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

Pallavi Asthana1, Hoi Leong Xavier Wong1

  • 1School of Chinese Medicine, Hong Kong Baptist University, Hong Kong.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|February 17, 2024
PubMed

Insights

Growth and differentiation factor 15 (GDF15) holds promise for obesity treatment. Our study reveals membrane-type 1 matrix metalloproteinase (MT1-MMP) regulates GDF15 signaling, offering a new target for metabolic disorders.

Area of Science:

  • Biochemistry
  • Metabolic Disorders
  • Molecular Biology

Background:

  • Obesity is a major risk factor for type 2 diabetes, yet effective treatments remain elusive.
  • Growth and differentiation factor 15 (GDF15) regulates appetite but its physiological control is poorly understood.
  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) is implicated in extracellular remodeling and metabolic disease.

Purpose of the Study:

  • To elucidate the role of MT1-MMP in the regulation of GDF15 signaling.
  • To investigate the contribution of MT1-MMP to obesity and insulin resistance.
  • To assess the therapeutic potential of targeting MT1-MMP for metabolic disorders.

Main Methods:

  • Investigated MT1-MMP-mediated proteolytic events.
  • Analyzed the cleavage of GDF15 receptor GFRAL in the hindbrain.
  • Examined MT1-MMP's effect on Insulin Receptor in metabolic tissues.
  • Evaluated the impact of MT1-MMP inhibition on obesity and diabetes models.

Main Results:

  • MT1-MMP mediates the cleavage of GFRAL, controlling appetite and body weight.
  • Increased MT1-MMP activity is linked to obesity and age-associated insulin resistance.
  • MT1-MMP cleaves the Insulin Receptor in key metabolic tissues.
  • Inhibition of MT1-MMP demonstrated protective effects against obesity and diabetes.

Conclusions:

  • MT1-MMP plays a critical role in regulating appetite and metabolic homeostasis.
  • Targeting MT1-MMP presents a promising therapeutic strategy for obesity and type 2 diabetes.
  • Understanding MT1-MMP's proteolytic functions is key to developing novel metabolic disorder treatments.
Keywords:
GDF15-GFRAL signalingInsulin resistanceMT1-MMPObesity

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