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 journalArticlepeer-review

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 languageEnglish
Pages (from-to)203–212
Number of pages10
JournalNature Metabolism
Volume4
Issue number2
DOIs
Publication statusPublished - 17 Feb 2022

Scopus Subject Areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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