GM-CSF driven myeloid cells in adipose tissue link weight gain and insulin resistance via formation of 2-aminoadipate.
GM-CSF driven myeloid cells in adipose tissue link weight gain and insulin resistance via formation of 2-aminoadipate.
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GM-CSF驱动的脂肪组织中的骨髓细胞通过形成2-氨基己二酸将体重增加和胰岛素抵抗联系起来。
DOI：
10.1038/s41598-018-29250-8
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发表时间：
2018-07-31
影响因子：
4.6
通讯作者：
Pamir N
中科院分区：
文献类型：
--
作者：
Plubell DL;Fenton AM;Wilmarth PA;Bergstrom P;Zhao Y;Minnier J;Heinecke JW;Yang X;Pamir N
在GM-CSF驱动的骨髓细胞缺陷小鼠模型（Csf 2 −/−）中，尽管肥胖增加，但仍保持了胰岛素敏感性，我们使用蛋白质组谱，代谢谱和基因调控网络的无偏三维整合来了解脂肪组织蛋白质组范围的变化及其代谢影响。使用多维液相色谱质谱和扩展多重质量标记来分析从Csf 2 +/+和Csf 2 −/−小鼠中分离的附睾脂肪组织的蛋白质组，这些小鼠被喂食低脂肪、高脂肪或高脂肪加胆固醇饮食8周。代谢健康（通过体重、肥胖、血浆空腹葡萄糖、胰岛素、甘油三酯、磷脂、总胆固醇水平以及葡萄糖和胰岛素耐量试验测量）随着两种基因型的饮食而恶化，而缺乏Csf 2的小鼠受到胰岛素抵抗的保护。无论饮食如何，30种主要是线粒体、分支链氨基酸（BCAA）和赖氨酸代谢蛋白在Csf 2 −/−和Csf 2 +/+小鼠之间发生了改变（FDR < 0.05）。缺乏GM-CSF驱动的骨髓细胞导致脂肪组织2-酮戊二酸脱氢酶复合物（DHTKD 1）水平降低，随后血浆2-氨基己二酸（2-AA）水平升高，据报道两者均与胰岛素抵抗相关。在Csf 2 −/−小鼠中，组织DHTKD 1水平上调>4倍，血浆2-AA水平降低>2倍（p < 0.05）。GM-CSF驱动的骨髓细胞通过赖氨酸代谢将外周胰岛素敏感性与肥胖联系起来，该代谢涉及DHTKD 1/2-AA轴，以饮食非依赖性方式。
In a GM-CSF driven myeloid cell deficient mouse model (Csf2−/−) that has preserved insulin sensitivity despite increased adiposity, we used unbiased three-dimensional integration of proteome profiles, metabolic profiles, and gene regulatory networks to understand adipose tissue proteome-wide changes and their metabolic implications. Multi-dimensional liquid chromatography mass spectrometry and extended multiplex mass labeling was used to analyze proteomes of epididymal adipose tissues isolated from Csf2+/+ and Csf2−/− mice that were fed low fat, high fat, or high fat plus cholesterol diets for 8 weeks. The metabolic health (as measured by body weight, adiposity, plasma fasting glucose, insulin, triglycerides, phospholipids, total cholesterol levels, and glucose and insulin tolerance tests) deteriorated with diet for both genotypes, while mice lacking Csf2 were protected from insulin resistance. Regardless of diet, 30 mostly mitochondrial, branch chain amino acids (BCAA), and lysine metabolism proteins were altered between Csf2−/− and Csf2+/+ mice (FDR < 0.05). Lack of GM-CSF driven myeloid cells lead to reduced adipose tissue 2-oxoglutarate dehydrogenase complex (DHTKD1) levels and subsequent increase in plasma 2-aminoadipate (2-AA) levels, both of which are reported to correlate with insulin resistance. Tissue DHTKD1 levels were >4-fold upregulated and plasma 2-AA levels were >2 fold reduced in Csf2−/− mice (p < 0.05). GM-CSF driven myeloid cells link peripheral insulin sensitivity to adiposity via lysine metabolism involving DHTKD1/2-AA axis in a diet independent manner.
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影响因子：
4.6
作者：
Morita S;Nakabayashi K;Kawai T;Hayashi K;Horii T;Kimura M;Kamei Y;Ogawa Y;Hata K;Hatada I
通讯作者：
Hatada I
DOI：
10.4049/jimmunol.1600820
发表时间：
2016-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cho KW;Zamarron BF;Muir LA;Singer K;Porsche CE;DelProposto JB;Geletka L;Meyer KA;O'Rourke RW;Lumeng CN
通讯作者：
Lumeng CN
影响因子：
4.4
作者：
Meierhofer, David;Weidner, Christopher;Sauer, Sascha
通讯作者：
Sauer, Sascha
鉴定驱动小鼠F2间交叉中心血管和代谢表型的基因和网络。
影响因子：
3.7
作者：
Derry JM;Zhong H;Molony C;MacNeil D;Guhathakurta D;Zhang B;Mudgett J;Small K;El Fertak L;Guimond A;Selloum M;Zhao W;Champy MF;Monassier L;Vogt T;Cully D;Kasarskis A;Schadt EE
通讯作者：
Schadt EE
影响因子：
3.7
作者：
Becker L;Liu NC;Averill MM;Yuan W;Pamir N;Peng Y;Irwin AD;Fu X;Bornfeldt KE;Heinecke JW
通讯作者：
Heinecke JW