Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, United States; Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
William Barr
Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
Samir Zaman
Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
Corey Model
Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
Annsea Park
Department of Immunobiology, Yale University, New Haven, United States
Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
Sarah K Szwed
Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, United States; Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
Francois Marchildon
Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
Audrey Crane
Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
Thomas S Carroll
Bioinformatics Resouce Center, Rockefeller University, New York, United States
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 adip ocytes. 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.
