Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Curr Med Sci. 2023 Apr;43(2):274-283. doi: 10.1007/s11596-022-2683-4. Epub 2023 Mar 13.
Intrauterine growth restriction followed by postnatal catch-up growth (CG-IUGR) increases the risk of insulin resistance-related diseases. Low-density lipoprotein receptor-related protein 6 (LRP6) plays a substantial role in glucose metabolism. However, whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear. This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.
The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction. The mRNA and protein expression of the components in the insulin pathway, LRP6/β-catenin and mammalian target of rapamycin (mTOR)/S6 kinase (S6K) signaling, was determined. Liver tissues were immunostained for the expression of LRP6 and β-catenin. LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.
Compared with the control rats, CG-IUGR rats showed higher homeostasis model assessment for insulin resistance (HOMA-IR) index and fasting insulin level, decreased insulin signaling, reduced mTOR/S6K/ insulin receptor substrate-1 (IRS-1) serine307 activity, and decreased LRP6/β-catenin in the liver tissue. The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age (AGA) rats led to reductions in insulin receptor (IR) signaling and mTOR/S6K/IRS-1 serine307 activity. In contrast, LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.
LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways, IR and mTOR-S6K signaling. LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.
宫内生长受限（IUGR）后继发的追赶性生长（CG-IUGR）增加了胰岛素抵抗相关疾病的风险。低密度脂蛋白受体相关蛋白 6（LRP6）在葡萄糖代谢中起着重要作用。然而，LRP6 是否参与 CG-IUGR 的胰岛素抵抗尚不清楚。本研究旨在探讨 LRP6 在 CG-IUGR 胰岛素信号转导中的作用。
通过母体妊娠期营养限制后减少产后窝仔数来建立 CG-IUGR 大鼠模型。测定胰岛素通路、LRP6/β-连环蛋白和哺乳动物雷帕霉素靶蛋白（mTOR）/S6 激酶（S6K）信号转导的组成部分的 mRNA 和蛋白表达。肝组织免疫染色检测 LRP6 和 β-连环蛋白的表达。在原代肝细胞中过表达或沉默 LRP6 以探讨其在胰岛素信号转导中的作用。
与对照组大鼠相比，CG-IUGR 大鼠的稳态模型评估胰岛素抵抗指数（HOMA-IR）和空腹胰岛素水平较高，胰岛素信号减弱，mTOR/S6K/胰岛素受体底物-1（IRS-1）丝氨酸 307 活性降低，肝组织中 LRP6/β-连环蛋白减少。在适当胎龄（AGA）大鼠的肝细胞中敲低 LRP6 导致胰岛素受体（IR）信号和 mTOR/S6K/IRS-1 丝氨酸 307 活性降低。相反，CG-IUGR 大鼠肝细胞中 LRP6 的过表达导致 IR 信号和 mTOR/S6K/IRS-1 丝氨酸 307 活性升高。
LRP6 通过两条不同的途径，即 IR 和 mTOR-S6K 信号通路，调节 CG-IUGR 大鼠的胰岛素信号转导。LRP6 可能是 CG-IUGR 个体胰岛素抵抗的潜在治疗靶点。
