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LRP6 Bidirectionally Regulates Insulin Sensitivity through Insulin Receptor and S6K Signaling in Rats with CG-IUGR
Xue-Mei Xie1, Qiu-Li Cao1, Yu-Jie Sun1
1Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
Current Medical Science
|March 13, 2023
Summary
Catch-up growth after intrauterine growth restriction (IUGR) increases insulin resistance. Low-density lipoprotein receptor-related protein 6 (LRP6) impacts glucose metabolism and insulin signaling, suggesting it as a therapeutic target for IUGR-related insulin resistance.
Area of Science:
- Metabolic Research
- Endocrinology
- Developmental Biology
Background:
- Intrauterine growth restriction (IUGR) followed by catch-up growth (CG-IUGR) is linked to increased risk of insulin resistance and related diseases.
- Low-density lipoprotein receptor-related protein 6 (LRP6) is known to influence glucose metabolism, but its role in CG-IUGR-induced insulin resistance is not well understood.
Purpose of the Study:
- To investigate the role of LRP6 in insulin signaling pathways within the context of CG-IUGR.
- To explore the potential of LRP6 as a therapeutic target for managing insulin resistance in individuals with a history of CG-IUGR.
Main Methods:
- Establishment of a CG-IUGR rat model through maternal nutritional restriction and postnatal litter size adjustment.
- Analysis of insulin pathway components, LRP6/β-catenin, and mTOR/S6K signaling via mRNA and protein expression.
- In vitro studies involving LRP6 overexpression and knockdown in primary hepatocytes to elucidate its direct impact on insulin signaling.
Main Results:
- CG-IUGR rats exhibited elevated insulin resistance (HOMA-IR), increased fasting insulin, diminished insulin receptor (IR) signaling, and reduced activity in mTOR/S6K/IRS-1 pathways compared to controls.
- LRP6 knockdown in hepatocytes impaired IR signaling and mTOR/S6K/IRS-1 activity, while LRP6 overexpression in CG-IUGR hepatocytes restored IR signaling and pathway activity.
Conclusions:
- LRP6 modulates insulin signaling in CG-IUGR rats through both IR and mTOR-S6K pathways.
- LRP6 emerges as a promising therapeutic target for addressing insulin resistance associated with CG-IUGR.
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