To sum up, our findings provide several lines of evidence demonstrating that fasting drives the lipid droplet accumulation in obese mice, which is mediated by the AMPK-PPARγ-Cidec signaling axis, contributing to understand the molecular basis of the fasting effect on the obesity and develop the feasible strategies to prevent and treat the obesity in humans. Here, PRKAA2 is linked to obesity due to melanocortin 4 receptor deficiency.