Science Tokyo uncovers how high-calorie diets impair brain function

A research team including Specially Appointed Professor Hitoshi Okazawa and Project Associate Professor Hikari Tanaka of the Center for Brain Integration Research, Institute of Biomedical Engineering, Institute of Science Tokyo, in collaboration with Specially Appointed Professor Masanobu Kano of Teikyo University's Advanced Comprehensive Research Organization and Professor Albert La Spada of the University of California, Irvine, has elucidated the molecular mechanisms by which long-term consumption of a high-calorie diet impairs brain function and demonstrated a potential therapeutic strategy. The findings were published in Molecular Psychiatry.

High-calorie states have been shown in many previous studies to impair brain function. Persistent high-calorie states are also risk factors for diabetes and Alzheimer's disease. However, the mechanisms by which high-calorie states impair brain function, and how such effects might be prevented or treated, have remained unclear.

The present study began with the discovery that both short-term and long-term high-calorie states reduce the transcription of PQBP1, a factor involved in cognitive function, in brain tissue. This reduction was observed only in neurons and not in astrocytes or microglia.

The researchers found that the resulting decrease in PQBP1 protein suppresses the RNA splicing of synapse-related molecules, one of PQBP1's major functions. This leads to abnormalities in synapse-related proteins, ultimately causing a reduction in synapse numbers and impairing synaptic function.

The study also revealed that PQBP1 transcription is regulated by the transcription factor PPARγ, which is known to play important roles in a variety of biological processes, including diabetes. Furthermore, the insulin signaling pathway activated under high-calorie conditions was found to phosphorylate PPARγ and inhibit its transcriptional activity, thereby reducing PQBP1 expression.

The research team also used RNA-seq analysis to identify synapse-related molecules that are most strongly affected by changes in RNA splicing caused by reduced PQBP1 levels.

The researchers then tested several therapeutic approaches in mice whose cognitive function had declined as a result of a high-calorie diet. These included administration of an oral antidiabetic drug that enhances PPARγ activity, gene therapy targeting PQBP1, and gene therapy using synapse-related molecules regulated by PQBP1.

Experiments using animal models demonstrated that these treatments improved both synaptic dysfunction and cognitive impairment in mice fed a high-calorie diet.

The findings indicate that a major mechanism underlying cognitive decline associated with high-calorie states is the reduction of PQBP1 protein levels, which leads to abnormalities in synaptic function and subsequent cognitive impairment.

Furthermore, the study suggests that regulating PQBP1 levels may provide a basis for developing new preventive and therapeutic approaches for brain dysfunction associated with overeating, obesity, and diabetes.

Because some of the treatments examined in this study involve antidiabetic drugs that are already commercially available, the researchers expect that their potential application in humans, as well as that of related pharmaceuticals, will be investigated in future studies.

In addition, because the PQBP1 gene has already been implicated in intellectual disability and Alzheimer's disease, similar oral medications and gene therapies may also have potential applications for these disorders, although further research will be needed.

Journal Information
Publication: Molecular Psychiatry
Title: PQBP1-dependent alternative RNA splicing underlies high calorie diet-induced cognitive impairment
DOI: 10.1038/s41380-026-03868-x