Here, we find that mice housed at thermoneutrality have elevations in mast cells, Tph1 and serotonin in WAT that are associated with reductions in Ucp1. In mice fed a high-fat diet, genetic removal of Tph1 in mast cells from two distinct mouse models elevates basal metabolic rate, increases WAT Ucp1 and protects mice from obesity, insulin resistance and fatty liver disease compared to relevant controls. Here, TPH1 is linked to obesity due to melanocortin 4 receptor deficiency.