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

Aakash Y. Gandhi, Jinhai Yu, Arun Gupta, Tong Guo, Puneeth Iyengar, Rodney E. Infante

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number841758
JournalFrontiers in Oncology
Volume12
DOIs
StatePublished - Jun 15 2022

Keywords

  • adipocyte lipolysis
  • adipose triglyceride lipase (ATGL)
  • adipose wasting (malnutrition)
  • cancer cachexia
  • interleukin-6 (IL-6)
  • leukemia inhibitor factor
  • signal transducer and activator of transcription 3 (STAT3)
  • β-adrenergic signaling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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