Loss of bone morphogenetic protein-binding endothelial regulator causes insulin resistance.
Loss of bone morphogenetic protein-binding endothelial regulator causes insulin resistance.
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DOI：
10.1038/s41467-021-22130-2
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发表时间：
2021-03-26
影响因子：
16.6
通讯作者：
Pi X
中科院分区：
文献类型：
--
作者：
Mao H;Li L;Fan Q;Angelini A;Saha PK;Wu H;Ballantyne CM;Hartig SM;Xie L;Pi X
越来越多的证据表明，代谢组织的慢性炎症在肥胖诱导的胰岛素抵抗中起着因果作用。然而，特定的内皮因子如何影响代谢组织仍未确定。骨形态发生蛋白(BMP)结合的内皮调节因子(BMPER)可使内皮细胞适应不同器官微环境中的炎性应激。在这里，我们证明BMPER是胰岛素敏感性的驱动因素。BMPER的全局和内皮细胞特异性的可诱导敲除都会导致高胰岛素血症、葡萄糖耐量异常和胰岛素抵抗，而不会增加小鼠代谢组织中的炎症。BMPER可以直接激活胰岛素信号，这需要它内化并与Niemann-Pick C1(NPC1)相互作用，NPC1是一种运输细胞内胆固醇的完整膜蛋白。这些结果表明，血管内皮细胞的内分泌功能维持着血糖的稳态。潜在的翻译意义是，BMPER重组蛋白的传递或其过表达可以缓解高脂饮食喂养的小鼠和Leprdb/db(db/db)糖尿病小鼠的胰岛素抵抗和高血糖。我们认为BMPER在治疗糖尿病方面显示出潜在的治疗潜力。2型糖尿病与慢性炎症有关，以胰岛素抵抗为特征。在这里，作者确定了内皮BMPER功能在葡萄糖稳态中的关键作用，并且BMPER过表达被证明可以缓解糖尿病小鼠的胰岛素抵抗和高血糖。
Accumulating evidence suggests that chronic inflammation of metabolic tissues plays a causal role in obesity-induced insulin resistance. Yet, how specific endothelial factors impact metabolic tissues remains undefined. Bone morphogenetic protein (BMP)–binding endothelial regulator (BMPER) adapts endothelial cells to inflammatory stress in diverse organ microenvironments. Here, we demonstrate that BMPER is a driver of insulin sensitivity. Both global and endothelial cell-specific inducible knockout of BMPER cause hyperinsulinemia, glucose intolerance and insulin resistance without increasing inflammation in metabolic tissues in mice. BMPER can directly activate insulin signaling, which requires its internalization and interaction with Niemann-Pick C1 (NPC1), an integral membrane protein that transports intracellular cholesterol. These results suggest that the endocrine function of the vascular endothelium maintains glucose homeostasis. Of potential translational significance, the delivery of BMPER recombinant protein or its overexpression alleviates insulin resistance and hyperglycemia in high-fat diet-fed mice and Leprdb/db (db/db) diabetic mice. We conclude that BMPER exhibits therapeutic potential for the treatment of diabetes. Type 2 diabetes is associated with chronic inflammation and is characterized by insulin resistance. Here, the authors identify a crucial role for endothelial BMPER function in glucose homeostasis, and BMPER overexpression was shown to alleviate insulin resistance and hyperglycemia in diabetic mice.
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DOI：
10.1007/978-1-59745-019-5_13
发表时间：
2010-01-01
期刊：
MOUSE CELL CULTURE: METHODS AND PROTOCOLS
影响因子：
--
作者：
Li, Wan-Chun;Ralphs, Kate L.;Tosh, David
通讯作者：
Tosh, David
影响因子：
5.8
作者：
Khan, Ilvira M.;Pokharel, Yashashwi;Ballantyne, Christie M.
通讯作者：
Ballantyne, Christie M.
影响因子：
5.3
作者：
Moser, M;Binder, O;Patterson, C
通讯作者：
Patterson, C
影响因子：
5.1
作者：
Cho, N. H.;Shaw, J. E.;Malanda, B.
通讯作者：
Malanda, B.
影响因子：
16
作者：
Michael, MD;Kulkarni, RN;Kahn, CR
通讯作者：
Kahn, CR