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Incretin-induced changes in the transcriptome of skeletal muscles of fa/fa Zucker rat (ZFR) with obesity, without diabetes

International Journal of Obesity volume 46, pages 1311–1318 (2022)Cite this article

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Abstract

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are increasingly used in treating type 2 diabetes and obesity. Exendin-4 (Ex-4), a long acting GLP-1ra, was previously reported to decrease oxidative stress in hepatocytes, adipocytes and skeletal muscle cells in obese nondiabetic fa/fa Zucker rats (ZFR), thereby improving insulin resistance.

Aim

We aimed first to identify Ex-4-induced changes in the transcriptome of skeletal muscle cells in ZFR.

Results

Ontology analysis of differentially expressed genes (DEGs) in ZFR versus lean animals (LR) showed that the extracellular matrix (ECM) is the first most affected cellular compartment, followed by myofibrils and endoplasmic reticulum (ER). Interestingly, among 15 genes regulated in ZFR versus LR, 14 of them were inversely regulated by Ex-4, as further confirmed by RT-qPCR. Picro-Sirius red histological staining showed that decreased ECM fiber area in ZFR is partially restored by Ex-4. Ontology analysis of the myofibril compartment revealed that decreased muscle contractile function in ZFR is partially restored by Ex-4, as confirmed by Phalloidin histological staining that showed a partial restoration by Ex-4 of altered contractile apparatus in ZFR. Ontology analysis of ER DEGs in ZFR versus LR showed that some of them are related to the AMP-activated protein kinase (AMPK) signaling pathway. Phosphorylated AMPK levels were strongly increased in Ex-4-treated ZFR.

Conclusion

Altogether, our results suggest that GLP-1ra strongly restructure ECM and reinforce contractile capabilities in ZFR, while optimizing the cellular metabolism through AMPK.

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Fig. 1: Decreased extracellular matrix in ZFR is partially reversed by Ex-4.
Fig. 2: Decreased expression of genes involved in muscle cell function in ZFR is partially restored by Ex-4.
Fig. 3: Effect of Ex-4 on genes of the endoplasmic reticulum compartment.
Fig. 4: RNAseq results: highly regulated genes.

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Data availability

Data available within the article or its Supplementary Materials. RNAseq row data available on request from the authors.

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Acknowledgements

Authors thanks Mrs Catherine Rasse (support en méthodologie et calcul statistique, Louvain institute of data analysis and modeling in economics and statistics, Université catholique de Louvain (UCLouvain)) for her help in statistical analysis.

Funding

This study was supported by a grant from the “Fonds de la Recherche Scientifique dans le Hainaut 2018”, and from the King Baudouin Foundation “Amelie G488730 fund”.

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Authors and Affiliations

  1. Endocrino-Diabetology Research Unit, Centre Hospitalier Régional (CHR) Mons-Hainaut/Groupe Jolimont, Mons, Belgium

    Ides M. Colin & Anne-Catherine Gérard

  2. Group of Animal Molecular and Cellular Biology, Louvain Institute of Biomolecular Science and Technology (LIBST), Université Catholique de Louvain (UCLouvain), Louvain-La-Neuve, Belgium

    Bernard Knoops & Anne-Catherine Gérard

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  1. Ides M. Colin
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  2. Bernard Knoops
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Contributions

IMC conceived and designed the study, participated to results interpretation, and wrote the manuscript. BK participated to results interpretation and critical revision of the manuscript. ACG participated to conception and design of the study, performed experiments, data collection, data analysis, and figures design, contributed to manuscript. All authors approved the final version to be published.

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Correspondence to Ides M. Colin.

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Colin, I.M., Knoops, B. & Gérard, AC. Incretin-induced changes in the transcriptome of skeletal muscles of fa/fa Zucker rat (ZFR) with obesity, without diabetes. Int J Obes 46, 1311–1318 (2022). https://doi.org/10.1038/s41366-022-01114-2

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