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It shares sequence homology with sarcolipin (SLN), which negatively regulates the sarco(endo)plasmic reticulum Ca<jats:sup>2+<\/jats:sup>\u2010ATPase (SERCA) that maintains energy homeostasis in muscles. Here, we examined whether NNAT could uncouple the Ca<jats:sup>2+<\/jats:sup> transport activity of SERCA from ATP hydrolysis, similarly to SLN. NNAT significantly reduced Ca<jats:sup>2+<\/jats:sup> uptake without altering SERCA activity, ultimately lowering the apparent coupling ratio of SERCA. This effect of NNAT was reversed by the adenylyl cyclase activator forskolin. Furthermore, soleus muscles from high fat diet (HFD)\u2010fed mice showed a significant downregulation in NNAT content compared with chow\u2010fed mice, whereas an upregulation in NNAT content was observed in fast\u2010twitch muscles from HFD\u2010 versus chow\u2010 fed mice. Therefore, NNAT is a SERCA uncoupler in cells and may function in adaptive thermogenesis.<\/jats:p>","DOI":"10.1002\/1873-3468.14213","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T03:35:41Z","timestamp":1635132941000},"page":"2756-2767","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Neuronatin promotes SERCA uncoupling and its expression is altered in skeletal muscles of high\u2010fat diet\u2010fed mice"],"prefix":"10.1002","volume":"595","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9196-0757","authenticated-orcid":false,"given":"Jessica L.","family":"Braun","sequence":"first","affiliation":[{"name":"Department of Kinesiology Brock University St. Catharines Canada"},{"name":"Centre for Bone and Muscle Health Brock University St. Catharines Canada"},{"name":"Centre for Neuroscience Brock University St. Catharines Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen C. 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