While much discussion in the literature has suggested that mitochondrial dysfunction linked to the pathogenesis and/or progression of metabolic disease can be explained by downstream effects of mitochondria generated reactive oxygen species, our results indicate that TNAP itself may influence mitochondrial function, which could be relevant to the worldwide epidemics of obesity, diabetes, and metabolic syndrome. Here, ALPL is linked to obesity due to melanocortin 4 receptor deficiency.