We found that the absence of 4-1BB-mediated inflammatory signaling increased activation of AMPK and transcript levels of the oxidative genes or proteins (COX IV) in the skeletal muscle, indicating that the absence of 4-1BB signal may attenuate obesity-induced muscle oxidative metabolic dysfunction through activation of the AMPK-PGC-1α pathway, leading to protection of atrophic response. This evidence concerns the gene COX4I1 and obesity due to melanocortin 4 receptor deficiency.