Lipocalin 2 regulates retinoic acid-induced activation of beige adipocytes.
Lipocalin 2 regulates retinoic acid-induced activation of beige adipocytes.
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DOI：
10.1530/jme-18-0017
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发表时间：
2018-10-01
影响因子：
3.5
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Deis JA;Guo H;Wu Y;Liu C;Bernlohr DA;Chen X
脂质运载蛋白-2（Lcn 2）是一种调节小鼠棕色脂肪组织产热激活和维甲酸（RA）诱导的产热的脂肪因子。本研究旨在探讨Lcn 2在视黄酸诱导的棕色或“米色”脂肪细胞的募集和激活中的作用和机制。我们发现Lcn 2缺乏减少了产热的关键标志物，包括来自Lcn 2 −/−小鼠的腹股沟白色脂肪组织（iWAT）和腹股沟脂肪细胞中的解偶联蛋白1（UCP 1）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）。Lcn 2 −/−腹股沟脂肪细胞减弱了胰岛素诱导的产热基因表达上调和p38丝裂原活化蛋白激酶（p38 MAPK）信号通路激活。这伴随着Lcn 2 −/−腹股沟脂肪细胞的基础和最大氧化能力降低，表明线粒体功能障碍。重组Lcn 2能够在野生型（WT）和Lcn 2 −/−腹股沟脂肪细胞中恢复胰岛素诱导的p38 MAPK磷酸化。在Lcn 2 −/−脂肪细胞分化过程中，罗格列酮处理能够以正常水平募集米色脂肪细胞，然而，在Lcn 2不存在的情况下，胰岛素和RA对米色脂肪细胞的进一步激活受到损害。此外，胰岛素和RA对UCP 1和PGC-1α表达的协同作用在Lcn 2 −/−腹股沟脂肪细胞中显著降低。最有趣的是，Lcn 2和视黄酸受体-α（RAR-α）同时易位到脂肪细胞的质膜，以响应胰岛素，这种胰岛素诱导的RAR-α易位在Lcn 2缺陷的脂肪细胞中不存在。我们的数据表明，一种新的Lcn 2介导的途径，RA和胰岛素协同调节激活米色脂肪细胞通过非基因组途径的RA行动。
Lipocalin-2 (Lcn2) has been previously characterized as an adipokine regulating thermogenic activation of brown adipose tissue and retinoic acid (RA)-induced thermogenesis in mice. The objective of this study was to explore the role and mechanism for Lcn2 in the recruitment and retinoic acid-induced activation of brown-like or “beige” adipocytes. We found Lcn2 deficiency reduces key markers of thermogenesis including uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in inguinal white adipose tissue (iWAT) and inguinal adipocytes derived from Lcn2−/− mice. Lcn2−/− inguinal adipocytes have attenuated insulin-induced upregulation of thermogenic gene expression and p38 mitogen-activated protein kinase (p38MAPK) signaling pathway activation. This is accompanied by a lower basal and maximal oxidative capacity in Lcn2−/− inguinal adipocytes, indicating mitochondrial dysfunction. Recombinant Lcn2 was able to restore insulin-induced p38MAPK phosphorylation in both wild-type (WT) and Lcn2−/− inguinal adipocytes. Rosiglitazone treatment during differentiation of Lcn2−/− adipocytes is able to recruit beige adipocytes at a normal level, however further activation of beige adipocytes by insulin and RA is impaired in the absence of Lcn2. Further, the synergistic effect of insulin and RA on UCP1 and PGC-1α expression is markedly reduced in Lcn2−/− inguinal adipocytes. Most intriguingly, Lcn2 and the retinoic acid receptor-alpha (RAR-α) are concurrently translocated to the plasma membrane of adipocytes in response to insulin, and this insulin-induced RAR-α translocation is absent in adipocytes deficient in Lcn2. Our data suggests a novel Lcn2-mediated pathway by which RA and insulin synergistically regulates activation of beige adipocytes via a non-genomic pathway of RA action.