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在雄性大鼠中，伴有追赶生长程序的宫内生长受限通过低密度脂蛋白受体相关蛋白6/胰岛素受体底物1损害胰岛素敏感性。

IUGR with catch-up growth programs impaired insulin sensitivity through LRP6/IRS-1 in male rats.

作者信息

Long Wenjun, Zhou Tuo, Xuan Xiuping, Cao Qiuli, Luo Zuojie, Qin Yingfen, Ning Qin, Luo Xiaoping, Xie Xuemei

机构信息

Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.

出版信息

Endocr Connect. 2022 Jan 10;11(1):e210203. doi: 10.1530/EC-21-0203.

DOI:10.1530/EC-21-0203
PMID:34825892
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8789020/
Abstract

Intrauterine growth restriction combined with postnatal accelerated growth (CG-IUGR) could lead to long-term detrimental metabolic outcomes characterized by insulin resistance. As an indispensable co-receptor of Wnt signaling, LRP6 plays a critical role in the susceptibility of metabolic disorders. However, whether LRP6 is involved in the metabolic programing is still unknown. We hypothesized that CG-IUGR programed impaired insulin sensitivity through the impaired LRP6-mediated Wnt signaling in skeletal muscle. A CG-IUGR rat model was employed. The transcriptional and translational alterations of the components of the Wnt and the insulin signaling in the skeletal muscle of the male CG-IUGR rats were determined. The role of LRP6 on the insulin signaling was evaluated by shRNA knockdown or Wnt3a stimulation of LRP6. Compared with controls, the male CG-IUGR rats showed an insulin-resistant phenotype, with impaired insulin signaling and decreased expression of LRP6/β-catenin in skeletal muscle. LRP6 knockdown led to reduced expression of the IR-β/IRS-1 in C2C12 cell line, while Wnt3a-mediated LRP6 expression increased the expression of IRS-1 and IGF-1R but not IR-β in the primary muscle cells of male CG-IUGR rats. The impaired LRP6/β-catenin/IGF-1R/IRS-1 signaling is probably one of the critical mechanisms underlying the programed impaired insulin sensitivity in male CG-IUGR.

摘要

宫内生长受限合并出生后加速生长（CG-IUGR）可导致以胰岛素抵抗为特征的长期有害代谢后果。作为Wnt信号不可或缺的共受体，低密度脂蛋白受体相关蛋白6（LRP6）在代谢紊乱易感性中起关键作用。然而，LRP6是否参与代谢编程仍不清楚。我们假设CG-IUGR通过骨骼肌中LRP6介导的Wnt信号受损来编程胰岛素敏感性受损。采用CG-IUGR大鼠模型。测定雄性CG-IUGR大鼠骨骼肌中Wnt和胰岛素信号成分的转录和翻译改变。通过shRNA敲低或Wnt3a刺激LRP6来评估LRP6对胰岛素信号的作用。与对照组相比，雄性CG-IUGR大鼠表现出胰岛素抵抗表型，胰岛素信号受损，骨骼肌中LRP6/β-连环蛋白表达降低。在C2C12细胞系中，LRP6敲低导致胰岛素受体β亚基（IR-β）/胰岛素受体底物-1（IRS-1）表达降低，而在雄性CG-IUGR大鼠原代肌细胞中，Wnt3a介导的LRP6表达增加了IRS-1和胰岛素样生长因子-1受体（IGF-1R）的表达，但未增加IR-β的表达。LRP6/β-连环蛋白/IGF-1R/IRS-1信号受损可能是雄性CG-IUGR中编程胰岛素敏感性受损的关键机制之一。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/87f2a0a44979/EC-21-0203fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/e7a3970498de/EC-21-0203fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/9278bad8859e/EC-21-0203fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/0c95b690ae25/EC-21-0203fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/c562237ff0c2/EC-21-0203fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/dd1ed328e34c/EC-21-0203fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/87f2a0a44979/EC-21-0203fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/e7a3970498de/EC-21-0203fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/9278bad8859e/EC-21-0203fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/0c95b690ae25/EC-21-0203fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/c562237ff0c2/EC-21-0203fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/dd1ed328e34c/EC-21-0203fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3281/8789020/87f2a0a44979/EC-21-0203fig6.jpg

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