After over a decade of study of the physiological function of MKP-1 in the regulation of metabolic homeostasis in mice and more recently in humans, these data collectively point to the notion that chronic upregulation of MKP-1 in skeletal muscle is part of a stress response mediated by p38 MAPK and JNK activities and this may play an important contributing role in the development of insulin resistance, T2D and obesity. This evidence concerns the gene DUSP1 and obesity due to melanocortin 4 receptor deficiency.