Irs2 is a paralog of Irs1 encoding insulin receptor substrate-2, which is similarly phosphorylated by insulin receptor kinase and linked to diabetes (Almind et al., 1999; Mammarella et al., 2000), but additionally has haplotypes associated with severe obesity (Lautier et al., 2003). Here, IRS2 is linked to obesity due to melanocortin 4 receptor deficiency.