Endothelial Cells Induced Progenitors Into Brown Fat to Reduce Atherosclerosis.
Endothelial Cells Induced Progenitors Into Brown Fat to Reduce Atherosclerosis.
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DOI：
10.1161/circresaha.121.319582
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发表时间：
2022-07-08
影响因子：
20.1
通讯作者：
King, George L.
中科院分区：
文献类型：
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作者：
Park, Kyoungmin;Li, Qian;Lynes, Matthew D.;Yokomizo, Hisashi;Maddaloni, Ernesto;Shinjo, Takanori;St-Louis, Ronald;Li, Qin;Katagiri, Sayaka;Fu, Jialin;Clermont, Allen;Park, Hyunseok;Wu, I-Hsien;Yu, Marc Gregory;Shah, Hetal;Tseng, Yu-Hua;King, George L.
关键词：
胰岛素抵抗（IR）可通过诱导内皮功能障碍（ED）、减少一氧化氮（NO）产生和加速动脉炎症来增加动脉粥样硬化和心血管风险。目的是确定 EC 中胰岛素作用和 NO 产生通过血管周围祖细胞 (PPC) 分化为棕色脂肪细胞 (BAT) 改善全身生物能学并减少动脉粥样硬化的机制。研究使用胰岛素受体、eNOS 和 ETB 受体的各种内皮转基因和 ApoE−/− 缺失突变小鼠来评估动脉粥样硬化。从血管周围脂肪和微血管中分离细胞，用于研究 BAT 中 NO、胰岛素和脂因子反应的分化和信号传导机制。即使在高脂肪饮食的情况下，通过诱导 PPC 分化为米色/BAT，增强胰岛素对 ECIRS1 转基因小鼠 EC 和 NO 产生的作用，从而减轻体重并增加全身能量消耗以及 BAT 质量和活性。然而，在 ECIRS1 小鼠和 eNOSKO 小鼠中，内皮 NO 合酶 (eNOS) 抑制剂 L-NAME 抑制了生物能学、BAT 从 PPC 分化和体重减轻的积极变化。介导 NO 对 PPC 分化为 BAT 的作用的机制被确定为溶解鸟苷酸环化酶/cGMP 蛋白依赖性激酶 Iα/GSK3β 途径的激活。 NO 诱导 BAT 质量增加的 ECIRS1 小鼠的血浆脂质组学显示 12,13-diHOME 产量增加。输注 12,13-diHOME 可改善 ED 并减少动脉粥样硬化，而其减少在 ApoE−/− 小鼠中产生相反的效果。胰岛素对 eNOS 和 EC 的激活增强了 PPC 向 BAT 及其脂因子的分化，并改善了全身生物能学和动脉粥样硬化，表明 ED 是肥胖中能量不平衡的主要原因。
Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction (ED), decreasing nitric oxide (NO) production and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in EC can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT). Studies used various endothelial transgenic and deletion mutant ApoE−/− mice of insulin receptors, eNOS and ETB receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin and lipokines from BAT. Enhancing insulin’s actions on EC and NO production in ECIRS1 transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by L-NAME, an inhibitor of endothelial NO synthase (eNOS), in ECIRS1 mice and eNOSKO mice. The mechanism mediating NO’s action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/cGMP protein-dependent kinase Iα/GSK3β pathways. Plasma lipidomics from ECIRS1 mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved ED and decreased atherosclerosis, whereas its reduction had opposite effects in ApoE−/− mice. Activation of eNOS and EC by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that ED is a major contributor of energy disequilibrium in obesity.
DOI：
10.1084/jem.167.3.1003
发表时间：
1988-03-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Nayak RC;Berman AB;George KL;Eisenbarth GS;King GL
通讯作者：
King GL