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; Simon, Anna Katharina
(2023) EMBO Journal, volume 42, issue 6, pp. 1 - 20
(Article)
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
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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.
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Keywords: adipocyte, autophagy, IL-10, inflammation, oxylipin, General Biochemistry,Genetics and Molecular Biology, General Immunology and Microbiology, Molecular Biology, General Neuroscience, Journal Article
ISSN: 0261-4189
Publisher: Springer Science and Business Media Deutschland GmbH
Note: Funding Information: We thank Patricia Cotta Moreira, Daniel Andrew, and Mino Medghalchi from the Kennedy Institute animal facility for their excellent care and assistance of animal well-being. Dr. Alina Janney and Dr. Luca Baù for their help with R coding. Discussions about experimental design for the transcriptomic experiments and sequencing were performed with help of Prof. Stephen Samson, Dr. Lada Koneva, Dr. Moustafa Attar, and the Oxford Genomics Centre. Histology was performed with the help from the Kennedy Institute Histology Facility, especially Dr. Ida Parisi. We thank the IBDome (SFB-TRR 241) for the IBD patient recruitment and the organization of resections. This work was supported by grants from the Wellcome Trust (Investigator award 103830/Z/14/Z and 220784/Z/20/Z to AKS, Investigator award 212240/Z/18/Z to FP, PhD studentship award 203803/Z16/Z to FCR, PhD studentship award 108869/Z/15/Z to SKW), the Kenneth Rainin Foundation (Innovator award 20210017 to AKS and FP, jointly), the Kennedy Trust Studentship (KEN192001 to KP), the Marie Sklodowska-Curie - European Fellowship (893676 to MB), Blood Cancer UK (15026 and 17012 to CME), the NIH – NIEHS (RIVER Award R35 ES030443-01 and Superfund Award – P42 ES004699) and the IBDome (Project-ID 375876048 – SFB TRR 241 B01 to BS, CW and JH). Li-cor Odyssey imager was funded by ERC AdG 670930. Funding Information: We thank Patricia Cotta Moreira, Daniel Andrew, and Mino Medghalchi from the Kennedy Institute animal facility for their excellent care and assistance of animal well‐being. Dr. Alina Janney and Dr. Luca Baù for their help with R coding. Discussions about experimental design for the transcriptomic experiments and sequencing were performed with help of Prof. Stephen Samson, Dr. Lada Koneva, Dr. Moustafa Attar, and the Oxford Genomics Centre. Histology was performed with the help from the Kennedy Institute Histology Facility, especially Dr. Ida Parisi. We thank the IBDome (SFB‐TRR 241) for the IBD patient recruitment and the organization of resections. This work was supported by grants from the Wellcome Trust (Investigator award 103830/Z/14/Z and 220784/Z/20/Z to AKS, Investigator award 212240/Z/18/Z to FP, PhD studentship award 203803/Z16/Z to FCR, PhD studentship award 108869/Z/15/Z to SKW), the Kenneth Rainin Foundation (Innovator award 20210017 to AKS and FP, jointly), the Kennedy Trust Studentship (KEN192001 to KP), the Marie Sklodowska‐Curie ‐ European Fellowship (893676 to MB), Blood Cancer UK (15026 and 17012 to CME), the NIH – NIEHS (RIVER Award R35 ES030443‐01 and Superfund Award – P42 ES004699) and the IBDome (Project‐ID 375876048 – SFB TRR 241 B01 to BS, CW and JH). Li‐cor Odyssey imager was funded by ERC AdG 670930. Publisher Copyright: © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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