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

• Published in: Nature metabolism Vol. 4; no. 2; p. 203
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Germany 01.02.2022
• Subjects: Animals; Anorexia - metabolism; Body Weight; Glial Cell Line-Derived Neurotrophic Factor Receptors - genetics; Glial Cell Line-Derived Neurotrophic Factor Receptors - metabolism; Matrix Metalloproteinase 14 - therapeutic use; Mice; Obesity - metabolism
• DOI: 10.1038/s42255-022-00529-5

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.