Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.
Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.
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肥胖症中巨噬细胞 PEPD 的失调决定了脂肪组织纤维炎症和胰岛素抵抗。
DOI：
10.1038/s42255-022-00561-5
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发表时间：
2022
影响因子：
20.8
通讯作者：
Mora,
中科院分区：
文献类型：
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作者：
Pellegrinelli,V;Rodriguez-Cuenca,S;Rouault,C;Figueroa-Juarez,E;Schilbert,H;Virtue,S;Moreno-Navarrete,JM;Bidault,G;Vázquez-Borrego,MC;Dias,AR;Pucker,B;Dale,M;Campbell,M;Carobbio,S;Lin,YH;Vacca,M;Aron-Wisnewsky,J;Mora,
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。脯氨酰二肽酶，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起着至关重要的作用，但其在AT中的具体功能相关性尚不清楚。在这里，我们表明，在人类和小鼠肥胖，PEPD的表达和活性降低AT，PEPD被释放到体循环，这促进纤维化和AT IR。PEPD的酶功能的遗传消融或药理学抑制的损失导致AT纤维化小鼠。除了其细胞内酶促作用外，分泌的细胞外PEPD蛋白通过EGFR信号传导增强巨噬细胞和脂肪细胞纤维炎症反应，从而促进AT纤维化和IR。我们进一步表明，氨酰基脯氨酸二肽酶活性降低与作为AT纤维化和IR的致病性触发因素的PEPD的全身水平增加相关联。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。
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.