Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity.
Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity.
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作者：
Law IK;Xu A;Lam KS;Berger T;Mak TW;Vanhoutte PM;Liu JT;Sweeney G;Zhou M;Yang B;Wang Y
由脂肪组织产生的促炎细胞因子/脂肪因子以自分泌和/或内分泌方式起作用以使局部炎症持续并诱导外周胰岛素抵抗。本研究调查是否脂质运载蛋白-2缺乏或补充与这种脂肪因子有任何影响全身胰岛素敏感性和潜在的机制。在衰老或饮食/遗传诱导的肥胖症的条件下，脂质运载蛋白-2基因敲除（Lcn 2-KO）小鼠与其野生型同窝仔相比显示出显著降低的空腹葡萄糖和胰岛素水平以及改善的胰岛素敏感性。尽管脂肪量增大，但Lcn 2-KO小鼠脂肪组织中的炎症和脂质过氧化产物的积累显著减弱。这些小鼠的脂肪脂肪酸组成与野生型动物有显著差异。花生四烯酸（C20：4 n6）的量因衰老和肥胖而升高，并且矛盾的是在脂肪组织中进一步增加，而不是在Lcn 2-KO小鼠的骨骼肌和肝脏中。另一方面，12-脂氧合酶（一种负责代谢花生四烯酸的酶）的表达和活性以及肿瘤坏死因子-α（TNF-α）（一种关键的胰岛素抵抗诱导因子）的产生在很大程度上受到脂质运载蛋白-2缺乏的抑制。Lipocalin-2刺激脂肪组织中12-脂氧合酶和TNF-α的表达和活性。肉桂酰-3，4-二羟基-α-氰基肉桂酸酯（CDC）是一种花生四烯酸脂氧合酶抑制剂，可阻止脂质运载蛋白-2诱导的TNF-α表达。此外，用TNF-α中和抗体或CDC治疗显著减弱了野生型和Lcn 2-KO小鼠之间的胰岛素敏感性差异。Lipocalin-2缺乏主要通过调节脂肪组织中的12-脂氧合酶和TNF-α水平来保护小鼠免于发展衰老和肥胖诱导的胰岛素抵抗。
The proinflammatory cytokines/adipokines produced from adipose tissue act in an autocrine and/or endocrine manner to perpetuate local inflammation and to induce peripheral insulin resistance. The present study investigates whether lipocalin-2 deficiency or replenishment with this adipokine has any impact on systemic insulin sensitivity and the underlying mechanisms. Under conditions of aging or dietary-/genetic-induced obesity, lipocalin-2 knockout (Lcn2-KO) mice show significantly decreased fasting glucose and insulin levels and improved insulin sensitivity compared with their wild-type littermates. Despite enlarged fat mass, inflammation and the accumulation of lipid peroxidation products are significantly attenuated in the adipose tissues of Lcn2-KO mice. Adipose fatty acid composition of these mice varies significantly from that in wild-type animals. The amounts of arachidonic acid (C20:4 n6) are elevated by aging and obesity and are paradoxically further increased in adipose tissue, but not skeletal muscle and liver of Lcn2-KO mice. On the other hand, the expression and activity of 12-lipoxygenase, an enzyme responsible for metabolizing arachidonic acid, and the production of tumor necrosis factor-α (TNF-α), a critical insulin resistance–inducing factor, are largely inhibited by lipocalin-2 deficiency. Lipocalin-2 stimulates the expression and activity of 12-lipoxygenase and TNF-α production in fat tissues. Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), an arachidonate lipoxygenase inhibitor, prevents TNF-α expression induced by lipocalin-2. Moreover, treatment with TNF-α neutralization antibody or CDC significantly attenuated the differences of insulin sensitivity between wild-type and Lcn2-KO mice. Lipocalin-2 deficiency protects mice from developing aging- and obesity-induced insulin resistance largely by modulating 12-lipoxygenase and TNF-α levels in adipose tissue.
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DOI：
10.1016/0167-4889(91)90077-b
发表时间：
1991-10-26
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
DAVIS, TR;TABATABAI, L;NILSENHAMILTON, M
通讯作者：
NILSENHAMILTON, M
影响因子：
4.4
作者：
Cowland, Jack B.;Muta, Tatsushi;Borregaard, Niels
通讯作者：
Borregaard, Niels
影响因子：
3.5
作者：
Jessen, BA;Stevens, GJ
通讯作者：
Stevens, GJ
DOI：
10.1073/pnas.0510847103
发表时间：
2006-02-07
影响因子：
11.1
作者：
Berger, T;Togawa, A;Mak, TW
通讯作者：
Mak, TW
DOI：
10.1093/gerona/52a.4.b190
发表时间：
1997-07-01
影响因子：
5.1
作者：
Morin, CL;Pagliassotti, MJ;Eckel, RH
通讯作者：
Eckel, RH