First, rather than the expected increase in leptin/insulin signaling commensurate with increased caloric intake and adiposity, obesity has been associated with reduced sensitivity to leptin/insulin (Arase et al., 1988; Lin et al., 2001; Wang et al., 2001b; Myers, 2004; Figlewicz et al., 2006; Enriori et al., 2007; Davis et al., 2010a; Figlewicz and Sipols, 2010; Koek et al., 2012). Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.