As soon as a healthy liver fails to clear gut-derived endotoxins (which appear in the portal vein even in health), it might have consequences for the host as presence of systemic endotoxin results in ‘metabolic endotoxaemia’ causing potentially chronic metabolic inflammation as observed in obesity and related disorders.85 86 Endotoxin exerts its proinflammatory functions via various mechanisms including activation of toll-like receptor 4 (TLR4) and various strategies besides the above discussed immunosuppressive macrophages might be needed to counteract and control endotoxin exposure. This evidence concerns the gene TLR4 and obesity due to melanocortin 4 receptor deficiency.