A novel IKKβ inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance
A novel IKKβ inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance
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DOI：
10.1016/j.bbrc.2004.08.083
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发表时间：
2004-10-08
影响因子：
3.1
通讯作者：
Kadowaki, T
中科院分区：
文献类型：
--
作者：
Kamon, J;Yamauchi, T;Kadowaki, T
脂联素是一种仅由脂肪细胞分泌的抗糖尿病和抗动脉粥样硬化激素。肥胖患者和肥胖模型小鼠血清脂联素水平降低，尽管脂肪组织质量增加。阐明肥胖和糖尿病患者血浆脂联素水平降低的机制将有助于深入了解肥胖诱发糖尿病的原因和治疗进展。本研究采用3T3-L1脂肪细胞和糖尿病/肥胖小鼠模型研究脂联素分泌的调节。一种新的胰岛素增敏剂，IkappaB激酶β (ikkβ)抑制剂，改善了高脂肪饮食的KKA(y)小鼠的胰岛素抵抗和上调血浆脂联素水平，而不会产生显著的体重变化。IKKbeta抑制剂取消了tnfalpha介导的脂联素分泌下调，同时上调了3T3-L1脂肪细胞中Akt的磷酸化。利用Akt或PKClambda（磷酸肌肽激酶下游效应因子）的显性阴性突变体，发现胰岛素刺激的Akt活性在3T3-L1脂肪细胞中胰岛素分泌脂联素的调节中起重要作用。这些观察结果表明，“胰岛素刺激脂肪细胞中Akt活性”可能在调节脂联素分泌中发挥重要作用。(C) 2004爱思唯尔公司版权所有。
Adiponectin is an anti-diabetic and anti-atherogenic hormone that is exclusively secreted from fat cells. Serum adiponectin levels are reduced in obese patients and obese model mice, despite increased adipose tissue mass. Elucidation of the mechanism(s) by which plasma adiponectin levels are decreased in obese and diabetic patients would provide insight into the cause of obesity-induced diabetes and the development of therapeutic advances. In the present study, the regulation of adiponectin secretion was investigated using 3T3-L1 adipocytes and a diabetic-/obese-mouse model. A novel insulin sensitizer, IkappaB kinase beta (IKKbeta) inhibitor, ameliorated insulin resistance and up-regulated plasma levels of adiponectin without producing a significant change in body weight in KKA(y) mice that were fed a high-fat diet. The IKKbeta inhibitor cancelled the TNFalpha-mediated down-regulation of adiponectin secretion and simultaneously up-regulated the phosphorylation of Akt in 3T3-L1 adipocytes. Using dominant-negative mutants of Akt or PKClambda, (downstream effectors of phosphoinositide 3-kinase), insulin-stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes. These observations suggest that "insulin-stimulated Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion. (C) 2004 Elsevier Inc. All rights reserved.