The protective effect of genistein against ER stress‐mediated neuronal degeneration in db/db mice

Insulin resistance is shown to be associated with an increased risk for Alzheimer's disease. Therefore, we investigated the molecular mechanism involved in insulin resistance‐mediated neuronal degeneration in db/db mice and determined the neuroprotective effect of genistein, which has been shown to prevent ER stress‐mediated neurotoxicity in neuronal cells. Both male C57BL/6‐ db/db and db/+ were fed either methionine‐choline‐sufficient (MCS) diet or lipogenic methionine‐choline‐deficient (MCD) diet for 6 wks. An additional group of db/db was fed MCD diet supplemented with genistein (GEN, 0.5g/kg diet). Although we observed a significant induction of hepatosteatosis in mice fed MCD diet, MCD diet significantly reduced serum glucose, cholesterol, and insulin levels. ER stress was significantly induced in the brain of db/+ mice fed MCD diet and db/db mice. GEN significantly alleviated ER stress in db/db mice. We observed the significantly increased tau hyperphosphorylation in the cortex and hippocampus of db/db mice, which was reduced by GEN. GEN significantly reduced serum insulin level and increased brain insulin signaling determined by Akt and GSK3β phosphorylation. In conclusion, our results demonstrate that GEN may alleviate insulin resistance and ER stress‐mediated neuronal degeneration in db/db mice fed MCD diet. Supported by Korea Research Foundation.