Skeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning

Abstract Skeletal muscle is the largest metabolic and endocrine organ. It secretes various peptides that contribute to regulating body energy homeostasis by communicating with other metabolic organs. However, it is unknown whether muscle-secreted lipids exert a similar function. Myod is specifically expressed in skeletal muscle. Here, we report that genetic deletion of Myod in mice enhanced the oxidative metabolism of muscle and, intriguingly, rendered the mice resistant to HFD-induced obesity. By performing lipidomic analysis in muscle-conditioned medium and serum, we identified 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as a muscle-released lipid that is responsible for MyoD-orchestrated body energy homeostasis in Myod KO mice. Functionally, the administration of DLPC significantly ameliorated HFD-induced obesity in mice. Mechanistically, DLPC was found to induce white adipose browning via lipid peroxidation-mediated p38 signaling in mice. Collectively, our findings uncover DLPC as the first muscle-derived lipokine and suggest that it might have clinical potential for treating obesity in humans.