Blocking the extracellular action of MIF by a neutralizing anti-MIF antibody significantly prevented the development of HFD-induced obesity which is associated with reduced adipose AMPK/JNK signaling and reversed HSL in HFD mice, further suggesting a role for extracellular MIF in downregulating HSL. This evidence concerns the gene MAPK8 and obesity due to melanocortin 4 receptor deficiency.