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

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 c...

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Autores principales: Gandhi, Aakash Y., Yu, Jinhai, Gupta, Arun, Guo, Tong, Iyengar, Puneeth, Infante, Rodney E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240385/
https://www.ncbi.nlm.nih.gov/pubmed/35785158
http://dx.doi.org/10.3389/fonc.2022.841758
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author Gandhi, Aakash Y.
Yu, Jinhai
Gupta, Arun
Guo, Tong
Iyengar, Puneeth
Infante, Rodney E.
author_facet Gandhi, Aakash Y.
Yu, Jinhai
Gupta, Arun
Guo, Tong
Iyengar, Puneeth
Infante, Rodney E.
author_sort Gandhi, Aakash Y.
collection PubMed
description 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.
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spelling pubmed-92403852022-06-30 Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia Gandhi, Aakash Y. Yu, Jinhai Gupta, Arun Guo, Tong Iyengar, Puneeth Infante, Rodney E. Front Oncol Oncology 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. Frontiers Media S.A. 2022-06-15 /pmc/articles/PMC9240385/ /pubmed/35785158 http://dx.doi.org/10.3389/fonc.2022.841758 Text en Copyright © 2022 Gandhi, Yu, Gupta, Guo, Iyengar and Infante https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Gandhi, Aakash Y.
Yu, Jinhai
Gupta, Arun
Guo, Tong
Iyengar, Puneeth
Infante, Rodney E.
Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia
title Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia
title_full Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia
title_fullStr Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia
title_full_unstemmed Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia
title_short Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia
title_sort cytokine-mediated stat3 transcription supports atgl/cgi-58-dependent adipocyte lipolysis in cancer cachexia
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240385/
https://www.ncbi.nlm.nih.gov/pubmed/35785158
http://dx.doi.org/10.3389/fonc.2022.841758
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