Reduced Endoplasmic Reticulum Stress-Mediated Autophagy Is Required for Leptin Alleviating Inflammation in Adipose Tissue.
Reduced Endoplasmic Reticulum Stress-Mediated Autophagy Is Required for Leptin Alleviating Inflammation in Adipose Tissue.
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减少内质网应激介导的自噬是瘦素减轻脂肪组织炎症所必需的。
DOI：
10.3389/fimmu.2017.01507
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发表时间：
2017
影响因子：
7.3
通讯作者：
Sun C
中科院分区：
文献类型：
--
作者：
Gan L;Liu Z;Luo D;Ren Q;Wu H;Li C;Sun C
瘦素是一种脂肪细胞来源的激素，在挑战条件下维持脂肪功能。自噬对于维持细胞内环境稳定和调节脂肪组织的特性也是必不可少的。然而，瘦素对脂肪细胞自噬的影响尚不清楚。在这里，我们通过脂肪组织的转录组测序证明了内质网（ER）应激和瘦素与自噬和炎症相关。瘦素介导的自噬抑制参与了ER应激蛋白如Chop、GRP 78和Atf 4的上游减少，因为使用药理学方法阻断自噬对衣霉素诱导的ER应激没有影响。此外，我们确定KLF 4，Atf 4的潜在转录因子，是所需的瘦素介导的自噬在调节脂肪细胞炎症。重要的是，ATF 4与ATG 5物理相互作用，随后形成复合物以促进脂肪细胞自噬。进一步的分析表明，Atg 5，自噬体的核心组成部分，是瘦素介导的自噬的目标。此外，瘦素通过减少脂肪细胞中自噬介导的IκB降解来减轻ER应激诱导的炎症。外源性瘦素治疗也改善了ob/ob小鼠白色脂肪组织的自噬和炎症。综上所述，我们的研究结果表明，瘦素抑制ER应激介导的自噬和炎症通过负向调节Atf 4/Atg 5复合物在脂肪细胞。这些发现为干预自噬以预防或治疗肥胖引起的哺乳动物代谢综合征提供了一种新的潜在手段。
Leptin is an adipocyte-derived hormone and maintains adipose function under challenged conditions. Autophagy is also essential to maintain cellular homeostasis and regulate characteristics of adipose tissue. However, the effects of leptin on autophagy of adipocyte remain elusive. Here, we demonstrated endoplasmic reticulum (ER) stress and leptin were correlated with autophagy and inflammation by transcriptome sequencing of adipose tissue. Leptin-mediated inhibition of autophagy was involved in upstream reduction of ER stress proteins such as Chop, GRP78, and Atf4, since blockage of autophagy using pharmacological approach had no effect on tunicamycin-induced ER stress. Moreover, we determined KLF4, the potential transcriptional factor of Atf4, was required for the leptin-mediated autophagy in the regulation of adipocyte inflammation. Importantly, ATF4 physically interacted with ATG5 and subsequently formed a complex to promote adipocyte autophagy. Further analysis revealed that Atg5, a core component of autophagosome, was the target for leptin-mediate autophagy. In addition, leptin alleviated ER stress-induced inflammation by reducing autophagy-mediated degradation of IκB in adipocytes. Exogenous leptin treatment also ameliorated autophagy and inflammation of white adipose tissue in ob/ob mice. Taken together, our results indicated that leptin inhibited ER stress-mediated autophagy and inflammation through the negatively regulation of Atf4/Atg5 complex in adipocytes. These findings identify a new potential means for intervention of autophagy to prevent or treat obese caused metabolic syndrome of mammals.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
29
作者：
Altshuler-Keylin S;Shinoda K;Hasegawa Y;Ikeda K;Hong H;Kang Q;Yang Y;Perera RM;Debnath J;Kajimura S
通讯作者：
Kajimura S
影响因子：
32.4
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
通讯作者：
O'Riordan MX
影响因子：
29
作者：
Arteaga-Solis E;Zee T;Emala CW;Vinson C;Wess J;Karsenty G
通讯作者：
Karsenty G
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影响因子：
4.6
作者：
Gan L;Liu Z;Chen Y;Dan Luo;Feng F;Liu G;Sun C
通讯作者：
Sun C