While a genetic deficiency of CD40-TRAF2/3/5 signaling aggravates obesity and promotes metabolic dysfunction and hepatic steatosis, mice lacking the CD40-TRAF6 binding site are protected from obesity-associated complications, arguing for opposite roles of CD40-TRAF2/3/5 and CD40-TRAF6 signaling in obesity-associated metabolic dysregulation. Here, TRAF6 is linked to obesity due to melanocortin 4 receptor deficiency.