Homozygous Sim1 mice die perinatally (Michaud et al., 1998), but heterozygous mutants exhibit hyperphagic obesity, increased body fat percentage (Holder et al., 2004; Michaud et al., 2001), as well as higher levels of POMC expression and resistance to α-MSH (Kublaoui et al., 2006). Here, POMC is linked to obesity due to melanocortin 4 receptor deficiency.