Severe mitochondrial dysfunction which is induced by CRIF1 homodeficiency in hypothalamic proopiomelanocortin (POMC) neurons unexpectedly leads to maturity-onset obesity, reduced energy expenditure, and glucose intolerance resembling features of human diabetes mellitus type 2 (DM2) in both male and female mice. Here, GADD45GIP1 is linked to type 2 diabetes mellitus.