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Knockout of ICAT in Adipose Tissue Alleviates Fibro-inflammation in Obese Mice

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Abstract

The E2 promoter binding factor 1 (E2F1) and the Wnt/β-catenin signaling are crucial in regulating metabolic homeostasis including obesity. The β-catenin interacting protein 1 (CTNNBIP1), also known as the inhibitor of β-catenin and TCF4 (ICAT), is required for E2F1 to inhibit the activity of β-catenin. However, the role of ICAT in E2F1 regulating obesity-related metabolic disorders remains unknown. In the present study, male adipose tissue-specific ICAT knockout (ICATadi−/−) C57BL/6 J mice and control littermates aged 6–8 weeks were fed with high-fat diet (HFD) for 12 weeks to explore the effect of ICAT on lipid metabolism and obesity-related disorders. Results showed that the adipose tissue-specific ICAT knockout had negligible effect on lipid metabolism, reflected by no difference in body weight, fat mass, and the expression of proteins involved in lipid metabolism in white adipose tissue (WAT) and the liver between the ICATadi−/− mice and the control littermate (ICATfl/fl) mice. However, the knockout of ICAT reduced inflammatory response in WAT and the liver. Additionally, Sirius red staining results showed that deletion of ICAT attenuated fibrosis and reduced mRNA levels of transforming growth factor β1(TGF-β1), matrix metallopeptidase 2 (Mmp2), Mmp3, and collagen, type V, alpha 1 (Col5a1) in WAT and the liver. These results suggested that knockout of ICAT improved the metabolic abnormalities of obese mice through attenuating adipose tissue and the liver inflammation as well as fibrosis. Our findings may provide a new insight to understand the role of ICAT in inflammation and fibrosis.

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Data Availability

Data that support the results of the present study are available from the corresponding author upon reasonable request.

Abbreviations

eWAT:

Epididymal WAT

iWAT:

Inguinal WAT

ACC:

Acetyl-CoA carboxylase

C/EBPα:

CAAT/enhancer binding protein α

Col5a1 :

Collagen, type V, alpha 1

E2F1:

E2 promoter binding factor 1

ICAT:

β-Catenin interacting protein 1 (CTNNBIP1), inhibitor of β-catenin and TCF4

Mmp2 :

Matrix metallopeptidase 2

PPARγ:

Peroxisome proliferators-activated receptor γ

TGF-β1 :

Transforming growth factor β1

Timp2 (3) :

Tissue inhibitor of metalloproteinase 2 (3)

WAT:

White adipose tissue

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Funding

This work was supported by the National Natural Science Foundation of China (No. 31625025 and No. 32000082), China Postdoctoral Science Foundation (No.2022M713405), and the 2115 Talent Development of China Agricultual University.

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Authors and Affiliations

  1. Department of Animal Nutrition and Feed Science, State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, 100193, China

    Zhuan Song, Ning Liu, Yu He, Jun Li & Zhenlong Wu

  2. Laboratory Animal Center of the Academy of Military Medical Sciences, Beijing, 100193, China

    Jingqing Chen

  3. National Institute of Biological Sciences (NIBS), Beijing, 102206, China

    Fengchao Wang

  4. Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, 100193, China

    Ning Liu & Zhenlong Wu

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  1. Zhuan Song
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  3. Yu He
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Contributions

All authors participated in the study and supported the publication. Zhenlong Wu designed and conducted the research. Material preparation, data collection, and analysis were performed by Zhuan Song, Ning Liu, Yu He, Jingqing Chen, and Jun Li. Fengchao Wang constructed the knockout mice. The draft of the manuscript was written by Zhuan Song.

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Correspondence to Zhenlong Wu.

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The experimental protocol was approved by the Protocol Management and Review Committee of China Agricultural University (Beijing, China). All mice were raised and conformed to the Institutional Animal Care and Use Committee of China Agricultural University (AW72602202-1–7).

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Song, Z., Liu, N., He, Y. et al. Knockout of ICAT in Adipose Tissue Alleviates Fibro-inflammation in Obese Mice. Inflammation 46, 404–417 (2023). https://doi.org/10.1007/s10753-022-01742-w

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