Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice

Hyo Shin Yoon; Chung Hwan Cho; Myeong Sik Yun; Sung Jae Jang; Hyun Ju You; Jun hyeong Kim; Dohyun Han; Kwang Hyun Cha; Sung Hyun Moon; Kiuk Lee; Yeon Ji Kim; Sung Joon Lee; Tae Wook Nam; Gwang Pyo Ko

doi:10.1038/s41564-021-00880-5

Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice

Hyo Shin Yoon, Chung Hwan Cho, Myeong Sik Yun, Sung Jae Jang, Hyun Ju You, Jun hyeong Kim, Dohyun Han, Kwang Hyun Cha, Sung Hyun Moon, Kiuk Lee, Yeon Ji Kim, Sung Joon Lee, Tae Wook Nam, Gwang Pyo Ko

Department of Biotechnology

Research output: Contribution to journal › Article › peer-review

203 Citations (Scopus)

Abstract

The gut microbiota, which includes Akkermansia muciniphila, is known to modulate energy metabolism, glucose tolerance, immune system maturation and function in humans^1–4. Although A. muciniphila is correlated with metabolic diseases and its beneficial causal effects were reported on host metabolism^5–8, the molecular mechanisms involved have not been identified. Here, we report that A. muciniphila increases thermogenesis and glucagon-like peptide-1 (GLP-1) secretion in high-fat-diet (HFD)-induced C57BL/6J mice by induction of uncoupling protein 1 in brown adipose tissue and systemic GLP-1 secretion. We apply fast protein liquid chromatography and liquid chromatography coupled to mass spectrophotometry analysis to identify an 84 kDa protein, named P9, that is secreted by A. muciniphila. Using L cells and mice fed on an HFD, we show that purified P9 alone is sufficient to induce GLP-1 secretion and brown adipose tissue thermogenesis. Using ligand–receptor capture analysis, we find that P9 interacts with intercellular adhesion molecule 2 (ICAM-2). Interleukin-6 deficiency abrogates the effects of P9 in glucose homeostasis and downregulates ICAM-2 expression. Our results show that the interactions between P9 and ICAM-2 could be targeted by therapeutics for metabolic diseases.

Original language	English
Pages (from-to)	563-573
Number of pages	11
Journal	Nature Microbiology
Volume	6
Issue number	5
DOIs	https://doi.org/10.1038/s41564-021-00880-5
Publication status	Published - 2021 May

Bibliographical note

Funding Information:
We thank P. Helbling and M. Pavlou (Dualsystems Biotech) for their discussion regarding the LRC assay and proteomics analysis; K. Ge (National Institutes of Health, USA), J. B. Kim (Seoul National University, Korea) and O. J. Kwon (Catholic University, Korea) for providing the immortalized BACs; B. L. Roth (The University of North Carolina at Chapel Hill, USA) for providing HTLA cells; S. J. Lee (Korea University, Korea) for providing the calcium inhibitors; W. K. Huh (Seoul National University, Korea) for providing the GPCR inhibitors; J. S. Han (Seoul National University, Korea) for FPLC usage; Y. K. Oh (Seoul National University, Korea) for infrared camera usage; Y. Chung (Seoul National University, Korea) for temperature-controlled chamber usage; S. H. Yoon, L. Song, J. W. Kim and S. E. Choi (Seoul National University, Korea) for their technical assistance with the tissue sampling and preparation for FACS analysis; T. J. Ahn (KoBioLabs, Inc.) for cytokine analysis of bacterial isolates in cell lines; I. S. Cho (KoBioLabs, Inc.) for producing EcPrc; and the staff at the Samsung Medical Center for providing infant faecal samples. This work was supported by the National Research Foundation of Korea (NRF) (no. NRF-2018R1A2A1A05078258). C.H.C. was supported by the Global Ph.D. Fellowship program and a NRF grant funded by the Korean government (no. NRF-2018H1A2A1061914).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

Microbiology
Immunology
Applied Microbiology and Biotechnology
Genetics
Microbiology (medical)
Cell Biology

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10.1038/s41564-021-00880-5

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Yoon, H. S., Cho, C. H., Yun, M. S., Jang, S. J., You, H. J., Kim, J. H., Han, D., Cha, K. H., Moon, S. H., Lee, K., Kim, Y. J., Lee, S. J., Nam, T. W., & Ko, G. P. (2021). Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nature Microbiology, 6(5), 563-573. https://doi.org/10.1038/s41564-021-00880-5

Yoon, HS, Cho, CH, Yun, MS, Jang, SJ, You, HJ, Kim, JH, Han, D, Cha, KH, Moon, SH, Lee, K, Kim, YJ, Lee, SJ, Nam, TW & Ko, GP 2021, 'Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice', Nature Microbiology, vol. 6, no. 5, pp. 563-573. https://doi.org/10.1038/s41564-021-00880-5

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title = "Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice",

abstract = "The gut microbiota, which includes Akkermansia muciniphila, is known to modulate energy metabolism, glucose tolerance, immune system maturation and function in humans1–4. Although A. muciniphila is correlated with metabolic diseases and its beneficial causal effects were reported on host metabolism5–8, the molecular mechanisms involved have not been identified. Here, we report that A. muciniphila increases thermogenesis and glucagon-like peptide-1 (GLP-1) secretion in high-fat-diet (HFD)-induced C57BL/6J mice by induction of uncoupling protein 1 in brown adipose tissue and systemic GLP-1 secretion. We apply fast protein liquid chromatography and liquid chromatography coupled to mass spectrophotometry analysis to identify an 84 kDa protein, named P9, that is secreted by A. muciniphila. Using L cells and mice fed on an HFD, we show that purified P9 alone is sufficient to induce GLP-1 secretion and brown adipose tissue thermogenesis. Using ligand–receptor capture analysis, we find that P9 interacts with intercellular adhesion molecule 2 (ICAM-2). Interleukin-6 deficiency abrogates the effects of P9 in glucose homeostasis and downregulates ICAM-2 expression. Our results show that the interactions between P9 and ICAM-2 could be targeted by therapeutics for metabolic diseases.",

author = "Yoon, {Hyo Shin} and Cho, {Chung Hwan} and Yun, {Myeong Sik} and Jang, {Sung Jae} and You, {Hyun Ju} and Kim, {Jun hyeong} and Dohyun Han and Cha, {Kwang Hyun} and Moon, {Sung Hyun} and Kiuk Lee and Kim, {Yeon Ji} and Lee, {Sung Joon} and Nam, {Tae Wook} and Ko, {Gwang Pyo}",

note = "Funding Information: We thank P. Helbling and M. Pavlou (Dualsystems Biotech) for their discussion regarding the LRC assay and proteomics analysis; K. Ge (National Institutes of Health, USA), J. B. Kim (Seoul National University, Korea) and O. J. Kwon (Catholic University, Korea) for providing the immortalized BACs; B. L. Roth (The University of North Carolina at Chapel Hill, USA) for providing HTLA cells; S. J. Lee (Korea University, Korea) for providing the calcium inhibitors; W. K. Huh (Seoul National University, Korea) for providing the GPCR inhibitors; J. S. Han (Seoul National University, Korea) for FPLC usage; Y. K. Oh (Seoul National University, Korea) for infrared camera usage; Y. Chung (Seoul National University, Korea) for temperature-controlled chamber usage; S. H. Yoon, L. Song, J. W. Kim and S. E. Choi (Seoul National University, Korea) for their technical assistance with the tissue sampling and preparation for FACS analysis; T. J. Ahn (KoBioLabs, Inc.) for cytokine analysis of bacterial isolates in cell lines; I. S. Cho (KoBioLabs, Inc.) for producing EcPrc; and the staff at the Samsung Medical Center for providing infant faecal samples. This work was supported by the National Research Foundation of Korea (NRF) (no. NRF-2018R1A2A1A05078258). C.H.C. was supported by the Global Ph.D. Fellowship program and a NRF grant funded by the Korean government (no. NRF-2018H1A2A1061914). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

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AU - Yoon, Hyo Shin

AU - Cho, Chung Hwan

AU - Yun, Myeong Sik

AU - Jang, Sung Jae

AU - You, Hyun Ju

AU - Kim, Jun hyeong

AU - Han, Dohyun

AU - Cha, Kwang Hyun

AU - Moon, Sung Hyun

AU - Lee, Kiuk

AU - Kim, Yeon Ji

AU - Lee, Sung Joon

AU - Nam, Tae Wook

AU - Ko, Gwang Pyo

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N2 - The gut microbiota, which includes Akkermansia muciniphila, is known to modulate energy metabolism, glucose tolerance, immune system maturation and function in humans1–4. Although A. muciniphila is correlated with metabolic diseases and its beneficial causal effects were reported on host metabolism5–8, the molecular mechanisms involved have not been identified. Here, we report that A. muciniphila increases thermogenesis and glucagon-like peptide-1 (GLP-1) secretion in high-fat-diet (HFD)-induced C57BL/6J mice by induction of uncoupling protein 1 in brown adipose tissue and systemic GLP-1 secretion. We apply fast protein liquid chromatography and liquid chromatography coupled to mass spectrophotometry analysis to identify an 84 kDa protein, named P9, that is secreted by A. muciniphila. Using L cells and mice fed on an HFD, we show that purified P9 alone is sufficient to induce GLP-1 secretion and brown adipose tissue thermogenesis. Using ligand–receptor capture analysis, we find that P9 interacts with intercellular adhesion molecule 2 (ICAM-2). Interleukin-6 deficiency abrogates the effects of P9 in glucose homeostasis and downregulates ICAM-2 expression. Our results show that the interactions between P9 and ICAM-2 could be targeted by therapeutics for metabolic diseases.

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Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice

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