Feeding a low-carbohydrate and high-protein diet diminishes working memory in healthy mice: possible involvement of miR-539-3p/Lrp6/Igf1r axis in the hippocampus

A low-carbohydrate and high-protein (LC-HP) diet demonstrates favorable impacts on metabolic parameters, albeit it leads to a decline in hippocampal function among healthy mice. The reduction in working memory induced by LC-HP diets is attributed to the decreased expression of hippocampal IGF-1 receptor (IGF-1R). However, the precise mechanisms underlying this phenomenon remain unexplored. Here, we investigated that by analyzing alterations in hippocampal miRNA profiles. C57BL/6 mice were divided into the LC-HP diet-fed group (25.1% carbohydrate, 57.2% protein, and 17.7% fat as percentages of calories) and the control diet-fed group (58.9% carbohydrate, 24.0% protein, and 17.1% fat as percentages of calories). After four weeks, all mice underwent the Y-maze test, followed by analyses of mRNA and miRNA expressions in the hippocampus. Our investigation revealed that feeding the LC-HP diet suppressed working memory function and hippocampal Igf1r mRNA levels in mice. Sequencing of miRNA demonstrated 17 upregulated and 27 downregulated miRNAs in the hippocampus of LC-HP diet-fed mice. Notably, upregulation of miR-539-3p, predicted to modulate Igf1r gene expression, was observed. Consequently, we found decreased hippocampal mRNA levels of low-density lipoprotein receptor-related protein 6 (Lrp6), a gene modulated by miR-539-3p, in mice fed the LC-HP diet. Furthermore, a significant positive correlation was observed between Lrp6 and Igf1r mRNA levels in the hippocampus. These findings suggest that LC-HP diets may suppress hippocampal function via the miR-539-3p/Lrp6/Igf1r axis, offering a potential target for nutritional strategies to preserve hippocampal health.