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Here, we investigated whether the obestatin\/GPR39 system, an autocrine signalling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against chronic glucocorticoid\u2010induced muscle atrophy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we used an <jats:italic>in vivo<\/jats:italic> model of muscle atrophy induced by the synthetic glucocorticoid dexamethasone to examine the liaison molecules that define the interaction between the glucocorticoid receptor and the obestatin\/GPR39 systems. The findings were extended to <jats:italic>in vitro<\/jats:italic> effects on human atrophy using human KM155C25 myotubes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>KLF15 and FoxO transcription factors were identified as direct targets of obestatin signalling in the control of proteostasis in skeletal muscle. The KLF15\u2010triggered gene expression program, including atrogenes and FoxOs, was regulated via KLF15 ubiquitination by the E3 ubiquitin ligase NEDD4. Additionally, a specific pattern of FoxO post\u2010translational modification, including FoxO4 phosphorylation by Akt pathway, was critical in the regulation of the ubiquitin\u2013proteasome system. The functional cooperativity between Akt and NEDD4 in the regulation of FoxO and KLF15 provides integrated cues to counteract muscle proteostasis and re\u2010establish protein synthesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The effective control of FoxO activity in response to glucocorticoid is critical to counteract muscle\u2010related pathologies. These results highlight the potential of the obestatin\/GPR39 system to fine\u2010tune the effects of glucocorticoids on skeletal muscle wasting.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12677","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T12:08:54Z","timestamp":1615291734000},"page":"493-505","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Obestatin signalling counteracts glucocorticoid\u2010induced skeletal muscle atrophy via NEDD4\/KLF15 axis"],"prefix":"10.1002","volume":"12","author":[{"given":"Tania","family":"Cid\u2010D\u00edaz","sequence":"first","affiliation":[{"name":"Laboratorio de Endocrinolog\u00eda Celular, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS) Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS)  Trav. 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