Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.

由于胶原蛋白周转受损，纤维化是脂肪组织 (AT) 功能障碍和肥胖相关胰岛素抵抗 (IR) 的标志。脯氨酸酶，也称为肽酶 D (PEPD)，通过降解含脯氨酸的二肽在胶原蛋白周转中发挥着至关重要的作用，但其在 AT 中的具体功能相关性尚不清楚。在这里，我们发现在人类和小鼠肥胖中，AT中PEPD的表达和活性降低，并且PEPD被释放到体循环中，从而促进纤维化和AT IR。由于基因消融或药理抑制而导致 PEPD 酶功能丧失，导致小鼠 AT 纤维化。除了其细胞内酶促作用外，分泌的细胞外 PEPD 蛋白还可通过 EGFR 信号传导增强巨噬细胞和脂肪细胞的纤维炎症反应，从而促进 AT 纤维化和 IR。我们进一步表明，脯氨酸酶活性降低与 PEPD 全身水平升高相结合，PEPD 是 AT 纤维化和 IR 的致病触发因素。因此，巨噬细胞产生的 PEPD 可能作为 AT 纤维炎症的生物标志物，并可能代表 AT 纤维化和肥胖相关 IR 和 2 型糖尿病的治疗靶点。