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

Asthana, Pallavi, Wong, Hoi Leong Xavier·2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
DOI 10.1016/j.bbadis.2024.167081
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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.

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  • Physiologically, MMP14 cleaves a wide range of substrates, ranging from ECM to growth factor receptors, in a tissue-specific and contextual manner.

    “Physiologically, MMP14 cleaves a wide range of substrates, ranging from ECM to growth factor receptors, in a tissue-specific and contextual manner13,14.”

    From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [13]

  • The specificity of the blocking antibody 3A2 has been well-characterized in previous studies.

    “The specificity of this blocking antibody has been well-characterized in our previous studies, in which we showed that blocking the activity of MT1-MMP with this antibody effectively promotes body weight loss in obesity, improves metabolic functions in diabetes, and promotes viral clearance in SARS-CoV-2-infected mice13,15–17.”

    From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [13]

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Metadata

Authors
Asthana, P., & Wong, H. L. X.
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher
Elsevier BV
Published
2024-04
Volume
1870
Issue
4
Pages
167081
ISSN
0925-4439
DOI
10.1016/j.bbadis.2024.167081
Cited by
13
References
17
Language
en
Licence
Funders
  • National Natural Science Foundation of China (32322091)
  • University Grants Committee
  • Innovation and Technology Commission
  • Health and Medical Research Fund (08793626)
  • Innovation and Technology Fund (ITS/058/22MS)
  • General Research Fund of Shanghai Normal University (12102020, 22104123)

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