We have previously generated Pellino3-deficient mice to identify important roles for Pellino3 as a negative regulator of TLR3 signaling46 and TNF-induced cell killing47, a mediator of NOD2 signaling in the gut48 and a critical regulator of obesity-induced expression of IL-1β and insulin resistance49. Here, PELI3 is linked to obesity due to melanocortin 4 receptor deficiency.