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首页> 外文期刊>EBioMedicine >The imprinted gene Delta like non-canonical notch ligand 1 (Dlk1) associates with obesity and triggers insulin resistance through inhibition of skeletal muscle glucose uptake
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The imprinted gene Delta like non-canonical notch ligand 1 (Dlk1) associates with obesity and triggers insulin resistance through inhibition of skeletal muscle glucose uptake

机译：像非典型的缺口配体1（Dlk1）一样，印记的基因三角洲与肥胖相关联，并通过抑制骨骼肌葡萄糖摄取来触发胰岛素抵抗

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Background The imprinted gene Delta like non-canonical Notch ligand 1 ( Dlk1 ) is considered an inhibitor of adipogenesis, but its in vivo impact on fat mass indeed remains elusive and controversial. Methods Fat deposits were assessed by MRI and DXA scanning in two cohorts of non-diabetic men, whereas glucose disposal rate (GDR) was determined during euglycemic hyperinsulinemic clamp. Blood analyte measurements were used for correlation and mediation analysis to investigate how age, BMI, and fat percentage affect the relation between DLK1 and GDR. Confirmatory animal studies performed in normal (NC) and high fat diet (HFD) fed Dlk1 sup +/+ /sup and Dlk1 sup ?/? /sup mice included DXA scanning, glucose tolerance tests (GTTs), blood measurements, and skeletal muscle glucose uptake studies by positron emission tomography (PET), histology, qRT-PCR, and in vitro cell studies. Findings Overall, DLK1 is positively correlated with fat amounts, which is consistent with a negative linear relationship between DLK1 and GDR. This relationship is not mediated by age, BMI, or fat percentage. In support, DLK1 also correlates positively with HOMA-IR and ADIPO-IR in these humans, but has no linear relationship with the early diabetic inflammation marker MCP-1. In Dlk1sup?/?/sup mice, the increase in fat percentage and adipocyte size induced by HFD is attenuated, and these animals are protected against insulin resistance. These Dlk1 effects seem independent of gluconeogenesis, but at least partly relies on increased in vivo glucose uptake in skeletal muscles by Dlk1 regulating the major glucose transporter Glut4 in vivo as well as in two independent cell lines. Interpretation Thus, instead of an adipogenic inhibitor, Dlk1 should be regarded as a factor causally linked to obesity and insulin resistance, and may be used to predict development of type 2 diabetes. Fund The Danish Diabetes Academy supported by the Novo Nordisk Foundation , The Danish National Research Council (# 09-073648 ), The Lundbeck Foundation , University of Southern Denmark , and Dep. Of Clinical Biochemistry and Pharmacology/Odense University Hospital , the Swedish Research Council , the Swedish Diabetes Foundation , the Strategic Research Program in Diabetes at Karolinska Institute and an EFSD/Lilly grant.
机译：背景技术像非经典的Notch配体1（Dlk1）一样，印记基因Delta被认为是脂肪形成的抑制剂，但其对脂肪量的体内影响确实仍然难以捉摸和有争议。方法通过MRI和DXA扫描对两个非糖尿病男性队列中的脂肪沉积进行评估，而在正常血糖高胰岛素钳夹过程中测定葡萄糖处置率（GDR）。血液分析物的测量用于相关性和中介分析，以研究年龄，BMI和脂肪百分比如何影响DLK1和GDR之间的关系。在Dlk1 + / + 和Dlk1 ？/？喂养的正常（NC）和高脂饮食（HFD）中进行的动物验证性研究。 小鼠包括DXA扫描，葡萄糖耐量测试（GTT），血液测量以及通过正电子发射断层扫描（PET），组织学，qRT-PCR和体外细胞研究进行的骨骼肌葡萄糖摄取研究。总体而言，DLK1与脂肪含量呈正相关，这与DLK1与GDR之间的负线性关系一致。这种关系不受年龄，BMI或脂肪百分比的影响。在支持下，DLK1在这些人中也与HOMA-IR和ADIPO-IR正相关，但与早期糖尿病炎症标记MCP-1没有线性关系。在Dlk1 ？/？小鼠中，HFD诱导的脂肪百分比和脂肪细胞大小的增加被减弱，并且这些动物受到了胰岛素抵抗的保护。这些Dlk1效应似乎与糖异生无关，但至少部分依赖于Dlk1在体内以及在两个独立细胞系中调节主要的葡萄糖转运蛋白Glut4，从而增加了骨骼肌中体内葡萄糖的摄取。解释因此，应将Dlk1替代成脂抑制剂，认为其与肥胖和胰岛素抵抗具有因果关系，可用于预测2型糖尿病的发生。基金由诺和诺德基金会，丹麦国家研究委员会（＃09-073648），伦贝克基金会，南丹麦大学和Dep支持的丹麦糖尿病学会。欧登塞大学医院临床生物化学和药理学，瑞典研究委员会，瑞典糖尿病基金会，卡罗林斯卡研究所糖尿病战略研究计划以及EFSD /礼来公司的资助。

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