Abcc5 Knockout Mice Have Lower Fat Mass and Increased Levels of Circulating GLP-1
Abcc5 Knockout Mice Have Lower Fat Mass and Increased Levels of Circulating GLP-1
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DOI：
10.1002/oby.22521
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发表时间：
2019-08-01
期刊：
影响因子：
6.9
通讯作者：
de Wet, Heidi
中科院分区：
文献类型：
--
作者：
Cyranka, Malgorzata;Veprik, Anna;de Wet, Heidi
先前的一项全基因组关联研究表明，atp结合盒转运体ABCC5在人类中过表达，随着年龄的增长易患2型糖尿病。具体而言，ABCC5基因过表达被证明与内脏脂肪量增加和外周胰岛素敏感性降低密切相关。目前，ABCC5在糖尿病和肥胖症中的作用尚不清楚。本研究报道了Abcc5基因敲除小鼠的代谢表型。方法采用CRISPR/Cas9技术构建Abcc5（-/-）全基因组小鼠。每周一次EchoMRI测定脂肪量，并于第18周解剖脂肪垫并称重。通过口服葡萄糖耐量试验、腹腔葡萄糖耐量试验和腹腔胰岛素耐量试验确定葡萄糖稳态。使用PhenoMaster笼测量能量消耗和运动活动。采用酶联免疫吸附法测定血浆、原代肠道细胞培养物和GLUTag细胞中的胰高血糖素样肽1 （GLP-1）水平。结果Abcc5（-/-）小鼠脂肪量减少，血浆GLP-1水平升高，胰岛素敏感性增强，活性增强。重组ABCC5蛋白在GLUTag细胞中的过表达降低了GLP-1的释放。结论ABCC5蛋白表达水平与脂肪量呈负相关，可能参与调节肠内分泌细胞GLP-1的分泌。
Objective A previous genome-wide association study linked overexpression of an ATP-binding cassette transporter, ABCC5, in humans with a susceptibility to developing type 2 diabetes with age. Specifically, ABCC5 gene overexpression was shown to be strongly associated with increased visceral fat mass and reduced peripheral insulin sensitivity. Currently, the role of ABCC5 in diabetes and obesity is unknown. This study reports the metabolic phenotyping of a global Abcc5 knockout mouse. Methods A global Abcc5(-/-) mouse was generated by CRISPR/Cas9. Fat mass was determined by weekly EchoMRI and fat pads were dissected and weighed at week 18. Glucose homeostasis was ascertained by an oral glucose tolerance test, intraperitoneal glucose tolerance test, and intraperitoneal insulin tolerance test. Energy expenditure and locomotor activity were measured using PhenoMaster cages. Glucagon-like peptide 1 (GLP-1) levels in plasma, primary gut cell cultures, and GLUTag cells were determined by enzyme-linked immunosorbent assay. Results Abcc5(-/-) mice had decreased fat mass and increased plasma levels of GLP-1, and they were more insulin sensitive and more active. Recombinant overexpression of ABCC5 protein in GLUTag cells decreased GLP-1 release. Conclusions ABCC5 protein expression levels are inversely related to fat mass and appear to play a role in the regulation of GLP-1 secretion from enteroendocrine cells.