Body weight regulation via MT1-MMP-mediated cleavage of GFRAL
Body weight regulation via MT1-MMP-mediated cleavage of GFRAL
复制标题
通过 MT1-MMP 介导的 GFRAL 裂解调节体重
DOI：
10.1038/s42255-022-00529-5
复制
发表时间：
2022-02-17
影响因子：
20.8
通讯作者：
Wong, Hoi Leong Xavier
中科院分区：
文献类型：
--
作者：
Chow, Chi Fung Willis;Guo, Xuanming;Wong, Hoi Leong Xavier
gdnf家族受体a样（GFRAL）已被确定为生长/分化因子15 （GDF15/MIC-1）的同源受体，被认为是能量稳态和体重调节的关键信号轴。目前对GDF15-GFRAL信号通路的生理调控知之甚少。本研究表明，膜结合基质金属蛋白酶14 （MT1-MMP/MMP14）是肥胖背景下GFRAL的内源性负调节因子。营养过剩诱导的肥胖增加了MT1-MMP的激活，通过蛋白水解使GFRAL失活，从而抑制GDF15-GFRAL信号，从而在体内调节GDF15-GFRAL轴的厌食作用。基因消融GFRAL+神经元中的MT1-MMP恢复了GFRAL的表达，导致肥胖小鼠体重增加减少，同时食物摄入量减少。相反，GFRAL的消耗消除了MT1-MMP抑制的抗肥胖作用。MT1-MMP抑制也增强了肥胖表型中GDF15的活性。我们的研究结果确定了GFRAL的负调节因子控制非稳态体重调节，为GDF15敏感性的调节提供了机制见解，突出了GDF15 - GFRAL途径的负调节因子作为治疗肥胖的途径，并确定MT1-MMP是一个有希望的靶点。
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.