As a common energy sensor, AMPK has been demonstrated to play a vital role in a range of diseases including obesity and T2DM.[45, 46] Of note, the crosstalk between AMPK and epigenetic events has been uncovered recently.[41, 47] Evidence showed that the activity of DNMT1 might be regulated by AMPK.[41] Here we fill in the gap by showing that free fatty acid could promote DNMT1 mitochondrial translocation via activation of AMPK, thereby induce ND6 hypermethylation, mitochondrial dysfunction and IR. The gene discussed is DNMT1; the disease is obesity due to melanocortin 4 receptor deficiency.