In this study, we used Aldh2 homozygous knock-in (KI) and heterozygous knock-in (HE) mice, which mimic the East Asian-specific Glu504Lys mutation, to evaluate the effect of this mutation on diet-induced obesity, glucose homeostasis, fatty liver, and serum lipids, and tested the therapeutic effect of a feasible ALDH2 activator AD-5591 by dosing its prodrug AD-9308 for treating metabolic disorders. This evidence concerns the gene ALDH2 and metabolic disease.