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dc.contributor.authorJackisch, Laura
dc.contributor.authorMurphy, Alice M
dc.contributor.authorKumar, Sudhesh
dc.contributor.authorRandeva, Harpal
dc.contributor.authorTripathi, Gyanendra
dc.contributor.authorMcTernan, Philip G
dc.date.accessioned2020-06-17T09:48:00Z
dc.date.available2020-06-17T09:48:00Z
dc.date.issued2020-05-15
dc.identifier.citationJackisch, L., Murphy, A.M., Kumar, S., Randeva, H., Tripathi, G. and McTernan, P.G., (2020). 'Tunicamycin-induced Endoplasmic Reticulum stress mediates mitochondrial dysfunction in human adipocytes'. The Journal of Clinical Endocrinology & Metabolism, pp. 1-41.
dc.identifier.pmid32413131
dc.identifier.doi10.1210/clinem/dgaa258
dc.identifier.urihttp://hdl.handle.net/10545/624887
dc.description.abstractDysfunctional ER and mitochondria are known to contribute to the pathology of metabolic disease. This damage may occur, in part, as a consequence of ER-mitochondria cross-talk in conditions of nutrient excess such as obesity. To date insight into this dynamic relationship has not been characterised in adipose tissue. Therefore, this study investigated whether ER stress contributes to the development of mitochondrial inefficiency in human adipocytes from lean and obese participants. Human differentiated adipocytes from Chub-S7 cell line and primary abdominal subcutaneous adipocytes from lean and obese participants were treated with tunicamycin to induce ER stress. Key parameters of mitochondrial function were assessed, including mitochondrial respiration, membrane potential (MMP) and dynamics. ER stress led to increased respiratory capacity in a model adipocyte system (Chub-S7 adipocytes) in a concentration and time dependent manner (24hr: 23%↑; 48hr: 68%↑, (p<0.001); 72hr: 136%↑, (p<0.001)). This corresponded with mitochondrial inefficiency and diminished MMP, highlighting the formation of dysfunctional mitochondria. Morphological analysis revealed reorganisation of mitochondrial network, specifically mitochondrial fragmentation. Furthermore, p-DRP1, a key protein in fission, significantly increased (p<0.001). Additionally, adipocytes from obese subjects displayed lower basal respiration (49%↓, p<0.01) and were unresponsive to tunicamycin in contrast to their lean counterparts, demonstrating inefficient mitochondrial oxidative capacity. These human data suggest that adipocyte mitochondrial inefficiency is driven by ER stress and exacerbated in obesity. Nutrient excess induced ER stress leads to mitochondrial dysfunction that may therefore shift lipid deposition ectopically and thus have further implications on the development of related metabolic disorders.en_US
dc.description.sponsorshipWe extend our thanks to the surgeons, theater staff, and Arden Tissue Bank at University Hospitals Coventry and Warwickshire NHS Trust Hospital, Coventry for the collection of samples. Financial Support: LJ was a recipient of the Warwick Medical School Chancellors PhD Scholarship. AM was supported by an NTU postdoctoral research fellowship.en_US
dc.language.isoenen_US
dc.publisherOxford University Pressen_US
dc.relation.urlhttps://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa258/5837767en_US
dc.rights© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
dc.subjectER stressen_US
dc.subjectObesityen_US
dc.subjecthuman adipocytesen_US
dc.subjectmitochondrial dysfunctionen_US
dc.titleTunicamycin-induced Endoplasmic Reticulum stress mediates mitochondrial dysfunction in human adipocytes.en_US
dc.typeArticleen_US
dc.identifier.eissn1945-7197
dc.contributor.departmentUniversity of Warwicken_US
dc.contributor.departmentNottingham Trent Universityen_US
dc.contributor.departmentUniversity of Derbyen_US
dc.identifier.journalThe Journal of clinical endocrinology and metabolismen_US
dc.source.journaltitleThe Journal of clinical endocrinology and metabolism
dcterms.dateAccepted2020
dc.author.detail786763en_US
dc.source.countryUnited States


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