We propose that during obesity, Ca2+ binding-led conformational changes in c-Cbl induce dissociation or altered association of c-Cbl and TRAF6, whereafter TAK1 competes with c-Cbl to bind to TRAF6, thereby facilitating and stabilizing the formation of the TRAF6-TAK1 complex. This evidence concerns the gene CBL and obesity due to melanocortin 4 receptor deficiency.