Red Blood Cell Endothelial Nitric Oxide Attenuates Insulin Resistance
红细胞内皮一氧化氮减弱胰岛素抵抗
基本信息
- 批准号:9767272
- 负责人:
- 金额:$ 56.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-20 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAdultAffectAgeArginineAtherosclerosisAttenuatedBiological AvailabilityBlood VesselsBlood flowBone MarrowCellsChronicClinical ResearchDataDevelopmentDiabetes MellitusDiseaseEndothelial CellsEndotheliumErythrocytesErythroidErythropoietin ReceptorFatty acid glycerol estersGeneticGenetic ModelsHepaticHomeostasisImmuneImmune responseInflammationInflammation MediatorsInflammatoryInsulinInsulin ResistanceKnock-outKupffer CellsLaboratoriesLiverMacrophage ActivationMediatingMediator of activation proteinMetabolicModelingMusMuscleNOS3 geneNitric OxideNon-Insulin-Dependent Diabetes MellitusNutrientObesityPathway interactionsPatientsPharmacologyPhysiologicalPlayPopulationProductionRisk FactorsRoleSourceSpleenTestingTherapeuticTissuesUnited StatesWorkarginaseendothelial dysfunctionfeedingimprovedinsulin sensitivitymacrophagemetabolomicsnovelobesity developmentoverexpressionpathogenpreservationprevent
项目摘要
Nitric oxide and endothelial nitric oxide synthase (eNOS or Nos3) are well-established contributors
to vascular homeostasis. Nevertheless, loss of Nos3 appears to result in metabolic derangements that
contribute to insulin resistance. More specifically, a reduction in Nos3-derived NO during obesity
precedes the development of insulin resistance4 and genetic deletion of Nos3 (Nos3–/– mouse) is
associated with both systemic and hepatic insulin resistance. Moreover, pharmacologic strategies that
restore NO bioavailability during obesity (e.g. PDE5 inhibition) and genetic strategies that increase NO
production (e.g. Nos3 overexpression) restore insulin sensitivity in mice.
Our laboratory and others have long attributed the salutary metabolic effects of Nos3 to
endothelium-mediated improvement of blood flow that increases delivery of nutrients to insulin-sensitive
tissues such as liver, muscle, and adipose tissue, thereby facilitating nutrient utilization or storage and
maintaining metabolic homeostasis. However, recent work from our laboratory suggests that, during
obesity, bone marrow derived cell Nos3—not endothelial Nos3—preserves metabolic homeostasis.
Here we propose a novel model in which NO produced by red blood cell (RBC) Nos3 acts as a
physiological brake on inflammatory activation. During obesity, we propose that a reduction in RBC-
derived NO releases this brake, increasing hepatic macrophage activation and promoting insulin
resistance.
Crosstalk between RBC and macrophage are crucial for RBC clearance, since residential
macrophages scrutinize passing RBC and remove damaged RBC in the liver and spleen and work also
suggests that RBC participate in macrophage-mediated immune responses to pathogens. These
observations establish an important yet under-investigated interaction between RBC and immune cells.
We propose the novel hypothesis that RBC Nos3/NO is required to maintain hepatic insulin
sensitivity through its effects to limit activation of Kupffer cells, and that the loss of these effects of NO
leads to obesity-associated hepatic insulin resistance. If this hypothesis is correct, the translational
significance will be considerable because therapeutic options that increase NO bioavailability are
already available. These therapies might prevent obesity-mediated insulin resistance. Furthermore,
studies proposed here may uncover a novel RBC dependent pathway for attenuating macrophage
activation in states of low-grade chronic inflammation such as obesity or atherosclerosis. We propose
the following aims: Aim 1. To test the hypothesis that RBC Nos3 is sufficient to maintain hepatic insulin
sensitivity by attenuating Kupffer cell activation during obesity. Aim 2. To determine whether T2D is
associated with reduced RBC NO content and increased arginase 1 activity.
一氧化氮和内皮型一氧化氮合酶(eNOS或Nos3)是公认的贡献者
血管内环境的平衡然而,Nos3的缺失似乎会导致代谢紊乱,
导致胰岛素抵抗。更具体地说,肥胖期间Nos3衍生的NO减少
在胰岛素抵抗的发展之前4和Nos3的遗传缺失(Nos3-/-小鼠)是
与全身和肝脏胰岛素抵抗相关。此外,
在肥胖期间恢复NO生物利用度(例如,PDE5抑制)和增加NO的遗传策略
在小鼠中,胰岛素生产(例如Nos3过表达)恢复胰岛素敏感性。
我们的实验室和其他实验室长期以来一直将Nos3的有益代谢作用归因于
内皮介导的血流改善,增加向胰岛素敏感性
组织如肝脏、肌肉和脂肪组织,从而促进营养利用或储存,
维持代谢平衡然而,我们实验室最近的工作表明,
在肥胖症中,骨髓来源的细胞Nos3-而不是内皮Nos3-保持代谢稳态。
在这里,我们提出了一种新的模型,其中由红细胞(RBC)Nos3产生的NO作为一种新的细胞因子。
对炎症激活的生理制动。在肥胖期间,我们建议减少红细胞-
衍生的NO释放该制动器,增加肝巨噬细胞活化并促进胰岛素分泌。
阻力
红细胞和巨噬细胞之间的串扰对于红细胞清除至关重要,
巨噬细胞仔细检查通过的红细胞,清除肝脏和脾脏中受损的红细胞,
表明RBC参与巨噬细胞介导的对病原体的免疫应答。这些
这些观察建立了RBC和免疫细胞之间重要但研究不足的相互作用。
我们提出了新的假说,即红细胞Nos 3/NO是维持肝脏胰岛素所必需的
敏感性通过其影响,以限制激活库普弗细胞,并认为这些影响的损失,
导致肥胖相关的肝脏胰岛素抵抗。如果这一假设是正确的,
重要性是相当大的,因为增加NO生物利用度的治疗选择
已经有了。这些疗法可能会预防肥胖介导的胰岛素抵抗。此外,委员会认为,
本文提出的研究可能揭示了一种新的红细胞依赖性途径,
在轻度慢性炎症状态如肥胖或动脉粥样硬化中激活。我们提出
目标:目标1。为了检验RBC Nos 3足以维持肝脏胰岛素的假设,
通过减弱肥胖期间库普弗细胞激活来增强对高敏感性的敏感性。目标二。为了确定T2D是否
与红细胞NO含量降低和红细胞脱氢酶1活性增加有关。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Francis Kim其他文献
Francis Kim的其他文献
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{{ truncateString('Francis Kim', 18)}}的其他基金
Red Blood Cell Endothelial Nitric Oxide Attenuates Insulin Resistance
红细胞内皮一氧化氮减弱胰岛素抵抗
- 批准号:
10181020 - 财政年份:2018
- 资助金额:
$ 56.37万 - 项目类别:
Endothelial nitric oxide synthase and regulation of macrophage function
内皮一氧化氮合酶与巨噬细胞功能的调节
- 批准号:
9126069 - 财政年份:2016
- 资助金额:
$ 56.37万 - 项目类别:
Randomized clinical trial of sodium nitrite for out of hospital cardiac arrest
亚硝酸钠治疗院外心脏骤停的随机临床试验
- 批准号:
9922344 - 财政年份:2016
- 资助金额:
$ 56.37万 - 项目类别:
Mild Hypothermia for Resuscitated Out-of-Hospital Cardiac Arrest Patients
院外心脏骤停复苏患者的轻度低温治疗
- 批准号:
7683141 - 财政年份:2008
- 资助金额:
$ 56.37万 - 项目类别:
Mild Hypothermia for Resuscitated Out-of-Hospital Cardiac Arrest Patients
院外心脏骤停复苏患者的轻度低温治疗
- 批准号:
8316240 - 财政年份:2008
- 资助金额:
$ 56.37万 - 项目类别:
Mild Hypothermia for Resuscitated Out-of-Hospital Cardiac Arrest Patients
院外心脏骤停复苏患者的轻度低温治疗
- 批准号:
8097237 - 财政年份:2008
- 资助金额:
$ 56.37万 - 项目类别:
Mild Hypothermia for Resuscitated Out-of-Hospital Cardiac Arrest Patients
院外心脏骤停复苏患者的轻度低温治疗
- 批准号:
7459480 - 财政年份:2008
- 资助金额:
$ 56.37万 - 项目类别:
Mild Hypothermia for Resuscitated Out-of-Hospital Cardiac Arrest Patients
院外心脏骤停复苏患者的轻度低温治疗
- 批准号:
7899796 - 财政年份:2008
- 资助金额:
$ 56.37万 - 项目类别:
IKKBeta Mediated Impairment of Endothelial Nitric Oxide Production
IKKβ 介导的内皮一氧化氮生成损伤
- 批准号:
7269389 - 财政年份:2006
- 资助金额:
$ 56.37万 - 项目类别:
IKKBeta Mediated Impairment of Endothelial Nitric Oxide Production
IKKβ 介导的内皮一氧化氮生成损伤
- 批准号:
7455212 - 财政年份:2006
- 资助金额:
$ 56.37万 - 项目类别:
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