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This study aimed to explore the role of endoplasmic reticulum (ER) stress in mediating obesity\u2010induced diaphragmatic dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A pulmonary function test and ultrasound were applied to evaluate diaphragmatic function and magnetic resonance imaging was applied to measure diaphragmatic lipid deposition in human patients. For the mechanistic study, obese mice were introduced to a high\u2010fat diet for 24\u2009weeks, followed by diaphragmatic ultrasound measurement, transcriptomic sequencing, and respective biochemical analysis. Automatic force mapping was applied to measure the mechanical properties of C2C12 myotubes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>People with obesity showed significant diaphragm weakness and lipid accumulation, which was further confirmed in obese mice. Consistently, diaphragms from obese mice showed altered gene expression profile in lipid metabolism and activation of ER stress response, indicated by elevated protein kinase R\u2010like ER kinase (PERK) and c\u2010Jun NH<jats:sub>2<\/jats:sub>\u2010terminal kinase (JNK) activation. In C2C12 myotubes, inhibition of PERK or JNK signaling abrogated lipotoxicity\u2010induced intracellular lipid deposition and insulin resistance. Inhibition of JNK signaling reversed lipotoxicity\u2010induced impairment of elasticity in C2C12 myotubes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These data suggest that ectopic lipid deposition impairs the diaphragmatic function of people with obesity. Activation of PERK\/JNK signaling is involved in the pathogenesis of lipotoxicity\u2010induced diaphragm weakness in obesity hypoventilation syndrome.<\/jats:p><\/jats:sec>","DOI":"10.1002\/oby.23809","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T07:17:59Z","timestamp":1689923879000},"page":"2076-2089","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<scp>ER<\/scp> stress aggravates diaphragm weakness through activating <scp>PERK<\/scp>\/<scp>JNK<\/scp> signaling in obesity hypoventilation syndrome"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6908-9889","authenticated-orcid":false,"given":"Xiaoxin","family":"Xiang","sequence":"first","affiliation":[{"name":"Department of Endocrinology &amp; Metabolism, Medical Center for Comprehensive Weight Control The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou Guangdong 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