Fisman Enrique Z, Tenenbaum Alexander
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Cardiovasc Diabetol. 2014 Jun 23;13:103. doi: 10.1186/1475-2840-13-103.
Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T-cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists.
脂联素是脂肪细胞分泌的最丰富的肽，是肥胖、胰岛素抵抗和炎症之间相互关系的关键组成部分。伴有胰岛素抵抗的中心性肥胖是代谢综合征（MS）及未来大血管并发症发生发展的关键因素。此外，冠状动脉疾病（CAD）与糖代谢改变之间的显著相关性增加了动脉粥样硬化和2型糖尿病（T2DM）可能具有共同生物学背景的可能性。我们在此总结了目前关于脂联素对胰岛素敏感性和内皮功能影响的知识，讨论了其未来前景以及作为MS、T2DM和心血管疾病治疗靶点的潜在作用。脂联素以二聚体、三聚体或高分子量六聚体（>400 kDa）的蛋白质复合物形式存在于循环中。AdipoR1和AdipoR2是其体内介导代谢作用的主要受体。脂联素刺激磷酸化和AMP（单磷酸腺苷）激酶激活，对血管内皮产生直接作用，减少对机械损伤的炎症反应，并在载脂蛋白E缺乏的情况下增强内皮保护。低脂联素血症一直与肥胖、MS、动脉粥样硬化、CAD、T2DM相关。生活方式的调整有助于有益地改变血浆脂联素水平。肥胖患者的低脂联素血症通过糖尿病和非糖尿病个体持续的体重减轻计划而升高，同时促炎因子也会减少。饮食调整，如摄入鱼类、补充ω-3脂肪酸、坚持地中海饮食模式和饮用咖啡也会增加脂联素水平。抗糖尿病和心血管药物，如格列酮类、格列美脲、血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂也能够提高脂联素浓度。贝特类药物，如苯扎贝特和非诺贝特，也已被报道可提高脂联素水平。T-钙黏蛋白是一种缺乏细胞内结构域的膜相关脂联素结合蛋白，似乎是脂联素抗动脉粥样硬化作用的主要介质。寻找能够提高血浆脂联素水平的新型药物应该是深入研究的目标。有趣的未来方法可能是开发化学设计用于诱导其受体激活和/或受体后信号通路激活的脂联素靶向药物，或者开发特异性脂联素激动剂。
