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The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.

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

Chow, Chi Fung Willis, Guo, Xuanming, Asthana, Pallavi, Zhang, Shuo, Wong, Sheung Kin Ken, Fallah, Samane, Che, Sijia, Gurung, Susma, Wang, Zening, Lee, Ki Baek, Ge, Xin, Yuan, Shiyang, Xu, Haoyu, Ip, Jacque Pak Kan, Jiang, Zhixin, Zhai, Lixiang, Wu, Jiayan, Zhang, Yijing, Mahato, Arun Kumar, Saarma, Mart, Lin, Cheng Yuan, Kwan, Hiu Yee, Huang, Tao, Lyu, Aiping, Zhou, Zhongjun, Bian, Zhao-Xiang, Wong, Hoi Leong Xavier·2022·Nature Metabolism
DOI 10.1038/s42255-022-00529-5
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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.

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Crossref · 10.1038/s42255-022-00529-5

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  • Systemic inhibition of MT1-MMP improved metabolic functions in aged mice.

    “In line with our previous studies with Mmp14+/− mice15,17, we found that systemic inhibition of MT1-MMP also improved metabolic functions in aged mice.”

    From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [15]

  • HFD-induced obesity led to increased expression of hippocampal MT1-MMP, which was reversed by the lentivirus-mediated knockdown of MT1-MMP.

    “In line with our previous findings15, HFD-induced obesity led to increased expression of hippocampal MT1-MMP, which was reversed by the lentivirus-mediated knockdown of MT1-MMP (Supplementary Fig. S5b).”

    From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [15]

  • Systemic inhibition of MT1-MMP improved metabolic functions in obese mice as evidenced by the reductions in body weight, blood glucose, TG, and total cholesterol.

    “Consistent with our previous studies with Mmp14+/− mice15,17, systemic inhibition of MT1-MMP also improved metabolic functions in obese mice as evidenced by the reductions in body weight, blood glucose, TG, and total cholesterol (Supplementary Fig. S8f–i).”

    From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [15]

  • MT1-MMP is a key regulator of energy homeostasis and a series of proteolytic events mediated by MT1-MMP contribute to the pathogenesis of multiple age-associated metabolic disorders, including obesity, diabetes, and atherosclerosis.

    “Our recent findings, along with those of other studies, demonstrate that MT1-MMP is a key regulator of energy homeostasis and that a series of proteolytic events mediated by MT1-MMP contribute to the pathogenesis of multiple age-associated metabolic disorders, including obesity, diabetes, and atherosclerosis15–17.”

    From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [15]

  • Proteolytic cleavage of the anorectic receptor GDNF family receptor alpha-like (GFRAL) by neuronal MT1-MMP regulates the satiety center in the brainstem, exerting non-homeostatic control of food intake and body weight.

    “In particular, proteolytic cleavage of the anorectic receptor GDNF family receptor alpha-like (GFRAL) by neuronal MT1-MMP regulates the satiety center in the brainstem, exerting non-homeostatic control of food intake and body weight15.”

    From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [15]

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Research works printed but not linked: 29

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Metadata

Authors
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., Saarma, M., Lin, C. Y., Kwan, H. Y., Huang, T., Lyu, A., Zhou, Z., Bian, Z.-X., & Wong, H. L. X.
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2022-02-17
Volume
4
Issue
2
Pages
203-212
ISSN
2522-5812
DOI
10.1038/s42255-022-00529-5
Cited by
37
References
8
Language
en
Licence
Funders
  • Research Grants Council, University Grants Committee (12101019, 12102020)
  • Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (06170056, 08793626)
  • National Natural Science Foundation of China (81802838)
  • Natural Science Foundation of Guangdong Province (2021A1515011128)

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