Linarin from Lycii cortex alleviates high-fat diet-induced cognitive impairment by improving hippocampal insulin signaling and synaptic plasticity.

Linarin, a natural flavonoid, has been reported to exert antioxidant and anti-diabetic effects. However, its role in obesity-related cognitive dysfunction remains unclear. Here, we investigated whether linarin protects against high-fat diet (HFD)-induced cognitive impairment by restoring hippocampal insulin signaling and synaptic plasticity. HFD-fed mice were orally administered linarin at 100 mg/kg/d, and an insulin-resistance (IR)-like model was established in primary hippocampal neurons. Linarin reduced blood glucose and plasma free fatty acid levels in HFD-fed mice and restored hippocampal insulin levels. In parallel, linarin increased the phosphorylation of IRS-1, Akt, and GSK-3β in the hippocampus, accompanied by improved spatial memory, restored hippocampal long-term potentiation, increased dendritic spine density in the CA1 region, and elevated expression of synapse-related proteins, including PSD95, GluN1, and GluN2B. In primary hippocampal neurons exposed to IR conditions, linarin at 7.5 µM restored insulin signaling, promoted neurite outgrowth, and improved dendritic spine morphology. Furthermore, pharmacological inhibition of IRS/Akt/GSK-3β signaling with LY294002 attenuated the protective effects of linarin on dendritic spine morphology in IR neurons. Collectively, these findings suggest that linarin alleviates HFD-induced cognitive dysfunction, at least in part, by improving hippocampal insulin sensitivity and facilitating synaptic function, indicate linarin could be a possibly therapeutic agent against obesity-associated cognitive impairment.