Fatty diet may harm mouse cognition through RNA-splicing changes
In mice, a high-calorie diet reduced levels of the nuclear protein PQBP1, altering RNA splicing needed for synaptic function. The animals showed synaptic abnormalities and cognitive impairment. Restoring PQBP1 with pioglitazone or AAV-PQBP1 improved synaptic and cognitive outcomes.
In mice, a calorie-dense high-fat regimen lowered PQBP1 in the cerebral cortex. The drop was tied to reduced PPARγ-driven transcription of the PQBP1 gene, with insulin-related signaling suggested as a possible upstream factor. Researchers compared RNA splicing after one or six weeks of diet with neuronal PQBP1 loss and found overlapping changes in genes tied to synaptic function.
Those splicing shifts accompanied structural and functional synaptic defects and poorer cognition. Restoring PQBP1—via pioglitazone or AAV-PQBP1—improved synaptic and cognitive measures, pointing to PQBP1-dependent splicing as a possible therapeutic target.
For people consuming calorie-rich diets, especially those with obesity or metabolic disorders, this mouse work may reinforce concerns about cognitive risk, though it does not establish human causation. It could shape future research on splicing-based therapies and biomarkers, potentially affecting patients with diet-linked cognitive decline, their caregivers, and health systems weighing prevention and treatment options. Any societal benefit would depend on replication in humans and clinical testing.