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

Nature Metabolism volume 4, pages 203–212 (2022)Cite this article

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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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Fig. 1: Haplodeficiency of MT1-MMP protects mice from high-fat-diet-induced obesity and insulin resistance.
Fig. 2: Upregulation of MT1-MMP in the brain of obese mice.
Fig. 3: Haplodeficiency of MT1-MMP enhances GDF15-mediated weight loss and food intake reduction.
Fig. 4: The direct cleavage of GFRAL by MT1-MMP.
Fig. 5: MT1-MMP cleaves GFRAL to inhibit GFRAL–GDF15-mediated signaling.
Fig. 6: Genetic ablation of GFRAL restores weight gain and food intake in Mmp14+/− mice.
Fig. 7: Targeted deletion of MT1-MMP in GFRAL neurons potentiates GDF15–GFRAL signaling.

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The raw data that support the findings of this study can be found in the source data provided with this paper. Source data are provided with this paper.

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Acknowledgements

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.).

Author information

Author notes

  1. Chi Fung Willis Chow

    Present address: Center for Systems Biology Dresden, Max Planck Institute for Molecular Cell and Biology, Dresden, Germany

  2. These authors contributed equally: Chi Fung Willis Chow, Xuanming Guo, Pallavi Asthana.

Authors and Affiliations

  1. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

    Chi Fung Willis Chow, Xuanming Guo, Pallavi Asthana, Samane Fallah, Sijia Che, Susma Gurung, Lixiang Zhai, Jiayan Wu, Yijing Zhang, Cheng Yuan Lin, Hiu Yee Kwan, Tao Huang, Aiping Lyu, Zhao-Xiang Bian & Hoi Leong Xavier Wong

  2. School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China

    Shuo Zhang, Sheung Kin Ken Wong, Zhixin Jiang & Zhongjun Zhou

  3. Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

    Zening Wang, Ki Baek Lee & Xin Ge

  4. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China

    Shiyang Yuan, Haoyu Xu & Jacque Pak Kan Ip

  5. Institute of Biotechnology-HILIFE, University of Helsinki, Helsinki, Finland

    Arun Kumar Mahato & Mart Saarma

  6. Centre for Chinese Herbal Medicine Drug Development Limited, Hong Kong Baptist University, Hong Kong SAR, China

    Cheng Yuan Lin & Zhao-Xiang Bian

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Contributions

C.F.W.C., X. Guo, P.A. and H.L.X.W. performed most of the experiments. S.Z., J.W., Y.Z. and Z.J. helped to collect samples. S.F., S.C., S.K.K.W., S.G., S.Y., H.X. and J.P.K.I. performed some of the experiments and data analyses. Z.W., K.B.L. and X. Ge provided experimental materials for experiments. C.Y.L., H.Y.K., T.H., A.L. and Z-.X.B. contributed to the discussion. Z.Z. provided animal models and helped in the initiation of the project. C.F.W.C. and H.L.X.W. designed the experiments and prepared the manuscript. H.L.X.W. and Z-.X.B. supervised the project.

Corresponding authors

Correspondence to Zhao-Xiang Bian or Hoi Leong Xavier Wong.

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Nature Metabolism thanks Sebastian Beck Jørgensen, Stephen O’Rahilly and Yoshifumi Itoh for their contribution to the peer review of this work. Primary handling editors: Isabella Samuelson and Ashley Castellanos-Jankiewicz.

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Extended data

Extended Data Fig. 1 Inhibition of MT1-MMP improves metabolic parameters in mice with high fat diet-induced obesity.

Body weight (a), average daily food intake (b), blood glucose concentration (c), triglyceride, cholesterol concentrations (d) and fat mass (e) of male mice with high fat diet-induced obesity after receiving (twice a week) treatment with either 3A2 antibody or control IgG for 4 weeks (n=8). Data are reported as average ± s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001. two-way ANOVA for (a), two-sided unpaired t-test for (b-e).

Source data

Extended Data Fig. 2 Inhibition of MT1-MMP improves metabolic parameters in ob/ob mice.

Body weight (a), average daily food intake (b), blood glucose concentration (c) and insulin level (d) of male ob/ob mice after receiving (twice a week) treatment with either 3A2 antibody or control IgG for 4 weeks (n=8). Data are reported as average ± s.e.m. two-sided unpaired t-test for (a-d).

Source data

Extended Data Fig. 3 Increased Mmp activity in the brain of obese mice.

(a) Representative gelatin zymography showing the activity of gelatinases including Mmp2 and Mmp9 that are primarily activated by MT1-MMP in the brain of mice fed a high fat diet (HFD) and a standard diet (CD). (b) Quantification of the band intensity in (a). Data are reported as average ± s.e.m. (n=5) two-sided unpaired t-test.

Source data

Extended Data Fig. 4 Inhibition of MT1-MMP activity potentiates GDF15 functions.

(a) Change in body weight (%) in high fat diet-induced obese mice treated with control IgG or 3A2 after daily subcutaneous administration of recombinant GDF15 (10nmol/kg) for 6 days. (b-c) Cumulative food intake (b) and changes in food intake (%) (c) in mice with diet-induced obesity from (a). (d-e) Quantification of the percentage of GFRAL-positive cells that co-expressed cFOS in the area postrema of mice treated with control IgG or 3A2 (d) and the relative changes in cFOS +GFRAL+ cells (e) after receiving a single subcutaneous injection of recombinant GDF15 (10nmol/kg). Data are reported as average ± s.e.m. (n=6) P < 0.05; **P < 0.01; ***P < 0.001. two-sided unpaired t-test (c,e) or one-way ANOVA (a-b, d).

Source data

Extended Data Fig. 5 Haplodeficiency of MT1-MMP does not affect GLP-1 induced changes in food intake.

12-h food intake after subcutaneous administration of liraglutide (27nmol/kg) to WT and Mmp14+/− mice. Data are reported as average ± s.e.m. (n=8; one-way ANOVA).

Source data

Extended Data Fig. 6 Colocalization of MT1-MMP and GFRAL in the brainstem.

(a) Immunofluorescent staining of MT1-MMP (green) and GFRAL (red) in the Area Postrema from mice. (n=6) (scale: 10μm) (b) Spearmen’s correlation analyses of the colocalization of MT1-MMP and GFRAL (R=0.64, analyses of 10 cells per mice, n=6).

Extended Data Fig. 7 Loss of MT1-MMP does not alter the mRNA expression of Gfral.

qPCR analyses of Gfral expression in the area postrema of brains from WT, Mmp14+/- and Mmp14-/- mice. Data are reported as average ± s.e.m. (n=7 for WT and Mmp14+/- mice; n=5 for Mmp14-/- mice).

Source data

Extended Data Fig. 8 GFRAL is essential for GDF15-induced weight loss and reduction in food intake.

(a-b) Change in body weight (%) (a) and food intake (b) after subcutaneous administration of GDF15 to WT, Mmp14+/-, Gfral-/- and Mmp14+/- Gfral-/-mice. Data are reported as average ± s.e.m. *P < 0.05; ***P < 0.001. (n=8) for (a-b); two-sided unpaired t-test for (a-b).

Source data

Extended Data Fig. 9 Genetic ablation of GFRAL attenuates 3A2-induced weight loss and reduction in food intake.

(a-c) Absolute body weight (a), changes in body weight (%) (b) and average daily food intake (c) of WT and Gfral-/- mice with high fat diet-induced obesity after receiving (twice a week) treatment with either 3A2 antibody or control IgG for 4 weeks (n=8). Data are reported as average ± s.e.m. two-way ANOVA for (a) (WT+3A2 & Gfral-/-+3A2: p=0.037 for 14 days; p=0.0046 for 21 days; p<0.0001 for 28 days); one-way ANOVA for (b-c).

Source data

Extended Data Fig. 10 MT1-MMP deletion in GFRAL neurons abolishes obese-induced downregulation of GFRAL.

(a) Immunostaining of GFRAL in the brainstems from Mmp14f/fGfralcre+ mice on high fat diet and Mmp14f/+Gfralcre- on standard or high fat diet. (scale: 20μm) (b) Quantification of the relative fluorescence intensity of GFRAL staining in (a). (n=6) (c) qPCR analyses of Gfral expression in the AP from Mmp14f/fGfralcre+ mice on high fat diet and Mmp14f/+Gfralcre- on standard or high fat diet. (n=6) Data are reported as average ± s.e.m. one-way ANOVA.

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Chow, C.F.W., Guo, X., Asthana, P. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nat Metab 4, 203–212 (2022). https://doi.org/10.1038/s42255-022-00529-5

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