We demonstrated that Aldh2 KI mice carrying the East Asian-specific Glu504Lys mutation were more prone to develop diet-induced obesity, fatty liver, insulin resistance and glucose intolerance than WT mice Importantly, the ALDH2 activator AD-9308 increased both the catalytic activity of WT and mutant enzyme, reduced serum 4-HNE levels, and effectively alleviated diet-induced obesity, fatty liver, insulin resistance, and glucose intolerance in both Aldh2 KI and WT mice in a dose-dependent manner. Here, ALDH2 is linked to Glucose intolerance.