LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation
- Rockefeller University, United States
- Yale University, United States
Abstract
While dysregulation of adipocyte endocrine function plays a central role in obesity and its complications, the vast majority of adipokines remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry to comprehensively characterize the secretome of murine visceral and subcutaneous white and interscapular brown adipocytes. Over 600 proteins were identified, the majority of which showed cell type-specific enrichment. We here describe a metabolic role for leucine-rich α-2 glycoprotein 1 (LRG1) as an obesity-regulated adipokine secreted by mature adipocytes. LRG1 overexpression significantly improved glucose homeostasis in diet-induced and genetically obese mice. This was associated with markedly reduced white adipose tissue macrophage accumulation and systemic inflammation. Mechanistically, we found LRG1 binds cytochrome c in circulation to dampen its pro-inflammatory effect. These data support a new role for LRG1 as an insulin sensitizer with therapeutic potential given its immunomodulatory function at the nexus of obesity, inflammation, and associated pathology.
Data availability
Proteomic dataset has been deposited to Proteomexchange PRIDE under accession PXD035318. RNA-Seq data have been deposited to GEO under accession GSE208219. All original gels and blots are available as Source Data Files.
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AAV-mediated LRG1 overexpression in diabetic miceNCBI Gene Expression Omnibus, GSE208219.
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RNA-seq from ENCODE/LICRNCBI Gene Expression Omnibus, GSE36026.
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tissue-specific pattern of mRNA expressionNCBI Gene Expression Omnibus, GSE1133.
Article and author information
Author details
Funding
American Diabetes Association (1-17-ACE-17)
- Paul Cohen
National Institutes of Health (RC2 DK129961)
- Paul Cohen
National Institute of General Medical Sciences (T32GM007739)
- Chan Hee J Choi
- Sarah K Szwed
Sarnoff Cardiovascular Research Foundation
- Samir Zaman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Peter Tontonoz, University of California, Los Angeles, United States
Ethics
Animal experimentation: All animal studies were performed in accordance with the institutional guidelines of the Rockefeller University Institutional Animal Care and Use Committee (IACUC) protocol (18016-H). Experiments involving adenoviral and AAV8 vectors were performed under general anesthesia using isoflurane, in accordance with the institutional ABSL-2 guidelines.
Version history
- Preprint posted: July 12, 2021 (view preprint)
- Received: July 2, 2022
- Accepted: November 6, 2022
- Accepted Manuscript published: November 8, 2022 (version 1)
- Version of Record published: November 18, 2022 (version 2)
Copyright
© 2022, Choi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation
eLife 11:e81559.
https://doi.org/10.7554/eLife.81559
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