We found that BACE2 knock-out (BKO) mice fed with a HFD presented an exacerbated body weight gain, hyperphagia, hyperinsulinemia, and insulin resistance compared to their wild-type (WT) littermates, indicating that BACE2 suppression aggravates the adverse metabolic effects induced by obesogenic diets. Here, BACE2 is linked to hyperinsulinism.