Here, we demonstrate that the absence of a 4-1BB-mediated signal reduces obesity-induced atrophic responses in skeletal muscle by suppressing NF-κB activation, and that this is associated with increased activation of adenosine monophosphate-activated protein kinase (AMPK) and mitochondrial oxidative metabolism accompanied by increased oxidative fiber type in the skeletal muscle. The gene discussed is NFKB1; the disease is obesity due to melanocortin 4 receptor deficiency.