ADIPOSE TISSUE INFLAMMATION & VASCULARITY

人们越来越认识到，脂肪组织巨噬细胞活化在与肥胖相关的慢性炎症和代谢功能障碍的发展中起重要作用。肥胖的生物体也显示毛细血管稀疏和减少灌注在他们的脂肪垫。脂肪组织缺氧被认为与炎症有关，因为这种压力将有利于脂肪细胞坏死并导致巨噬细胞招募。反过来，肥胖生物体的脂肪垫环境将有利于巨噬细胞活化并导致血管床的进一步降解。因此，可以合理地推测，肥胖有利于脂肪组织中缺氧和炎症的恶性循环。 脂联素是一种脂肪源性细胞因子，具有抗炎和促血管生成活性。 来自瘦肉型生物体的脂肪组织表达高水平的脂联素，并且随着脂肪量的增加，脂联素表达逐渐下降。炎症细胞因子和缺氧都将导致脂肪细胞脂联素表达的减少。我实验室已发表的研究表明，脂联素在各种缺血模型中促进内皮细胞功能和血管生成，但脂联素在脂肪垫血管化中的作用从未被研究过。此外，虽然脂联素具有公认的抗炎特性，但其对脂肪组织巨噬细胞极化的影响从未被系统地描述过。在这个建议中，我们将进行一系列的实验来研究脂联素在脂肪垫生物学中的作用，以确定肥胖症中炎症和缺氧之间的功能相互关系。所提出的实验将测试脂联素作为巨噬细胞表型的直接调节剂的假设，有利于抗炎，M2样极化，它促进脂肪垫灌注。我们认为脂联素的这些活性控制脂肪垫的微环境，从而影响全身代谢和心血管功能。此外，基因消融 将在体外和小鼠遗传模型中进行实验，以确定赋予脂联素对脂肪垫灌注和炎症作用的受体的鉴定。

It is becoming increasingly appreciated that adipose tissue macrophage activation plays an important role in the development of chronic inflammation and metabolic dysfunction associated with obesity. Obese organisms also display capillary rarefaction and diminished perfusion in their fat pads. Adipose tissue hypoxia is thought to be linked to inflammation because this stress will favor adipocyte necrosis and lead to macrophage recruitment. In turn, the fat pad milieu of an obese organism will favor macrophage activation and lead to further degradation of the vascular bed. Thus, it is reasonable to speculate that obesity favors a vicious cycle of hypoxia and inflammation in adipose tissue. Adiponectin is a fat-derived cytokine that has both anti-inflammatory and pro-angiogenic activities. Adipose tissues from lean organisms express high levels of adiponectin and there is a progressive decline in adiponectin expression as fat mass increases. Both infiammatory cytokines and hypoxia will lead to reductions in adiponectin expression by adipocytes. Published work from my lab has shown that adiponectin will promote endothelial cell function and angiogenesis in a variety of ischemia models, but the role of adiponecfin in fat pad vascularization has never been examined. Furthermore, while adiponectin has recognized anti-inflammatory properties, its effect on adipose tissue macrophage polarization has never been systematically delineated. In this proposal, we will perform a series of experiments to investigate the role of adiponectin in fat pad biology to define the functional interrelationship between inflammation and hypoxia in obesity. The proposed experiments will test the hypotheses that adiponectin functions as a direct regulator of macrophage phenotype, favoring anti-inflammatory, M2-like polarization, and that it promotes fat pad perfusion. We propose that these activities of adiponectin control the microenvironment of the fat pad, and thereby infiuence systemic metabolism and cardiovascular function. Furthermore, gene ablation experiments in vitro and in mouse genetic models will be performed to determine the identifies of the receptors that confer adiponectin¿s actions on fat pad perfusion and inflammation.