Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance,Nature

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Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance
Nature ( IF 50.5 ) Pub Date : 2018-03-01 , DOI: 10.1038/nature26138
Devram S Ghorpade ₁ , Lale Ozcan ₁ , Ze Zheng ₁ , Sarah M Nicoloro ₂ , Yuefei Shen ₂ , Emily Chen _{3,

4} , Matthias Blüher ₅ , Michael P Czech ₂ , Ira Tabas _{1,

6}

Affiliation

Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT). In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs). In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.

中文翻译：

肥胖症中肝细胞分泌的 DPP4 促进脂肪炎症和胰岛素抵抗

肥胖引起的代谢疾病涉及通过循环因子在多个器官之间进行功能整合，但对肝脏和内脏脂肪组织 (VAT) 之间的串扰知之甚少。在肥胖症中，VAT 会充满炎性脂肪组织巨噬细胞 (ATM)。在肥胖的人类中，脂肪组织炎症与胰岛素抵抗之间存在密切的相关性，而在肥胖小鼠中，阻断全身性或 ATM 炎症可提高胰岛素敏感性。然而，促进肥胖中病理性脂肪组织炎症的过程尚不完全清楚。在这里，我们表明小鼠的肥胖会刺激肝细胞合成和分泌二肽基肽酶 4 (DPP4)，它与血浆因子 Xa 一起使 ATM 发炎。沉默肝细胞中 DPP4 的表达可抑制 VAT 的炎症和胰岛素抵抗；然而，口服 DPP4 抑制剂西格列汀没有观察到类似的效果。炎症和胰岛素抵抗也可以通过沉默 ATM 中caveolin-1 或 PAR2 的表达来抑制；这些蛋白质分别介导 DPP4 和 Xa 因子的作用。因此，肝细胞 DPP4 促进肥胖患者的 VAT 炎症和胰岛素抵抗，靶向该途径可能具有不同于口服 DPP4 抑制剂所观察到的代谢益处。

更新日期：2018-03-01

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