Although a subset of the phenotypes (e.g. improved glucose tolerance and insulin sensitivity) in ADAM17 mutant mice can be attributed to impaired TNF cleavage [40,41], the equal susceptibility of these TNF-null mice to obesity compared to WT mice [42] shows that the negative impact of ADAM17 on energy expenditure cannot be attributed exclusively to TNF [40,41]. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.