Preventing obesity, insulin resistance and type 2 diabetes by targeting MT1-MMP

Pallavi Asthana, Hoi Leong Xavier Wong*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

Abstract

Obesity is one of the predominant risk factors for type 2 diabetes. Despite all the modern advances in medicine, an effective drug treatment for obesity without overt side effects has not yet been found. The discovery of growth and differentiation factor 15 (GDF15), an appetite-regulating hormone, created hopes for the treatment of obesity. However, an insufficient understanding of the physiological regulation of GDF15 has been a major obstacle to mitigating GDF15-centric treatment of obesity. Our recent studies revealed how a series of proteolytic events predominantly mediated by membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP14), a key cell-surface metalloproteinase involved in extracellular remodeling, contribute to the pathogenesis of metabolic disorders, including obesity and diabetes. The MT1-MMP-mediated cleavage of the GDNF family receptor-α-like (GFRAL), a key neuronal receptor of GDF15, controls the satiety center in the hindbrain, thereby regulating non-homeostatic appetite and bodyweight changes. Furthermore, increased activation of MT1-MMP does not only lead to increased risk of obesity, but also causes age-associated insulin resistance by cleaving Insulin Receptor in major metabolic tissues. Importantly, inhibition of MT1-MMP effectively protects against obesity and diabetes, revealing the therapeutic potential of targeting MT1-MMP for the management of metabolic disorders.

Original languageEnglish
Article number167081
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1870
Issue number4
Early online date16 Feb 2024
DOIs
Publication statusPublished - Apr 2024

Scopus Subject Areas

  • Molecular Medicine
  • Molecular Biology

User-Defined Keywords

  • GDF15-GFRAL signaling
  • Insulin resistance
  • MT1-MMP
  • Obesity

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