Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia

• Published in: Frontiers in oncology 2022-06, Vol.12, p.841758-841758
• Main Authors: Gandhi, Aakash Y., Yu, Jinhai, Gupta, Arun, Guo, Tong, Iyengar, Puneeth, Infante, Rodney E.
• Format: Article
• Language: English
• Subjects: adipocyte lipolysis; adipose triglyceride lipase (ATGL); adipose wasting (malnutrition); cancer cachexia; interleukin-6 (IL-6); leukemia inhibitor factor; Oncology
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2022.841758

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, β-adrenergic signaling, and adipocyte lipolysis. While β-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 β-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 β-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 β-adrenergic signals by employing JAK/STAT3-driven transcriptional changes to promote adipocyte ATGL/CGI-58-dependent lipolysis contributing to adipose wasting in cancer cachexia.