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Gut microbiota
Original research
A novel peptide protects against diet-induced obesity by suppressing appetite and modulating the gut microbiota
  1. Zhanzhan Li1,2,
  2. Bing Zhang1,2,
  3. Ning Wang1,2,
  4. Zhenqiang Zuo1,
  5. Hong Wei3,
  6. Fangqing Zhao1,2,4,5
  1. 1 Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
  2. 2 University of Chinese Academy of Sciences, Beijing, China
  3. 3 Laboratory Animal Department, College of Basic Medicine Army Medical University, Chongqing, China
  4. 4 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
  5. 5 Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
  1. Correspondence to Professor Fangqing Zhao, Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100045, China; zhfq{at}biols.ac.cn; Professor Hong Wei; weihong63528{at}163.com

Abstract

Objective The obesity epidemic and its metabolic complications continue to be a major global public health threat with limited effective treatments, especially drugs that can be taken orally. Peptides are a promising class of molecules that have gained increased interest for their applications in medicine and biotechnology. In this study, we focused on looking for peptides that can be administrated orally to treat obesity and exploring its mechanisms.

Design Here, a 9-amino-acid peptide named D3 was designed and administered orally to germ-free (GF) mice and wild-type (WT) mice, rats and macaques. The effects of D3 on body weight and other basal metabolic parameters were evaluated. The effects of D3 on gut microbiota were evaluated using 16S rRNA amplicon sequencing. To identify and confirm the mechanisms of D3, transcriptome analysis of ileum and molecular approaches on three animal models were performed.

Results A significant body weight reduction was observed both in WT (12%) and GF (9%) mice treated with D3. D3 ameliorated leptin resistance and upregulated the expression of uroguanylin (UGN), which suppresses appetite via the UGN-GUCY2C endocrine axis. Similar effects were also found in diet-induced obese rat and macaque models. Furthermore, the abundance of intestinal Akkermansia muciniphila increased about 100 times through the IFNγ-Irgm1 axis after D3 treatment, which may further inhibit fat absorption by downregulating Cd36.

Conclusion Our results indicated that D3 is a novel drug candidate for counteracting diet-induced obesity as a non-toxic and bioactive peptide. Targeting the UGN-GUCY2C endocrine axis may represent a therapeutic strategy for the treatment of obesity.

  • OBESITY
  • INTESTINAL MICROBIOLOGY
  • DRUG DEVELOPMENT

Data availability statement

Data are available upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2022-328035

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • ZL and BZ are joint first authors.

    • Twitter @Fangqing_Zhao

    • Contributors FZ is responsible for the overall content as the guarantor. FZ conceived and supervised the study. FZ and ZL designed the study, interpreted the results and wrote the manuscript. WH’s team fed the GF mice and recorded the experimental data. Ileal transcriptome and faecal flora diversity analyses were performed by BZ. ZL, HW, ZZ and NW performed all the other experiments and the data analysis and prepared the figures and tables.

    • Funding This work was supported by grants from the National Natural Science Foundation of China (32025009, 32001082), National Key R&D Project (2021YFA1301000, 2021YFC2301300) and the Strategic Priority Research Program of Chinese Academy of Sciences (XDB38020300). We thank Jingwei Wang, Xiuling Ma, You Yu and Yongxi Huang for their assistance in sample preprocessing.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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