Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL‐10

Richter, Felix Clemens, Friedrich, Matthias, Kampschulte, Nadja, Piletic, Klara, Alsaleh, Ghada, Zummach, Ramona, Hecker, Julia, Pohin, Mathilde, Ilott, Nicholas, Guschina, Irina, Wideman, Sarah Karin, Johnson, Errin, Borsa, Mariana, Hahn, Paula, Morriseau, Christophe, Hammock, Bruce D, Schipper, Henk Simon, Edwards, Claire M, Zechner, Rudolf, Siegmund, Britta, Weidinger, Carl, Schebb, Nils Helge, Powrie, Fiona and Simon, Anna Katharina 2023. Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL‐10. The EMBO Journal , e112202. 10.15252/embj.2022112202

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Abstract

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte‐specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti‐inflammatory energy substrates. Instead, Atg7‐deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2‐mediated upregulation of Ephx1. This shift reduced secretion of IL‐10 from adipose tissues, which was dependent on the cytochrome P450‐EPHX pathway, and lowered circulating levels of IL‐10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat‐gut crosstalk through an autophagy‐dependent regulation of anti‐inflammatory oxylipins via the cytochrome P450‐EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	EMBO Press
ISSN:	0261-4189
Date of First Compliant Deposit:	17 February 2023
Date of Acceptance:	17 January 2023
Last Modified:	16 May 2023 12:54
URI:	https://orca.cardiff.ac.uk/id/eprint/157105

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