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Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner

Utpal B Pajvani1, Carrie J Shawber, Varman T Samuel

  • 1Department of Medicine, Columbia University, New York, New York, USA.

Nature Medicine
|August 2, 2011
PubMed

Insights

Notch signaling inhibition improves insulin sensitivity by reducing hepatic glucose production, offering a new therapeutic strategy for diabetes. This approach targets the interplay between FoxO1 and Notch pathways.

Area of Science:

  • Metabolic regulation
  • Molecular endocrinology
  • Signaling pathways

Background:

  • Transcription factor FoxO1 is a key regulator of hepatic glucose production, making it a target for diabetes treatment.
  • Notch signaling alterations are implicated in cancer, with antagonists in clinical trials.
  • The interplay between FoxO1 and Notch in metabolic regulation is largely unexplored.

Purpose of the Study:

  • To investigate the coordinated roles of FoxO1 and Notch signaling in regulating hepatic glucose metabolism.
  • To determine the therapeutic potential of modulating Notch signaling for insulin resistance and diabetes.

Main Methods:

  • Genetic manipulation including combined haploinsufficiency of FoxO1 and Notch1, and liver-specific knockout of Rbp-Jκ.
  • In vivo administration of γ-secretase inhibitors to block Notch signaling.
  • Assessment of insulin sensitivity and hepatic glucose production in mouse models of diet-induced obesity and insulin resistance.

Main Results:

  • Combined haploinsufficiency of FoxO1 and Notch1, or knockout of Rbp-Jκ, significantly improved insulin sensitivity in diet-induced insulin-resistant mice.
  • Notch1 gain-of-function exacerbated insulin resistance in a FoxO1-dependent manner and increased glucose-6-phosphatase expression.
  • Pharmacological inhibition of Notch signaling using γ-secretase inhibitors enhanced insulin sensitivity in both lean and obese mice.

Conclusions:

  • Notch signaling plays a previously unrecognized role in hepatic glucose metabolism.
  • Inhibition of Notch signaling is a promising therapeutic strategy for diabetes, partly by counteracting FoxO1-mediated hepatic glucose production.
  • Targeting the Notch pathway offers a novel approach to improve insulin sensitivity and manage metabolic dysfunction.

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