30-OR: Identification of LRG1 as an Insulin Sensitizing Adipokine

Adipocytes play a central role in obesity, type 2 diabetes, and metabolic disease. White adipocytes store excess energy, and brown adipocytes dissipate chemical energy into heat. In addition to these bioenergetics functions, adipocytes also have important endocrine properties. Bioinformatic analyses suggest that adipocytes may secrete over 1,000 unique polypeptides, the vast majority of which remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) along with mass spectrometry to comprehensively characterize the secreted proteome of murine subcutaneous and visceral white adipocytes and interscapular brown adipocytes. We identified more than 700 unique proteins, with approximately 300 showing fat cell type specific enrichment. We here describe a novel role for leucine-rich alpha-2 glycoprotein 1 (LRG1), a secreted protein expressed across all types of adipose tissues. Plasma LRG1 levels were increased in aged and diet-induced obese (DIO) mice. Longitudinal overexpression of LRG1, using an adeno-associated virus (AAV) with tropism for adipose tissue, led to significantly improved glucose and insulin tolerance in DIO mice, despite equivalent body weights. AAV-mediated overexpression of LRG1 in the db/db model of type 2 diabetes resulted in accelerated weight gain due to increased white fat mass, but improved insulin tolerance and a delayed diabetic phenotype. LRG1 overexpressing mice had markedly reduced macrophage accumulation in white adipose tissues, and LRG1 significantly reduced pro-inflammatory gene expression. Taken together, these data suggest LRG1 acts as an insulin sensitizer by promoting healthier lipid storage with reduced inflammation.