MT-RNR1 and obesity due to melanocortin 4 receptor deficiency: MOTS-c, acting mostly via skeletal muscle, targets the methionine-folate cycle and connected de novo purine biosynthesis, increases the AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) levels and activates AMPK, thus ameliorating IR and diet-induced obesity [3].