Initially, tumor necrosis factor-α (TNFα) was considered a possible therapeutic target because its adipose tissue expression was increased in multiple rodent-obesity models and TNFα decreased insulin signaling in insulin sensitive tissues (Hotamisligil et al., 1993, 1994a,b; Hotamisligil and Spiegelman, 1994). Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.