LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation

Abstract
Data availability
Article and author information
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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.

The following data sets were generated

1. Molina H
(2022) LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation
PRIDE, PXD035318.

https://www.ebi.ac.uk/pride/
1. Choi CHJ
2. Cohen P
(2022) AAV-mediated LRG1 overexpression in diabetic mice
NCBI Gene Expression Omnibus, GSE208219.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE208219

The following previously published data sets were used

1. Shen Y
2. Ren B
(2012) RNA-seq from ENCODE/LICR
NCBI Gene Expression Omnibus, GSE36026.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE36026
(2004) tissue-specific pattern of mRNA expression
NCBI Gene Expression Omnibus, GSE1133.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE1133

Article and author information

Author details

Chan Hee J Choi

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
William Barr

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Samir Zaman

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Corey Model

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Annsea Park

Department of Immunobiology, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
Mascha Koenen

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1024-4506
Zeran Lin

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4418-2443
Sarah K Szwed

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
François Marchildon

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Audrey Crane

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Thomas S Carroll

Bioinformatics Resouce Center, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Henrik Molina

Proteomics Resource Center, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8950-4990
Paul Cohen

Laboratory of Molecular Metabolism, Rockefeller University, New York, United States

For correspondence
pcohen@rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2786-8585

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.

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.

Copyright

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.