Metabolic implications of adipose arterial function: Role of Robo4 and AMPK

脂肪动脉功能的代谢影响：Robo4 和 AMPK 的作用

• 批准号: 9275394
• 负责人: Lisa A Lesniewski
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275394
• 关键词: ADP-ribosylation factor 6; Adenosine Monophosphate; Adhesions; Adhesives; Adipocytes; Adipose tissue; Arteries; Binding; Biological Availability; Blood Vessels; Blood flow; Buffers; Caring; Cells; Chronic; Comorbidity; Consumption; Custom; Deposition; Endothelial Cells; Endothelium; Ensure; Event; Exercise; Family; Fatty acid glycerol esters; Fibrosis; Functional disorder; GTP-Binding Proteins; Glucose; Goals; Growth; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Health; Health Care Costs; High Fat Diet; Homeostasis; Hypoxia; Immune; Impairment; Infiltration; Inflammation; Insulin; Insulin Resistance; Knockout Mice; Lead; Leukocytes; Lipids; Liver; Longevity; Mediating; Metabolic; Metabolism; Mus; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obesity; Outcome; Overweight; Oxidative Stress; Oxygen; Pathway interactions; Perfusion; Pharmacology; Plasma; Play; Production; Protein Isoforms; Protein Kinase; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Research; Resistance; Role; Running; Signal Transduction; Signaling Molecule; Skeletal Muscle; Time; Tissues; Vascular Endothelial Growth Factors; Vascular Endothelium; Vasodilation; Vasodilator Agents; Veterans; adipocyte differentiation; adipokines; angiogenesis; axon guidance; chemokine; clinically relevant; cytokine; density; endothelial dysfunction; feeding; glucose uptake; impaired glucose tolerance; improved; improved functioning; inhibitor/antagonist; insulin sensitivity; mimetics; protein kinase inhibitor; public health relevance; response; wasting

DESCRIPTION (provided by applicant): The impact of overweight/obesity on Veterans' health and VA healthcare costs is staggering and a better understanding of the mechanisms by which overweight/obesity lead to metabolic dysfunction, as well as the mechanisms by which exercise improves this dysfunction, is required to effectively treat these comorbidities. In addition to the storage of energy, adipose tissue contributes to metabolic homeostasis by buffering plasma free fatty acids, limiting ectopic lipid accumulation and secreting adipokines. Appropriate adipose tissue blood flow is required for normal adipose function and is influenced by its resistance artery vasoreactivity and vascular density. Thus, arterial dysfunction characterized by a loss of nitric oxide (NO) may contribute to metabolic dysfunction by impairing adipose artery endothelium dependent dilation (EDD) and angiogenesis, limiting both blood flow and the entopic storage of lipids in white adipose depots. Recently, the pro-angiogenic effects of vascular endothelial growth factor (VEGF) were shown to be inhibited by the actions of roundabout4 (Robo4) and the downstream GTPase, ARF6. Here, we will determine if altered endothelial Robo4/ARF6 activity underlies adipose artery dysfunction and subsequent metabolic dysfunction with high fat feeding. In contrast to obesity, chronic exercise has beneficial effects on metabolism that may be mediated by adenosine monophosphate-activated protein kinase (AMPK). With exercise, increased AMPK activity leads to activation of energy conserving pathways in metabolically active tissues; whereas, in endothelial cells, AMPK activity leads to NO production that occurs downstream of VEGF. However, it is not known what role AMPK activation may play in improving adipose tissue function, if endothelial Robo4/ARF6 signaling modulates the activity of AMPK or if pharmacological activation of AMPK can serve as an exercise mimetic and improve adipose tissue function in the face of obesity.

描述（由申请人提供）： 超重/肥胖对退伍军人健康和退伍军人管理局医疗费用的影响是惊人的，需要更好地了解超重/肥胖导致代谢功能障碍的机制，以及运动改善这种功能障碍的机制，才能有效治疗这些合并症。除了储存能量外，脂肪组织还通过缓冲血浆游离脂肪酸、限制异位脂质积累和分泌脂肪因子来促进代谢稳态。适当的脂肪组织血流量是正常脂肪功能所必需的，并受到其阻力动脉血管反应性和血管密度的影响。因此，以一氧化氮（NO）损失为特征的动脉功能障碍可能会损害脂肪动脉内皮依赖性扩张（EDD）和血管生成，从而限制血流和白色脂肪库中脂质的原位储存，从而导致代谢功能障碍。最近，血管内皮生长因子 (VEGF) 的促血管生成作用被证明可被 roundabout4 (Robo4) 和下游 GTPase ARF6 的作用所抑制。在这里，我们将确定内皮 Robo4/ARF6 活性的改变是否是脂肪动脉功能障碍以及随后高脂肪喂养引起的代谢功能障碍的基础。与肥胖相反，长期运动对新陈代谢有有益的影响，这可能是由腺苷单磷酸激活蛋白激酶（AMPK）介导的。通过锻炼，AMPK 活性增加会激活代谢活跃组织中的能量保存途径；而在内皮细胞中，AMPK 活性会导致 VEGF 下游产生 NO。然而，尚不清楚 AMPK 激活在改善脂肪组织功能中可能发挥什么作用，如果内皮 Robo4/ARF6 信号传导调节 AMPK 的活性，或者 AMPK 的药理激活是否可以作为运动模拟并改善脂肪组织功能。肥胖。