Demonstrating the protective effect of myeloid Fas ablation on skeletal muscle insulin sensitivity in the context of diet-induced obesity and leptin-deficiency as well as in response to LPS suggests the possibility that myeloid Fas is not an initiator of inflammation in obesity, but rather an ‘intermediate integrator’ that may respond to inflammatory cues like increased plasma LPS levels in the obese state. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.