Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity.
Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity.
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DOI：
10.1038/srep35983
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发表时间：
2016-10-31
影响因子：
4.6
通讯作者：
Inagaki N
中科院分区：
文献类型：
--
作者：
Joo E;Fukushima T;Harada N;Reed JC;Matsuzawa SI;Inagaki N
肥胖与低度炎症相关，低度炎症通过Toll样受体（TLR）和TNF家族细胞因子受体（TNFR）信号通路导致胰岛素抵抗和2型糖尿病。Ubc 13是一种泛素结合酶，负责TLR和TNFR通路中涉及的TNF受体相关因子（TRAF）家族衔接蛋白的非经典K63连接的多泛素化。然而，Ubc 13与代谢性疾病之间的关系仍不清楚。在这项研究中，我们研究了Ubc 13在胰岛素抵抗和高脂饮食（HFD）诱导的肥胖中的作用。我们比较了正常饮食（ND）和HFD下的野生型（WT）和Ubc 13单倍不足（ubc 13 +/−）小鼠，因为纯合子敲除小鼠（ubc 13 −/−）是胚胎致死的。与WT小鼠相比，雄性和雌性ubc 13 +/−小鼠在ND和HFD下免受年龄相关的胰岛素抵抗。有趣的是，只有雌性ubc 13 +/−小鼠免受HFD诱导的肥胖和肝脂肪变性。此外，只有雌性HFD喂养的ubc 13 +/−小鼠表现出较低的炎性细胞因子表达，这是继发于其他组中不存在的体重增加减少。总之，我们的研究结果表明，Ubc 13活性的抑制可能发挥独立于其炎症功能的代谢作用。因此，Ubc 13可能代表胰岛素抵抗、饮食诱导的肥胖和相关代谢功能障碍的治疗靶点。
Obesity is associated with low-grade inflammation that leads to insulin resistance and type 2 diabetes via Toll-like Receptor (TLR) and TNF-family cytokine receptor (TNFR) signaling pathways. Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical K63-linked polyubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in TLR and TNFR pathways. However, the relationship between Ubc13 and metabolic disease remains unclear. In this study, we investigated the role of Ubc13 in insulin resistance and high-fat diet (HFD)-induced obesity. We compared wild-type (WT) and Ubc13 haploinsufficient (ubc13+/−) mice under normal diet (ND) and HFD, since homozygous knockout mice (ubc13−/−) are embryonic lethal. Male and female ubc13+/− mice were protected against age-related insulin resistance under ND and HFD compared to WT mice. Interestingly, only female ubc13+/− mice were protected against HFD-induced obesity and hepatic steatosis. Moreover, only female HFD-fed ubc13+/− mice showed lower expression of inflammatory cytokines that was secondary to reduction in weight gain not present in the other groups. In summary, our results indicate that suppression of Ubc13 activity may play a metabolic role independent of its inflammatory function. Thus, Ubc13 could represent a therapeutic target for insulin resistance, diet-induced obesity, and associated metabolic dysfunctions.
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影响因子：
30.5
作者：
Chang, Jae-Hoon;Xiao, Yichuan;Hu, Hongbo;Jin, Jin;Yu, Jiayi;Zhou, Xiaofei;Wu, Xuefeng;Johnson, Howard M.;Akira, Shizuo;Pasparakis, Manolis;Cheng, Xuhong;Sun, Shao-Cong
通讯作者：
Sun, Shao-Cong
影响因子：
4.8
作者：
Sayama, Koji;Yamamoto, Masahiro;Hashimoto, Koji
通讯作者：
Hashimoto, Koji
影响因子：
7.7
作者：
Nasteska, Daniela;Harada, Norio;Inagaki, Nobuya
通讯作者：
Inagaki, Nobuya
DOI：
10.1073/pnas.0700548104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Fukushima, Toru;Matsuzawa, Shu-ichi;Reed, John C.
通讯作者：
Reed, John C.
影响因子：
64.5
作者：
Deng, L;Wang, C;Chen, ZJ
通讯作者：
Chen, ZJ