Forkhead box O-1 modulation improves endothelial insulin resistance in human obesity.
Forkhead box O-1 modulation improves endothelial insulin resistance in human obesity.
复制标题
叉头盒 O-1 调节可改善人类肥胖症的内皮胰岛素抵抗。
DOI：
10.1161/atvbaha.114.305139
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Gokce,Noyan
中科院分区：
文献类型：
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作者：
Karki,Shakun;Farb,MelissaG;Ngo,DoanTM;Myers,Samantha;Puri,Vishwajeet;Hamburg,NaomiM;Carmine,Brian;Hess,DonaldT;Gokce,Noyan
内脏肥胖的增加与胰岛素抵抗、内皮功能障碍和肥胖的心脏代谢疾病密切相关，但病理生理机制知之甚少。我们试图通过描述特定的胰岛素反应来研究血管胰岛素抵抗的机制，并获得证据表明转录因子FOXO-1的功能改变可能在肥胖相关的内皮功能障碍中起重要作用。方法和结果我们在手术中收集了56例严重肥胖患者的成对皮下和内脏脂肪组织样本。（体重指数，43±7 kg/m2）和14名非肥胖受试者在计划的外科手术期间，并使用Western印迹和定量免疫荧光技术表征储库特异性胰岛素介导的应答。与肥胖受试者的皮下脂肪组织和内皮细胞相比，内脏中通过FOXO-1磷酸化和随后的内皮一氧化氮合酶刺激的胰岛素信号传导选择性受损。相比之下，胰岛素的组织作用在非肥胖个体中得到保留。药理学拮抗作用与AS 1842856和生物沉默使用小干扰RNA介导的FOXO-1敲低逆转胰岛素抵抗和恢复内皮型一氧化氮合酶激活在obes.ConclusionsWe观察到深刻的内皮胰岛素抵抗的内脏脂肪组织的肥胖的人，改善与FOXO-1抑制。FOXO-1的调节可能代表了一种新的治疗靶点，以减少血管胰岛素抵抗。此外，脂肪微环境中内皮胰岛素抵抗的特征可能为人类肥胖系统性疾病的机制提供线索。
ObjectiveIncreased visceral adiposity has been closely linked to insulin resistance, endothelial dysfunction, and cardiometabolic disease in obesity, but pathophysiological mechanisms are poorly understood. We sought to investigate mechanisms of vascular insulin resistance by characterizing depot-specific insulin responses and gain evidence that altered functionality of transcription factor forkhead box O-1 (FOXO-1) may play an important role in obesity-related endothelial dysfunction.Approach and ResultsWe intraoperatively collected paired subcutaneous and visceral adipose tissue samples from 56 severely obese (body mass index, 43±7 kg/m2) and 14 nonobese subjects during planned surgical operations, and characterized depot-specific insulin-mediated responses using Western blot and quantitative immunofluorescence techniques. Insulin signaling via phosphorylation of FOXO-1 and consequent endothelial nitric oxide synthase stimulation was selectively impaired in the visceral compared with subcutaneous adipose tissue and endothelial cells of obese subjects. In contrast, tissue actions of insulin were preserved in nonobese individuals. Pharmacological antagonism with AS1842856 and biological silencing using small interfering RNA–mediated FOXO-1 knockdown reversed insulin resistance and restored endothelial nitric oxide synthase activation in the obese.ConclusionsWe observed profound endothelial insulin resistance in the visceral adipose tissue of obese humans which improved with FOXO-1 inhibition. FOXO-1 modulation may represent a novel therapeutic target to diminish vascular insulin resistance. In addition, characterization of endothelial insulin resistance in the adipose microenvironment may provide clues to mechanisms of systemic disease in human obesity.