Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor γ agonists
Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor γ agonists
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DOI：
10.1074/jbc.m505311200
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发表时间：
2006-02-03
影响因子：
4.8
通讯作者：
Scherer, PE
中科院分区：
文献类型：
--
作者：
Nawrocki, AR;Rajala, MW;Scherer, PE
脂肪组织来源的激素脂联素改善胰岛素敏感性，其循环水平在肥胖引起的胰岛素抵抗中降低。在这里，我们报告的一代小鼠系与基因组破坏脂联素位点。我们的目的是确定这些小鼠是否会产生胰岛素抵抗，以及哪些是该模型中受影响的主要靶组织。通过血糖/胰岛素钳夹研究，我们证明这些小鼠表现出严重的肝脏胰岛素抵抗，而不是外周胰岛素抵抗。此外，我们想测试在饮食挑战的情况下，脂联素的缺乏是否会放大葡萄糖稳态的损害。当暴露于高脂肪饮食时，脂联素缺失的小鼠迅速发展为葡萄糖耐受不良。特异性PPAR γ激动剂如噻唑烷二酮（TZDs）改善胰岛素敏感性的机制很大程度上未知。激活PPAR γ后，体内循环脂联素水平显著上调。已经证明TZDs和脂联素在相同的靶组织中激活amp活化的蛋白激酶（AMPK）。我们想要确定TZDs改善葡萄糖耐量的能力是否依赖于脂联素，以及这种改善是否涉及AMPK的激活。我们证明PPAR γ激动剂改善缺乏脂联素的ob/ob小鼠葡萄糖耐量的能力减弱。脂联素是激活肝脏和肌肉中使用TZD后AMPK所必需的。综上所述，脂联素是PPAR γ介导的葡萄糖耐量改善的重要贡献者，其机制涉及AMPK通路的激活。
The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPAR gamma agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPAR gamma. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPAR gamma agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPAR gamma-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway.