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Adiponectin Alleviates Intestinal Fibrosis by Enhancing AMP-Activated Protein Kinase Phosphorylation

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Abstract

Background

Intestinal fibrosis is a common complication of Crohn’s disease (CD). Adiponectin reportedly exerts anti-inflammatory effects in various disease models, including colitis models.

Aims

In this study, we aimed to determine the effects of adiponectin on intestinal fibrosis and the underlying mechanisms.

Methods

A murine model of intestinal fibrosis was established by administering increasing doses of 2,4,6-trinitrobenzene sulfonic acid to Balb/c mice via enema for 7 weeks. Primary human fibroblasts were isolated from the colon tissues of patients with CD. The fibroblasts were incubated with transforming growth factor (TGF)-β1 to establish a fibrosis model in vitro. Pathway inhibitors were used to verify the potential signaling pathways involved in the anti-fibrogenic effect of adiponectin.

Results

Compared with the normal mesentery, adiponectin expression was significantly increased in the hypertrophic mesentery of patients with CD. Intraperitoneal injection of adiponectin significantly decreased the activity of myeloperoxidase and the expression of pro-inflammatory cytokines (tumor necrosis factor α and interleukin 6) in the colon of fibrosis model mice, whereas the expression of the anti-inflammatory cytokine interleukin 10 was substantially increased. Moreover, adiponectin treatment inhibited colon shortening, decreased colon weight, and reduced fibrotic protein deposition in the model mice. Adiponectin reduced the phosphorylation of Smad2 and collagen deposition induced by TGF-β1 in primary human intestinal fibroblasts, with an increase in AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, this phenomenon was reversed by the AMPK inhibitor.

Conclusions

Adiponectin can protect against intestinal fibrosis by enhancing the phosphorylation of AMPK and inhibiting the activity of the TGF-β1/Smad signaling pathway.

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Funding

This study was supported by the National Natural Science Foundation of China (81770557 and 82070684) and Guangdong Natural Science Fund for Outstanding Youth Scholars (2020B151502067).

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Author notes

  1. Minghao Xie, Zhizhong Xiong and Shi Yin have contributed equally to this work.

Authors and Affiliations

  1. Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People’s Republic of China

    Minghao Xie, Zhizhong Xiong, Shi Yin, Jiaqing Xiong, Xianzhe Li, Longyang Jin, Fengxiang Zhang, Huaxian Chen, Ping Lan & Lei Lian

  2. Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People’s Republic of China

    Minghao Xie, Zhizhong Xiong, Shi Yin, Jiaqing Xiong, Xianzhe Li, Longyang Jin, Fengxiang Zhang, Huaxian Chen, Ping Lan & Lei Lian

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  1. Minghao Xie
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  2. Zhizhong Xiong
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Correspondence to Lei Lian.

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The authors declare that they have no conflict of interest regarding the content of this article.

Ethics approval and consent to participate

The experiments were carried out under a protocol approved by the Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University. The institutional and national guide for the care and use of laboratory animals was followed in the animal experiments, and it was approved by the Institutional Animal Care and Use Committee of the Sixth Affiliated Hospital of Sun Yat-Sen University.

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All clinical samples collected and analyzed in this study were approved by the patients and all patients signed informed consent.

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Xie, M., Xiong, Z., Yin, S. et al. Adiponectin Alleviates Intestinal Fibrosis by Enhancing AMP-Activated Protein Kinase Phosphorylation. Dig Dis Sci 67, 2232–2243 (2022). https://doi.org/10.1007/s10620-021-07015-0

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