Background:Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT).Methods:Studies used various endothelial transgenic and deletion mutant ApoE^−/− mice of insulin receptors, eNOS (endothelial NO synthase) and ETBR (endothelin receptor type B) 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.Results:Enhancing insulin’s actions on endothelial cells 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 N(gamma)-nitro-L-arginine methyl ester (_L-NAME), an inhibitor of 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/PKGIα (cGMP protein-dependent kinase Iα)/GSK3β (glycogen synthase kinase 3β) pathways. Plasma lipidomics from ECIRS1 mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in ApoE^−/−mice.Conclusions:Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.

中文翻译：

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内皮细胞诱导祖细胞转化为棕色脂肪以减少动脉粥样硬化

背景：胰岛素抵抗（IR）可通过诱导内皮功能障碍、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。目的是确定内皮细胞中胰岛素作用和一氧化氮生成通过血管周围祖细胞 (PPC) 分化为棕色脂肪细胞 (BAT) 来改善全身生物能学并减少动脉粥样硬化的机制。方法：使用各种内皮转基因和缺失突变体进行研究ApoE ^−/−小鼠胰岛素受体、eNOS（内皮一氧化氮合酶）和 ETBR（B 型内皮素受体）受体用于评估动脉粥样硬化。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。 结果：增强 ECIRS1 转基因小鼠的胰岛素对内皮细胞的作用和 NO 的产生，减轻了体重并增加了全身性即使在高脂肪饮食的情况下，也可以通过诱导 PPC 分化为米色/BAT 来调节能量消耗以及 BAT 质量和活性。然而，在ECIRS1小鼠和eNOSKO小鼠中， eNOS 抑制剂N(gamma)-硝基-L-精氨酸甲酯 ( _L -NAME) 抑制生物能学、BAT 从 PPC 分化和体重减轻方面的积极变化。NO 介导 PPC 分化为 BAT 的作用机制被确定为溶解鸟苷酸环化酶/PKGIα（cGMP 蛋白依赖性激酶 Iα）/GSK3β（糖原合酶激酶 3β）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 可改善内皮功能障碍并减少动脉粥样硬化，而其减少在ApoE ^{− /−}小鼠中具有相反的作用。结论：胰岛素激活 eNOS 和内皮细胞增强了 PPC 向 BAT 及其脂因子的分化，并改善了全身性生物能量学和动脉粥样硬化，表明内皮功能障碍是肥胖能量不平衡的主要原因。