Body weight regulation via MT1-MMP-mediated cleavage of GFRAL

Chi Fung Willis Chow; Xuanming  Guo; Pallavi  Asthana; Shuo Zhang; Sheung Kin Ken Wong; Samane Fallah; Sijia  Che; Susma  Gurung; Zening Wang; Ki Baek Lee; Xin Ge; Shiyang Yuan; Haoyu Xu; Jacque Pak Kan Ip; Zhixin Jiang; Lixiang  Zhai; Jiayan  Wu; Yijing  Zhang; Arun Kumar Mahato; Mart Saarma; Cheng Yuan  Lin; Hiu Yee  Kwan; Tao  Huang; Aiping  Lyu; Zhongjun Zhou; Zhao Xiang  Bian; Hoi Leong Xavier  Wong

doi:10.1038/s42255-022-00529-5

Body weight regulation via MT1-MMP-mediated cleavage of GFRAL

Chi Fung Willis Chow, Xuanming Guo, Pallavi Asthana, Shuo Zhang, Sheung Kin Ken Wong, Samane Fallah, Sijia Che, Susma Gurung, Zening Wang, Ki Baek Lee, Xin Ge, Shiyang Yuan, Haoyu Xu, Jacque Pak Kan Ip, Zhixin Jiang, Lixiang Zhai, Jiayan Wu, Yijing Zhang, Arun Kumar Mahato, Mart SaarmaCheng Yuan Lin, Hiu Yee Kwan, Tao Huang, Aiping Lyu, Zhongjun Zhou, Zhao Xiang Bian^*, Hoi Leong Xavier Wong^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

29 Citations (Scopus)

Abstract

GDNF-family receptor a-like (GFRAL) has been identified as the cognate receptor of growth/differentiation factor 15 (GDF15/MIC-1), considered a key signaling axis in energy homeostasis and body weight regulation. Currently, little is known about the physiological regulation of the GDF15–GFRAL signaling pathway. Here we show that membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) is an endogenous negative regulator of GFRAL in the context of obesity. Overnutrition-induced obesity increased MT1-MMP activation, which proteolytically inactivated GFRAL to suppress GDF15–GFRAL signaling, thus modulating the anorectic effects of the GDF15–GFRAL axis in vivo. Genetic ablation of MT1-MMP specifically in GFRAL⁺ neurons restored GFRAL expression, resulting in reduced weight gain, along with decreased food intake in obese mice. Conversely, depletion of GFRAL abolished the anti-obesity effects of MT1-MMP inhibition. MT1-MMP inhibition also potentiated GDF15 activity specifically in obese phenotypes. Our findings identify a negative regulator of GFRAL for the control of non-homeostatic body weight regulation, provide mechanistic insights into the regulation of GDF15 sensitivity, highlight negative regulators of the GDF15–GFRAL pathway as a therapeutic avenue against obesity and identify MT1-MMP as a promising target.

Original language	English
Pages (from-to)	203–212
Number of pages	10
Journal	Nature Metabolism
Volume	4
Issue number	2
DOIs	https://doi.org/10.1038/s42255-022-00529-5
Publication status	Published - 17 Feb 2022

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10.1038/s42255-022-00529-5

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Chow, C. F. W., Guo, X., Asthana, P., Zhang, S., Wong, S. K. K., Fallah, S., Che, S., Gurung, S., Wang, Z., Lee, K. B., Ge, X., Yuan, S., Xu, H., Ip, J. P. K., Jiang, Z., Zhai, L., Wu, J., Zhang, Y., Mahato, A. K., ... Wong, H. L. X. (2022). Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nature Metabolism, 4(2), 203–212. https://doi.org/10.1038/s42255-022-00529-5

@article{6c515451fe0b445db67038999d5f6485,

title = "Body weight regulation via MT1-MMP-mediated cleavage of GFRAL",

abstract = "GDNF-family receptor a-like (GFRAL) has been identified as the cognate receptor of growth/differentiation factor 15 (GDF15/MIC-1), considered a key signaling axis in energy homeostasis and body weight regulation. Currently, little is known about the physiological regulation of the GDF15–GFRAL signaling pathway. Here we show that membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) is an endogenous negative regulator of GFRAL in the context of obesity. Overnutrition-induced obesity increased MT1-MMP activation, which proteolytically inactivated GFRAL to suppress GDF15–GFRAL signaling, thus modulating the anorectic effects of the GDF15–GFRAL axis in vivo. Genetic ablation of MT1-MMP specifically in GFRAL+ neurons restored GFRAL expression, resulting in reduced weight gain, along with decreased food intake in obese mice. Conversely, depletion of GFRAL abolished the anti-obesity effects of MT1-MMP inhibition. MT1-MMP inhibition also potentiated GDF15 activity specifically in obese phenotypes. Our findings identify a negative regulator of GFRAL for the control of non-homeostatic body weight regulation, provide mechanistic insights into the regulation of GDF15 sensitivity, highlight negative regulators of the GDF15–GFRAL pathway as a therapeutic avenue against obesity and identify MT1-MMP as a promising target.",

author = "Chow, {Chi Fung Willis} and Xuanming Guo and Pallavi Asthana and Shuo Zhang and Wong, {Sheung Kin Ken} and Samane Fallah and Sijia Che and Susma Gurung and Zening Wang and Lee, {Ki Baek} and Xin Ge and Shiyang Yuan and Haoyu Xu and Ip, {Jacque Pak Kan} and Zhixin Jiang and Lixiang Zhai and Jiayan Wu and Yijing Zhang and Mahato, {Arun Kumar} and Mart Saarma and Lin, {Cheng Yuan} and Kwan, {Hiu Yee} and Tao Huang and Aiping Lyu and Zhongjun Zhou and Bian, {Zhao Xiang} and Wong, {Hoi Leong Xavier}",

note = "Funding Information: The presented work was supported by General Research Fund (12101019 and 12102020 to H.L.X.W.), Health and Medical Research Fund (06170056 and 08793626 to H.L.X.W.), National Natural Science Fund (81802838 to H.L.X.W.) and Guangdong Natural Science Foundation (2021A1515011128 and 2019A1515011851 to H.L.X.W.). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited",

year = "2022",

month = feb,

day = "17",

doi = "10.1038/s42255-022-00529-5",

language = "English",

volume = "4",

pages = "203–212",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Nature Research",

number = "2",

}

Chow, CFW, Guo, X, Asthana, P, Zhang, S, Wong, SKK, Fallah, S, Che, S, Gurung, S, Wang, Z, Lee, KB, Ge, X, Yuan, S, Xu, H, Ip, JPK, Jiang, Z, Zhai, L, Wu, J, Zhang, Y, Mahato, AK, Saarma, M, Lin, CY, Kwan, HY, Huang, T, Lyu, A, Zhou, Z, Bian, ZX & Wong, HLX 2022, 'Body weight regulation via MT1-MMP-mediated cleavage of GFRAL', Nature Metabolism, vol. 4, no. 2, pp. 203–212. https://doi.org/10.1038/s42255-022-00529-5

TY - JOUR

T1 - Body weight regulation via MT1-MMP-mediated cleavage of GFRAL

AU - Chow, Chi Fung Willis

AU - Guo, Xuanming

AU - Asthana, Pallavi

AU - Zhang, Shuo

AU - Wong, Sheung Kin Ken

AU - Fallah, Samane

AU - Che, Sijia

AU - Gurung, Susma

AU - Wang, Zening

AU - Lee, Ki Baek

AU - Ge, Xin

AU - Yuan, Shiyang

AU - Xu, Haoyu

AU - Ip, Jacque Pak Kan

AU - Jiang, Zhixin

AU - Zhai, Lixiang

AU - Wu, Jiayan

AU - Zhang, Yijing

AU - Mahato, Arun Kumar

AU - Saarma, Mart

AU - Lin, Cheng Yuan

AU - Kwan, Hiu Yee

AU - Huang, Tao

AU - Lyu, Aiping

AU - Zhou, Zhongjun

AU - Bian, Zhao Xiang

AU - Wong, Hoi Leong Xavier

N1 - Funding Information: The presented work was supported by General Research Fund (12101019 and 12102020 to H.L.X.W.), Health and Medical Research Fund (06170056 and 08793626 to H.L.X.W.), National Natural Science Fund (81802838 to H.L.X.W.) and Guangdong Natural Science Foundation (2021A1515011128 and 2019A1515011851 to H.L.X.W.). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited

PY - 2022/2/17

Y1 - 2022/2/17

N2 - GDNF-family receptor a-like (GFRAL) has been identified as the cognate receptor of growth/differentiation factor 15 (GDF15/MIC-1), considered a key signaling axis in energy homeostasis and body weight regulation. Currently, little is known about the physiological regulation of the GDF15–GFRAL signaling pathway. Here we show that membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) is an endogenous negative regulator of GFRAL in the context of obesity. Overnutrition-induced obesity increased MT1-MMP activation, which proteolytically inactivated GFRAL to suppress GDF15–GFRAL signaling, thus modulating the anorectic effects of the GDF15–GFRAL axis in vivo. Genetic ablation of MT1-MMP specifically in GFRAL+ neurons restored GFRAL expression, resulting in reduced weight gain, along with decreased food intake in obese mice. Conversely, depletion of GFRAL abolished the anti-obesity effects of MT1-MMP inhibition. MT1-MMP inhibition also potentiated GDF15 activity specifically in obese phenotypes. Our findings identify a negative regulator of GFRAL for the control of non-homeostatic body weight regulation, provide mechanistic insights into the regulation of GDF15 sensitivity, highlight negative regulators of the GDF15–GFRAL pathway as a therapeutic avenue against obesity and identify MT1-MMP as a promising target.

AB - GDNF-family receptor a-like (GFRAL) has been identified as the cognate receptor of growth/differentiation factor 15 (GDF15/MIC-1), considered a key signaling axis in energy homeostasis and body weight regulation. Currently, little is known about the physiological regulation of the GDF15–GFRAL signaling pathway. Here we show that membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) is an endogenous negative regulator of GFRAL in the context of obesity. Overnutrition-induced obesity increased MT1-MMP activation, which proteolytically inactivated GFRAL to suppress GDF15–GFRAL signaling, thus modulating the anorectic effects of the GDF15–GFRAL axis in vivo. Genetic ablation of MT1-MMP specifically in GFRAL+ neurons restored GFRAL expression, resulting in reduced weight gain, along with decreased food intake in obese mice. Conversely, depletion of GFRAL abolished the anti-obesity effects of MT1-MMP inhibition. MT1-MMP inhibition also potentiated GDF15 activity specifically in obese phenotypes. Our findings identify a negative regulator of GFRAL for the control of non-homeostatic body weight regulation, provide mechanistic insights into the regulation of GDF15 sensitivity, highlight negative regulators of the GDF15–GFRAL pathway as a therapeutic avenue against obesity and identify MT1-MMP as a promising target.

UR - http://www.scopus.com/inward/record.url?scp=85124713561&partnerID=8YFLogxK

U2 - 10.1038/s42255-022-00529-5

DO - 10.1038/s42255-022-00529-5

M3 - Journal article

SN - 2522-5812

VL - 4

SP - 203

EP - 212

JO - Nature Metabolism

JF - Nature Metabolism

IS - 2

ER -

Body weight regulation via MT1-MMP-mediated cleavage of GFRAL

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