CREG1 heterozygous mice are susceptible to high fat diet-induced obesity and insulin resistance.
CREG1 heterozygous mice are susceptible to high fat diet-induced obesity and insulin resistance.
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CREG1杂合子小鼠易患高脂饮食引起的肥胖和胰岛素抵抗
DOI：
10.1371/journal.pone.0176873
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Han Y
中科院分区：
文献类型：
--
作者：
Tian X;Yan C;Liu M;Zhang Q;Liu D;Liu Y;Li S;Han Y
E1 A刺激基因的细胞阻遏物1（CREG 1）是一种小分子糖蛋白，其生理功能尚不清楚。在细胞培养研究中，CREG 1促进细胞分化和成熟。为了阐明其生理功能，我们删除了小鼠的Creg 1基因，发现CREG 1的缺失导致早期胚胎死亡，这表明它对早期发育至关重要。在对Creg 1杂合子小鼠的分析中，我们意外地观察到它们随着年龄的增长而肥胖。在这项研究中，我们进一步研究了这种表型喂养野生型（WT）和Creg 1杂合子（Creg 1 +/-）小鼠高脂肪饮食（HFD）16周。我们的数据表明，当受到HFD攻击时，与WT对照相比，Creg 1 +/-小鼠表现出更突出的肥胖表型，而食物摄入量没有变化。Creg 1单倍不足也加重了HFD诱导的肝脏脂肪变性、血脂异常和胰岛素抵抗。此外，与WT对照组相比，HFD显著增加Creg 1 +/-小鼠血浆和附睾脂肪组织中的促炎细胞因子。在Creg 1 +/-小鼠中，附睾脂肪组织中NF-κB（炎症反应的主要调节因子）的活化水平也与细胞因子平行升高。通过siRNA转染在CREG 1耗尽的3 T3-L1衍生的脂肪细胞中证实了CREG 1减少引起的这些促炎反应。鉴于脂肪组织炎症已被证明在肥胖诱导的胰岛素抵抗和代谢综合征中起关键作用，我们的研究结果表明，Creg 1单倍不足使脂肪组织对炎症的易感性增加，导致HFD挑战时肥胖和胰岛素抵抗加重。这项研究揭示了CREG 1在代谢紊乱中的新功能。
Cellular repressor of E1A-stimulated genes 1 (CREG1) is a small glycoprotein whose physiological function is unknown. In cell culture studies, CREG1 promotes cellular differentiation and maturation. To elucidate its physiological functions, we deleted the Creg1 gene in mice and found that loss of CREG1 leads to early embryonic death, suggesting that it is essential for early development. In the analysis of Creg1 heterozygous mice, we unexpectedly observed that they developed obesity as they get older. In this study, we further studied this phenotype by feeding wild type (WT) and Creg1 heterozygote (Creg1+/-) mice a high fat diet (HFD) for 16 weeks. Our data showed that Creg1+/- mice exhibited a more prominent obesity phenotype with no change in food intake compared with WT controls when challenged with HFD. Creg1 haploinsufficiency also exacerbated HFD-induced liver steatosis, dyslipidemia and insulin resistance. In addition, HFD markedly increased pro-inflammatory cytokines in plasma and epididymal adipose tissue in Creg1+/- mice as compared with WT controls. The activation level of NF-κB, a major regulator of inflammatory response, in epididymal adipose tissue was also elevated in parallel with the cytokines in Creg1+/- mice. These pro-inflammatory responses elicited by CREG1 reduction were confirmed in 3T3-L1-derived adipocytes with CREG1 depletion by siRNA transfection. Given that adipose tissue inflammation has been shown to play a key role in obesity-induced insulin resistance and metabolic syndrome, our results suggest that Creg1 haploinsufficiency confers increased susceptibility of adipose tissue to inflammation, leading to aggravated obesity and insulin resistance when challenged with HFD. This study uncovered a novel function of CREG1 in metabolic disorders.