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Oncol."],"abstract":"<jats:p>Adipose tissue inflammation is observed in multiple metabolically-altered states including cancer-associated cachexia and obesity. Although cachexia is a syndrome of adipose loss and obesity is a disease of adipose excess, both pathologies demonstrate increases in circulating levels of IL-6 family cytokines, \u03b2-adrenergic signaling, and adipocyte lipolysis. While \u03b2-adrenergic-stimulated adipocyte lipolysis is well described, there is limited mechanistic insight into how cancer cachexia-associated inflammatory cytokines contribute to adipocyte lipolysis under pathologic conditions. Here, we set out to compare adipocyte lipolysis signaling by cancer cachexia-associated IL-6 family cytokines (IL-6 and LIF) to that of the \u03b2-adrenergic agonist isoproterenol. Unlike isoproterenol, the IL-6 family of cytokines required JAK\/STAT3-dependent transcriptional changes to induce adipocyte lipolysis. Furthermore, cachexia-associated cytokines that used STAT3 to induce lipolysis were primarily dependent on the lipase ATGL and its cofactor CGI-58 rather than lipases HSL and MAGL. Finally, administration of JAK but not \u03b2-adrenergic inhibitors suppressed adipose STAT3 phosphorylation and associated adipose wasting in a murine model of cancer cachexia characterized by increased systemic IL-6 family cytokine levels. Combined, our results demonstrate how the IL-6 family of cytokines diverge from \u03b2-adrenergic signals by employing JAK\/STAT3-driven transcriptional changes to promote adipocyte ATGL\/CGI-58-dependent lipolysis contributing to adipose wasting in cancer cachexia.<\/jats:p>","DOI":"10.3389\/fonc.2022.841758","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T06:22:14Z","timestamp":1655274134000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Cytokine-Mediated STAT3 Transcription Supports ATGL\/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia"],"prefix":"10.3389","volume":"12","author":[{"given":"Aakash 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