LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation

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.

尽管脂肪细胞内分泌功能失调在肥胖及其并发症中发挥核心作用，但绝大多数脂肪因子仍未得到表征。本研究采用生物正交非经典氨基酸标记（bio-orthogonal non-canonical amino acid tagging, BONCAT）结合质谱技术，全面表征了小鼠内脏白色、皮下白色以及肩胛间棕色脂肪细胞的分泌组。本次研究共鉴定出600余种蛋白质，其中大多数呈现出细胞类型特异性富集特征。本研究揭示了富亮氨酸α-2糖蛋白1（leucine-rich α-2 glycoprotein 1, LRG1）的代谢功能：它是一种由成熟脂肪细胞分泌、受肥胖调控的脂肪因子。在饮食诱导型和遗传型肥胖小鼠中，LRG1过表达可显著改善葡萄糖稳态。该效应与白色脂肪组织巨噬细胞浸润及全身炎症水平显著降低密切相关。从机制层面来看，我们发现LRG1可在循环系统中结合细胞色素c，以抑制其促炎活性。上述研究结果表明，LRG1作为胰岛素增敏剂具有全新功能；鉴于其在肥胖、炎症及相关病理过程的关键节点发挥免疫调节作用，该蛋白具备潜在治疗价值。