{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:34:16Z","timestamp":1793255656701,"version":"4.5.0"},"reference-count":39,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,10,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Type 2 diabetes mellitus has been demonstrated to be strongly associated with obesity, in which adipose tissue distribution plays a critical role. Different adipose tissue depots, particularly subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), exert distinct effects on insulin resistance by influencing hepatocyte insulin signaling and glucose metabolism. Nevertheless, the molecular mechanisms underlying these depot\u2010specific effects remain incompletely understood. Our preliminary findings revealed that VAT secretes markedly higher levels of interleukin\u20108 (IL\u20108) than SAT, suggesting that IL\u20108 may act as a key mediator linking adipose tissue heterogeneity to hepatic insulin sensitivity. A Transwell\u2010based co\u2010culture system was established to allow paracrine interaction between human HepG2 cells and adipose tissue derived from different anatomical depots. This study supports a major role for CXCR2\u2010dependent signaling in hepatocyte insulin resistance and implicates VAT\u2010derived IL\u20108 as a likely upstream mediator. Specifically, co\u2010culture with adipose tissue resulted in a substantial impairment of insulin signaling, as evidenced by a decrease in the expression of IRS2, PI3K\u2010p85, and phosphorylated Akt2 (Ser473), accompanied by an increase in the phosphorylation of IRS2 at Ser731. Silencing CXCR2 in HepG2 cells partially reversed these effects, restoring insulin signaling protein expression. Functional assays revealed that CXCR2 knockdown enhanced glucose uptake and glycogen storage, while CXCR2 overexpression significantly suppressed these processes. These alterations were more pronounced in the VAT co\u2010culture group compared with the SAT group. In summary, the findings identify a critical role for CXCR2\u2010dependent signaling linking adipose tissue secretomes\u2014predominantly implicated with elevated VAT\u2010derived IL\u20108\u2014to the disruption of the IRS2\/PI3K\/Akt2 pathway in hepatocytes, supported by transcript\u2010level regulation and functional genetic modulation.<\/jats:p>","DOI":"10.1096\/fj.202601702rrrr","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:31:44Z","timestamp":1791905504000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>IL<\/scp>\n                    \u20108 From Explant\u2010Cultured Human Visceral and Subcutaneous Adipose Tissue Upregulates\n                    <scp>CXCR2<\/scp>\n                    Transcript Expression, Promoting\n                    <scp>CXCR2<\/scp>\n                    \u2010Dependent Insulin Resistance and Impaired Glucose Metabolism in Human\n                    <scp>HepG2<\/scp>\n                    Hepatocytes"],"prefix":"10.1096","volume":"40","author":[{"given":"Tian\u2010hang","family":"Ma","sequence":"first","affiliation":[{"name":"First Affiliated Hospital of Kunming Medical University  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han\u2010li","family":"Jiang","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital of Kunming Medical University  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan\u2010min","family":"Bai","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital of Kunming Medical University  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010qing","family":"Zhang","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital of Kunming Medical University  Kunming Yunnan 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