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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.

Titel:	Body weight regulation via MT1-MMP-mediated cleavage of GFRAL.
Autor/in / Beteiligte Person:	Chow, CFW ; Guo, X ; Asthana, P ; Zhang, S ; Wong, SKK ; Fallah, S ; Che, S ; Gurung, S ; Wang, Z ; Lee, KB ; Ge, X ; Yuan, S ; Xu, H ; Ip, JPK ; Jiang, Z ; Zhai, L ; Wu, J ; Zhang, Y ; Mahato, AK ; Saarma, M ; Lin, CY ; Kwan, HY ; Huang, T ; Lyu, A ; Zhou, Z ; Bian, ZX ; Wong, HLX
Link:	View record at Springer (Volltext)
Zeitschrift:	Nature metabolism, Jg. 4 (2022-02-01), Heft 2, S. 203-212
Veröffentlichung:	Berlin : Springer Nature, [2019]-, 2022
Medientyp:	academicJournal
ISSN:	2522-5812 (electronic)
DOI:	10.1038/s42255-022-00529-5
Schlagwort:	Animals Anorexia metabolism Body Weight Glial Cell Line-Derived Neurotrophic Factor Receptors genetics Glial Cell Line-Derived Neurotrophic Factor Receptors metabolism Mice Matrix Metalloproteinase 14 therapeutic use Obesity metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Nat Metab] 2022 Feb; Vol. 4 (2), pp. 203-212. <i>Date of Electronic Publication: </i>2022 Feb 17. MeSH Terms: Matrix Metalloproteinase 14* / therapeutic use ; Obesity* / metabolism ; Animals ; Anorexia / metabolism ; Body Weight ; Glial Cell Line-Derived Neurotrophic Factor Receptors / genetics ; Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism ; Mice Comments: Comment in: Nat Rev Endocrinol. 2022 May;18(5):266. (PMID: 35260814) References: Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aan8732 (2017). ; Johnen, H. et al. Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1. Nat. Med. 13, 1333–1340 (2007). (PMID: 10.1038/nm1677) ; Tsai, V. W. W., Lin, S., Brown, D. 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(PMID: 10.1038/s41467-019-09744-3) Substance Nomenclature: 0 (Glial Cell Line-Derived Neurotrophic Factor Receptors) ; EC 3.4.24.80 (Matrix Metalloproteinase 14) Entry Date(s): Date Created: 20220218 Date Completed: 20220427 Latest Revision: 20240313 Update Code: 20240313

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