Overnutrition and obesity promote a pro-inflammatory milieu in adipose tissue and other metabolically relevant tissues, and key extracellular mediators of inflammation, including cytokines like TNFα and IL-1β, and TLR ligands like LPS and cell-free DNA, are well established as endogenous drivers of insulin resistance38–41. This evidence concerns the gene TNF and obesity due to melanocortin 4 receptor deficiency.