To compensate for the insulin resistance in peripheral tissues, the demand for insulin synthesis is increased in obesity, where the excessive nutrients intake overloads ER protein folding capacity and thereby activates unfolded protein response (UPR) and PKR-like ER-associated kinase (PERK), resulting in inhibition of protein translation and insulin deficiency eventually (108). This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.