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Thyroid-stimulating hormone may participate in insulin resistance by activating toll-like receptor 4 in liver tissues of subclinical hypothyroid rats

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Abstract

Background

Thyroid-stimulating hormone (TSH) is an independent risk factor of and closely associated with metabolic disorders. In the present study, we explored the potential mechanism and adverse effects of TSH on insulin resistance in the liver of subclinical hypothyroidism models in vivo.

Methods

The mean glucose infusion rate (GIR), free fatty acids (FFAs), the homeostatic model assessment for insulin resistance (HOMA-IR), fasting plasma insulin (FINS), the TLR4 signal pathway and its intracellular negative regulator-toll-interacting protein (Tollip), and the modulators of insulin signaling were evaluated.

Results

Compared to the normal control group (NC group), the subclinical hypothyroidism rat group (SCH group) showed decreases in GIR and increases in FFAs, FINS, and HOMA-IR. The levels of TLR4 and of its downstream molecules like p-NF-κB, p-IRAK-1, IL-6 and TNF-α were evidently higher in the SCH group than in the NC group. Conversely, the level of Tollip was significantly lower in the SCH group than in the NC group. Compared to the NC group, the levels of phosphorylated IRS-1-Tyr and GLUT2 were decreased in the SCH group. Macrophage infiltration was higher in the SCH group than in the NC group.

Conclusion

TSH may participate in aggravating inflammation by increasing macrophage infiltration; furthermore, it may activate the TLR4-associated inflammatory signaling pathway, thus interfering with insulin signals in liver tissues. Targeting TSH may have therapeutic benefits against metabolic disorders.

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Data Availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Abbreviations

CH:

hypothyroidism group

FBG:

Fasting blood glucose

FFAs:

Free fatty acids

FINS:

Fasting insulin

GIR:

Glucose infusion rate

GLUT2:

Glucose transporter 2

HOMA-IR:

Homeostatic model assessment for insulin resistance

IRS-1:

Insulin receptor substrate-1

NC:

Normal control group

p-IRAK:

Phosphorylated interleukin receptor-related kinase-1

p-NF-κB:

Phosphorylated nuclear factor kappa-B

SCH:

Subclinical hypothyroidism group

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor-α

Tollip:

Toll-interacting protein

TSH:

Thyroid-stimulating hormone

TSHR:

Thyroid-stimulating hormone receptor

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Acknowledgements

We thank Medjaden Inc. for scientific editing of this manuscript.

Funding

This project was supported by the National Natural Science Foundation of China (grant no. 82000763) and the Tianjin Municipal Health Commission (grant no. KJ20009).

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Authors and Affiliations

  1. Department of Endocrinology, Tianjin First Central Hospital, No. 24 Fu Kang Road, Nankai District, Tianjin, 300192, China

    Suqing Bao, Lijun Duan, Junfeng Li & Xia Jiang

  2. Department of Orthopedics, Tianjin Hospital, No. 406 Jie fang South Road, Hexi District, Tianjin, 300211, China

    Fengbo Li

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  1. Suqing Bao
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Fengbo Li, Lijun Duan and Junfeng Li. Xia Jiang interpreted the data. The first draft of the manuscript was written by Suqing Bao, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Suqing Bao.

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All experimental procedures and animal use protocols were approved by the Animal Care and Use Committee of Nankai University and were in compliance with the National Institute of Health Guide for the Care and Use of Laboratory Animals.

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Bao, S., Li, F., Duan, L. et al. Thyroid-stimulating hormone may participate in insulin resistance by activating toll-like receptor 4 in liver tissues of subclinical hypothyroid rats. Mol Biol Rep 50, 10637–10650 (2023). https://doi.org/10.1007/s11033-023-08834-2

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