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

描述（由申请人提供）： 超重/肥胖对退伍军人健康和VA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，以有效地治疗这些合并症。除了储存能量外，脂肪组织还通过缓冲血浆游离脂肪酸、限制异位脂质积聚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，并且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通过损害脂肪动脉内皮依赖性扩张（EDD）和血管生成，限制血流和白色脂肪库中脂质的原位储存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roundabout 4（Robo 4）和下游GT3，ARF 6的作用所抑制。在这里，我们将确定是否改变内皮Robo 4/ARF 6活性的基础脂肪动脉功能障碍和随后的代谢功能障碍与高脂肪喂养。与肥胖相反，长期运动对代谢有有益的影响，这可能是由腺苷一磷酸活化蛋白激酶（AMPK）介导的。随着运动，AMPK活性增加导致代谢活性组织中能量保存途径的激活;而在内皮细胞中，AMPK活性导致VEGF下游发生的NO产生。然而，目前尚不清楚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Robo 4/ARF 6信号转导调节AMPK的活性，或者AMPK的药理学激活可以作为运动模拟物并改善肥胖症时的脂肪组织功能。

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.