The HIF-mediated reprogramming of energy metabolism, leading to promotion of insulin-independent glucose intake and upregulation of the non-oxygen demanding glycolytic metabolism and downregulation of oxidative phosphorylation, has been shown to mediate protection against obesity and metabolic syndrome resulting in reduced body weight and adiposity, lower serum cholesterol levels, less white adipose tissue inflammation and improved glucose tolerance and insulin sensitivity in human and mice, also during gestation13,33,34. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.