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. 2022 Feb;4(2):203-212.
doi: 10.1038/s42255-022-00529-5. Epub 2022 Feb 17.

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

Chi Fung Willis Chow #  1   2 , Xuanming Guo #  1 , Pallavi Asthana #  1 , Shuo Zhang  3 , Sheung Kin Ken Wong  3 , Samane Fallah  1 , Sijia Che  1 , Susma Gurung  1 , Zening Wang  4 , Ki Baek Lee  4 , Xin Ge  4 , Shiyang Yuan  5 , Haoyu Xu  5 , Jacque Pak Kan Ip  5 , Zhixin Jiang  3 , Lixiang Zhai  1 , Jiayan Wu  1 , Yijing Zhang  1 , Arun Kumar Mahato  6 , Mart Saarma  6 , Cheng Yuan Lin  1   7 , Hiu Yee Kwan  1 , Tao Huang  1 , Aiping Lyu  1 , Zhongjun Zhou  3 , Zhao-Xiang Bian  8   9 , Hoi Leong Xavier Wong  10
Affiliations

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

Chi Fung Willis Chow et al. Nat Metab. 2022 Feb.

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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References

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