{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T23:03:36Z","timestamp":1778540616289,"version":"3.51.4"},"reference-count":44,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2012,3,15]]},"abstract":"<jats:p> Central obesity is associated with chronic inflammation, insulin resistance, \u03b2-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12\/15-lipoxygenase enzyme (12\/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12\/15-LO is expressed in adipose tissue, we determined whether 12\/15-LO could mediate ER stress signals. Addition of 12\/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1\u03b1. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12\/15-LO activation. Addition of a 12\/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12\/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12\/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12\/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL\/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12\/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12\/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12\/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity. <\/jats:p>","DOI":"10.1152\/ajpendo.00373.2011","type":"journal-article","created":{"date-parts":[[2012,1,4]],"date-time":"2012-01-04T03:32:04Z","timestamp":1325647924000},"page":"E654-E665","source":"Crossref","is-referenced-by-count":46,"title":["12\/15-Lipoxygenase signaling in the endoplasmic reticulum stress response"],"prefix":"10.1152","volume":"302","author":[{"given":"Banumathi K.","family":"Cole","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norine S.","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, 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