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LRP6 Bidirectionally Regulates Insulin Sensitivity through Insulin Receptor and S6K Signaling in Rats with CG-IUGR

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Abstract

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

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Author notes

  1. The authors contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China

    Xue-mei ** Xuan

  2. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Wen-jun Long & ** Luo

  3. Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China

    Guan-dou Yuan

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  1. Xue-mei **e
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  2. Qiu-li Cao
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  3. Yu-jie Sun
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  4. Jie Zhang
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  5. Kai-li Liu
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  7. Wen-jun Long
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  8. Zuo-jie Luo
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  10. **ng-huan Liang
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  13. ** Xuan
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Corresponding authors

Correspondence to Jie Zhang or ** Xuan.

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Conflict of Interest Statement

The authors declare that they have no conflict of interest.

This work was supported by the National Natural Science Foundation of China (No. 82001651 and No. 81660268).

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**e, Xm., Cao, Ql., Sun, Yj. et al. LRP6 Bidirectionally Regulates Insulin Sensitivity through Insulin Receptor and S6K Signaling in Rats with CG-IUGR. CURR MED SCI 43, 274–283 (2023). https://doi.org/10.1007/s11596-022-2683-4

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