Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity.
Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity.
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DOI：
10.1016/j.celrep.2018.06.112
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发表时间：
2018-07-31
期刊：
影响因子：
8.8
通讯作者：
Dixit VD
中科院分区：
文献类型：
--
作者：
Ravussin A;Youm YH;Sander J;Ryu S;Nguyen K;Varela L;Shulman GI;Sidorov S;Horvath TL;Schultze JL;Dixit VD
饱腹感诱导剂是减轻肥胖相关疾病的减肥药物靶点。nucleobinin -2 （Nucb2）被认为在翻译后被加工成具有生物活性的nesfatin-1肽，据报道，它可以诱导饱腹感，导致体重减轻，从而改善胰岛素敏感性。在这里，我们发现缺失Nucb2并不影响食物摄入或肥胖，相反，在喂食高脂肪饮食的小鼠中引起胰岛素抵抗。此外，下丘脑缺氧Agrp神经元中Nucb2的消融不影响食物摄入，尽管Nucb2蛋白整体缺失，但血清中可检测到nesfatin-1。在高脂饲料喂养时，Nucb2的缺失以nfκ b依赖的方式加剧了脂肪组织巨噬细胞的代谢性炎症，而不诱导经典的M1或替代的m2样巨噬细胞极化。此外，髓细胞而非脂肪细胞中Nucb2的缺失介导了对高脂肪饮食的胰岛素抵抗。我们的研究表明，Nucb2将代谢炎症与胰岛素抵抗联系起来，而不影响体重增加和食物摄入。肥胖诱导脂肪巨噬细胞表达Nucb2，作为抑制代谢炎症的内源性制动器。Ravussin等人的研究表明，整体消融Nucb2或敲低促氧神经元和脂肪细胞并不影响食物摄入或肥胖。髓细胞中Nucb2的缺失导致高脂肪喂养后的炎症和胰岛素抵抗。
Inducers of satiety are drug targets for weight loss to mitigate obesity-associated diseases. Nucleobindin-2 (Nucb2) is thought to be post-translationally processed into bioactive nesfatin-1 peptide, which reportedly induces satiety, causes weight loss, and thus improves insulin sensitivity. Here, we show that deletion of Nucb2 did not affect food intake or adiposity and, instead, caused insulin resistance in mice fed a high-fat diet. In addition, ablation of Nucb2 in orexigenic hypothalamic Agrp neurons did not affect food intake, and nesfatin-1 was detectable in serum, despite global deletion of Nucb2 protein. Upon high-fat diet feeding, the loss of Nucb2 exacerbated metabolic inflammation in adipose tissue macrophages in an NFκB-dependent manner without inducing classical M1 or alternative M2-like macrophage polarization. Furthermore, the loss of Nucb2 in myeloid cells but not in adipocytes mediated the insulin resistance in response to a high-fat diet. Our study reveals that Nucb2 links metabolic inflammation to insulin resistance without affecting weight gain and food intake. Obesity induces Nucb2 expression in adipose macrophages as an endogenous brake to restrain metabolic inflammation. Ravussin et al. show that ablation of Nucb2 globally or knockdown in orexigenic neurons and adipocytes did not affect food intake or adiposity. The loss of Nucb2 in myeloid cells drive inflammation and insulin resistance upon high-fat feeding.
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影响因子：
5.5
作者：
Dixit, Vishwa Deep
通讯作者：
Dixit, Vishwa Deep
影响因子：
64.5
作者：
Lavin Y;Winter D;Blecher-Gonen R;David E;Keren-Shaul H;Merad M;Jung S;Amit I
通讯作者：
Amit I
DOI：
10.1007/978-1-62703-523-1_15
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Grant, Ryan;Youm, Yun-Hee;Ravussin, Anthony;Dixit, Vishwa Deep
通讯作者：
Dixit, Vishwa Deep
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1016/s0006-291x(05)81503-7
发表时间：
1992-08-31
影响因子：
3.1
作者：
MIURA, K;TITANI, K;KANAI, Y
通讯作者：
KANAI, Y