As ARNT2 is enriched in neurons, and Arnt2−/− mice phenocopy the loss of PVH neurons observed in Sim1−/− mice, it is hypothesized that disruption of the SIM1/ARNT2 axis drives obesity in humans with or without clinical features that are also described in Prader-Willi-like (PWL) syndrome. This evidence concerns the gene ARNT2 and obesity due to melanocortin 4 receptor deficiency.