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Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice

Dionysios V Chartoumpekis1, Yoko Yagishita1, Marco Fazzari1,2

  • 1Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

JCI Insight
|March 9, 2018
PubMed

Insights

Activating the Nrf2 pathway in mice with severe insulin resistance prevented cancer development. This suggests Nrf2 is a promising therapeutic target for combating insulin resistance and associated cancer risks.

Area of Science:

  • Metabolic disease research
  • Cancer biology
  • Molecular signaling pathways

Background:

  • Insulin resistance is linked to increased cancer incidence and progression.
  • Effective strategies to manage insulin resistance and halt cancer are needed.
  • The transcription factor Nrf2 (Nfe2l2) plays a key role in disease prevention.

Purpose of the Study:

  • To investigate if activating the Nrf2 pathway can ameliorate insulin resistance and prevent cancer.
  • To utilize a novel mouse model with lipodystrophy-induced insulin resistance and sarcoma development.

Main Methods:

  • Developed a mouse model overexpressing the Notch intracellular domain in adipocytes (AdNICD).
  • Activated the Nrf2 pathway by knocking down Keap1 (Nrf2 repressor) in the AdNICD model.
  • Assessed metabolic parameters (hepatic steatosis, dyslipidemia, insulin resistance) and sarcoma development.

Main Results:

  • Constitutive Nrf2 activation prevented hepatic steatosis, dyslipidemia, and insulin resistance.
  • Nrf2 activation repressed hepatic lipogenic pathways and normalized hepatic fatty acid profiles.
  • Nrf2 activation significantly reduced and delayed sarcoma incidence and latency in the model.

Conclusions:

  • The Nrf2 pathway is a potential therapeutic target for managing insulin resistance.
  • Nrf2 activation demonstrates protective effects against cancer development in this model.
  • Targeting Nrf2 may offer a strategy to mitigate risks associated with insulin resistance and cancer.
Keywords:
CancerDiabetesMetabolismOncology

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