes in the alternative splicing of specific genes associated with synaptic function. Additional experiments indicated that abnormal splicing of these downstream genes was associated with abnormalities in synaptic structure and function. These molecular and cellular changes occurred alongside impaired cognitive performance, linking diet-associated changes in gene regulation with impaired neuronal communication. The work was conducted in mice, and the reported effects should therefore not be interpreted as evidence that the same pathway causes cognitive decline in humans.

The researchers also tested whether selected molecular changes could be reversed in mice. Pioglitazone, a diabetes drug that activates PPARγ, restored PQBP1 levels in mice receiving the high-fat diet. It also corrected abnormal RNA splicing in key synapse-related genes and improved synaptic and cognitive outcomes. A separate gene-therapy approach that restored PQBP1 rescued synaptic and cognitive deficits, while restoring particular downstream genes also produced beneficial effects. These interventions were tested in the same experimental setting rather than in a human clinical trial, and their results show that the measured pathway can be modulated in affected mice. The findings identify PQBP1-dependent alternative RNA splicing as a potential therapeutic target for further investigation, but the study does not establish that pioglitazone or gene therapy is safe or effective for diet-associated cognitive impairment in people.

Subject of Research: Experimental mouse study of PQBP1-dependent RNA splicing in high-fat diet-induced cognitive impairment

Article Title: Exploring the correlation between high calorie diet and cognitive impairment

Article References: Exploring the correlation between high calorie diet and cognitive impairment. Original publication (Bibliographic details unavailable.)

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Keywords: high-fat diet, cognitive impairment, PQBP1, RNA splicing, synaptic dysfunction, cerebral cortex, PPARγ, pioglitazone, gene therapy, mouse study, Exploring, correlation