White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB–dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.
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December 14 2020
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
Feng He,
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Pathology, Yale School of Medicine, New Haven, CT
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Yanrui Huang,
Conceptualization, Formal analysis, Investigation, Validation, Visualization, Writing - original draft
1
Department of Pathology, Yale School of Medicine, New Haven, CT
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Zhi Song,
Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Supervision, Validation, Visualization
1
Department of Pathology, Yale School of Medicine, New Haven, CT
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Huanjiao Jenny Zhou,
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software
1
Department of Pathology, Yale School of Medicine, New Haven, CT
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Haifeng Zhang,
Haifeng Zhang
Investigation, Resources
1
Department of Pathology, Yale School of Medicine, New Haven, CT
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Rachel J. Perry,
Rachel J. Perry
Investigation, Writing - review & editing
2
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
3
Department of Internal Medicine, Yale School of Medicine, New Haven, CT
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Gerald I. Shulman,
Gerald I. Shulman
Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
2
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
3
Department of Internal Medicine, Yale School of Medicine, New Haven, CT
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Wang Min
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Pathology, Yale School of Medicine, New Haven, CT
Correspondence to Wang Min: mike.wang388@gmail.com
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Feng He
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Pathology, Yale School of Medicine, New Haven, CT
Yanrui Huang
Conceptualization, Formal analysis, Investigation, Validation, Visualization, Writing - original draft
1
Department of Pathology, Yale School of Medicine, New Haven, CT
Zhi Song
Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Supervision, Validation, Visualization
1
Department of Pathology, Yale School of Medicine, New Haven, CT
Huanjiao Jenny Zhou
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software
1
Department of Pathology, Yale School of Medicine, New Haven, CT
Haifeng Zhang
Investigation, Resources
1
Department of Pathology, Yale School of Medicine, New Haven, CT
Rachel J. Perry
Investigation, Writing - review & editing
2
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
3
Department of Internal Medicine, Yale School of Medicine, New Haven, CT
Gerald I. Shulman
Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
2
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
3
Department of Internal Medicine, Yale School of Medicine, New Haven, CT
Wang Min
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Pathology, Yale School of Medicine, New Haven, CT
Correspondence to Wang Min: mike.wang388@gmail.com
Gerald I. Shulman: gerald.shulman@yale.edu
*
F. He, Y. Huang, Z. Song, and H.J. Zhou contributed equally to this paper.
Received:
July 06 2020
Revision Received:
September 02 2020
Accepted:
October 19 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
American Heart Association
(19CDA34760284)
National Institutes of Health
(P30 DK045735, R01 HL109420, HL115148, R01 DK113984, R01 DK114793, R01 DK116774)
© 2020 He et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (3): e20201416.
Article history
Received:
July 06 2020
Revision Received:
September 02 2020
Accepted:
October 19 2020
Citation
Feng He, Yanrui Huang, Zhi Song, Huanjiao Jenny Zhou, Haifeng Zhang, Rachel J. Perry, Gerald I. Shulman, Wang Min; Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. J Exp Med 1 March 2021; 218 (3): e20201416. doi: https://doi.org/10.1084/jem.20201416
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