The mechanism by which GPR21 exerts its metabolic phenotype is difficult to pinpoint, with Osborn et al. suggesting that GPR21 may be a novel control point coordinating macrophage pro-inflammatory activity in the context of obesity-induced insulin resistance, thus hypothesising an indirect role for this receptor in the induction of insulin resistance. Here, GPR21 is linked to obesity due to melanocortin 4 receptor deficiency.