A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity
A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity
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DOI：
10.1210/en.2003-1068
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发表时间：
2004-01-01
期刊：
影响因子：
4.8
通讯作者：
Scherer, PE
中科院分区：
文献类型：
--
作者：
Combs, TP;Pajvani, UB;Scherer, PE
脂联素是一种仅在脂肪组织中表达的血浆蛋白。脂联素水平与胰岛素敏感性有关，但脂联素长期升高对改善胰岛素敏感性的直接作用尚未得到证实。我们在脂联素的胶原结构域中发现了一个显性突变，该突变使小鼠的循环脂联素值升高3倍。脂联素血症提高脂质清除率和脂蛋白脂酶活性，抑制胰岛素介导的内源性葡萄糖生成。在这些转基因动物中，青春期脂联素的诱导和成年脂联素值的性别二态性得以保留。由于脂联素升高，血清PRL值和棕色脂肪量均增加。对碳水化合物和脂质代谢的影响与肝脏中5 '-AMP活化蛋白激酶磷酸化水平升高以及白色脂肪组织中过氧化物酶体增殖物活化受体γ 2、小窝蛋白-1和线粒体标志物表达升高相关。这些研究有力地表明，增加内源性脂联素水平对胰岛素敏感性有直接影响，并可能诱导与过氧化物酶体增殖物激活受体γ激动剂长期治疗相似的生理反应。
Adiponectin is a plasma protein expressed exclusively in adipose tissue. Adiponectin levels are linked to insulin sensitivity, but a direct effect of chronically elevated adiponectin on improved insulin sensitivity has not yet been demonstrated. We identified a dominant mutation in the collagenous domain of adiponectin that elevated circulating adiponectin values in mice by 3-fold. Adiponectinemia raised lipid clearance and lipoprotein lipase activity, and suppressed insulin-mediated endogenous glucose production. The induction of adiponectin during puberty and the sexual dimorphism in adult adiponectin values were preserved in these transgenic animals. As a result of elevated adiponectin, serum PRL values and brown adipose mass both increased. The effects on carbohydrate and lipid metabolism were associated with elevated phosphorylation of 5'-AMP-activated protein kinase in liver and elevated expression of peroxisomal proliferator-activated receptor gamma2, caveolin-1, and mitochondrial markers in white adipose tissue. These studies strongly suggest that increasing endogenous adiponectin levels has direct effects on insulin sensitivity and may induce similar physiological responses as prolonged treatment with peroxisomal proliferator-activated receptor gamma agonists.