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: 8821224
• 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/8821224
• 关键词: ADP-ribosylation factor 6; Adenosine Monophosphate; Adhesions; Adhesives; Adipocytes; Adipose tissue; Arteries; Binding; Biological Availability; Blood Vessels; Blood flow; Boxing; Buffers; Caring; Cells; Chronic; Comorbidity; Consumption; Custom; Deposition; Diet; 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; 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; 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/肥胖对退伍军人的健康和退伍军人保健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，才能有效地治疗这些并存疾病。除了储存能量外，脂肪组织还通过缓冲血浆游离脂肪酸、限制异位脂肪堆积和分泌脂肪因子来促进代谢平衡。适当的脂肪组织血流量是正常脂肪功能所必需的，并受其阻力、动脉血管反应性和血管密度的影响。因此，以一氧化氮(NO)丢失为特征的动脉功能障碍可能通过损害脂肪动脉内皮依赖性扩张(EDD)和血管生成，限制白色脂肪库中的血流和脂质的在位储存，从而导致代谢功能障碍。最近，血管内皮细胞生长因子(VEGF)的促血管生成作用被证明被Roundabout 4(Robo4)及其下游的GTP酶ARF6所抑制。在这里，我们将确定内皮细胞Robo4/ARF6活性改变是否是高脂肪喂养下脂肪动脉功能障碍和随后的代谢功能障碍的基础。与肥胖相比，慢性运动对新陈代谢的有益影响可能是通过一磷酸腺苷激活的蛋白激酶(AMPK)介导的。在运动中，AMPK活性的增加导致代谢活跃的组织中能量守恒通路的激活；而在内皮细胞中，AMPK活性导致血管内皮生长因子下游的NO产生。然而，如果内皮细胞Robo4/ARF6信号调节AMPK的活性，或者AMPK的药理激活是否可以作为运动模拟物并在面对肥胖时改善脂肪组织功能，AMPK的激活在改善脂肪组织功能方面可能发挥什么作用尚不清楚。