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Our previous work demonstrated that visceral adipose tissues (VAT) are a major source of PAI\u20101, especially in the aged (murine endotoxemia), that circulating PAI\u20101 protein levels match the trajectory of PAI\u20101 transcript levels in VAT (clinical sepsis), and that PAI\u20101 in both VAT and plasma are positively associated with acute kidney injury (AKI) in septic patients. In the current study utilizing preclinical sepsis models, PAI\u20101 tissue distribution was examined and cellular sources, as well as mechanisms mediating PAI\u20101 induction in VAT, were identified. In aged mice with sepsis, PAI\u20101 gene expression was significantly higher in VAT than in other major organs. VAT PAI\u20101 gene expression correlated with PAI\u20101 protein levels in both VAT and plasma. Moreover, VAT and plasma levels of PAI\u20101 were positively associated with AKI markers, modeling our previous clinical data. Using explant cultures of VAT, we determined that PAI\u20101 is secreted robustly in response to recombinant transforming growth factor \u03b2 (TGF\u03b2) and tumor necrosis factor \u03b1 (TNF\u03b1) treatment; however, neutralization was effective only for TNF\u03b1\u00a0indicating that TGF\u03b2 is not an endogenous modulator of PAI\u20101. Within VAT, TNF\u03b1 was localized to neutrophils and macrophages. PAI\u20101 protein levels were fourfold higher in stromal vascular fraction (SVF) cells compared with mature adipocytes, and among SVF cells, both immune and nonimmune compartments expressed PAI\u20101 in a similar fashion. PAI\u20101 was localized predominantly to macrophages within the immune compartment and preadipocytes and endothelial cells within the nonimmune compartment. Collectively, these results indicate that induction and secretion of PAI\u20101 from VAT is facilitated by a complex interaction among immune and nonimmune cells. As circulating PAI\u20101 contributes to AKI in sepsis, understanding PAI\u20101 regulation in VAT could yield novel strategies for reducing systemic consequences of PAI\u20101 overproduction.<\/jats:p>","DOI":"10.1002\/jcp.30551","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T12:52:30Z","timestamp":1628513550000},"page":"706-719","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Visceral fat\u2010specific regulation of plasminogen activator inhibitor\u20101 in aged septic mice"],"prefix":"10.1002","volume":"237","author":[{"given":"Maria E. 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