Possible Involvement of Hippocampal miR‐539‐3p/<i>Lrp6</i>/<i>Igf1r</i> Axis for Diminished Working Memory in Mice Fed a Low‐Carbohydrate and High‐Protein Diet

A low-carbohydrate and high-protein (LC-HP) diet demonstrates favorable impacts on metabolic parameters, albeit it leads to a decline in hippocampal function with the decreased expression of hippocampal insulin-like growth factor-1 receptor (IGF-1R) among healthy mice. However, the precise mechanisms underlying this phenomenon remain unexplored. Eight-week-old male 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; n = 10) and the control diet-fed group (58.9% carbohydrate, 24.0% protein, and 17.1% fat; n = 10). After 4 weeks, all mice underwent the Y-maze test, followed by analyses of hippocampal mRNA and miRNA expressions. We revealed that feeding the LC-HP diet suppressed working memory function and hippocampal Igf1r mRNA levels in mice. Sequencing of hippocampal miRNA demonstrated 17 upregulated and 27 downregulated miRNAs in the LC-HP diet-fed mice. Notably, 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.