Although reduced PKB/Akt activation might not fully explain the effects we observed on GLUT4 translocation and glucose uptake in cells, these results per se, as well as the strong negative association of SIK2 expression with HOMA-IR, suggest that downregulation of SIK2 and SIK3 in obesity might contribute to the development of insulin resistance in vivo—at least in adipose tissue. Here, SIK2 is linked to obesity due to melanocortin 4 receptor deficiency.