Starting with the demonstration of tumor necrosis factor (TNF) production in mouse adipose tissue, going through the strong association detected between circulating TNF and insulin resistance to the final discovery that TNF inhibitors and weight loss are able to reverse insulin resistance in the same model, the cause-effect link between obesity, chronic inflammation, and metabolic derangements was lastly defined [12]. Here, TNF is linked to obesity due to melanocortin 4 receptor deficiency.