However, HMGB1 is also secreted by macrophages and damaged cells and mediates systemic inflammation45 by signalling through receptors such as the Receptor for Advanced Glycation End-products (RAGE) and Toll-Like receptors (TLRs), both of which have been implicated in obesity-driven inflammation and DPN46–49. Here, HMGB1 is linked to obesity due to melanocortin 4 receptor deficiency.