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Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice
Dionysios V. Chartoumpekis, … , Thomas W. Kensler, Nobunao Wakabayashi
Dionysios V. Chartoumpekis, … , Thomas W. Kensler, Nobunao Wakabayashi
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e97735. https://doi.org/10.1172/jci.insight.97735.
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Research Article Metabolism Oncology

Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice

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Abstract

Insulin resistance is associated with increased incidence and enhanced progression of cancers. However, little is known about strategies that can effectively ameliorate insulin resistance and consequently halt cancer progression. Herein, we propose that the transcription factor Nrf2 (also known as Nfe2l2) may be such a target, given its central role in disease prevention. To this end, we developed a mouse that overexpresses the Notch intracellular domain in adipocytes (AdNICD), leading to lipodystrophy-induced severe insulin resistance and subsequent development of sarcomas, as a model reflecting that Notch signaling is deregulated in cancers and shows positive associations with insulin resistance and fatty liver disease in humans. Nrf2 pathway activation was achieved by knocking down Keap1, a repressor of Nrf2, in the AdNICD background. Constitutively enhanced Nrf2 signaling in this setting led to prevention of hepatic steatosis, dyslipidemia, and insulin resistance by repressing hepatic lipogenic pathways and restoration of the hepatic fatty acid profile to control levels. This protective effect of Nrf2 against diabetes extended to significant reduction and delay in sarcoma incidence and latency. Our study highlights that the Nrf2 pathway, which has been induced by small molecules in clinical trials, is a potential therapeutic target against insulin resistance and subsequent risk of cancer.

Authors

Dionysios V. Chartoumpekis, Yoko Yagishita, Marco Fazzari, Dushani L. Palliyaguru, Uma N.M. Rao, Apostolos Zaravinos, Nicholas K.H. Khoo, Francisco J. Schopfer, Kurt R. Weiss, George K. Michalopoulos, Ian Sipula, Robert M. O’Doherty, Thomas W. Kensler, Nobunao Wakabayashi

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Figure 1

Activation of the Nrf2 pathway prevents energy metabolism disturbance in AdNICD lipodystrophic mice.

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Activation of the Nrf2 pathway prevents energy metabolism disturbance in...
(A) Body weights, (B) quantitative magnetic resonance–based measurement of fat mass, and (C) food consumption assessment over a 3-day period in 3-month-old male mice, plotted as body weight–corrected food consumption per day. (D) Energy expenditure assessment over a 3-day period in 2.5-month-old male mice plotted as body weight–corrected heat production per day. (E) Heat production and (F) respiratory exchange ratio (RER) tracing of mice of 3 genotypes (red line: AdNICD; blue line: Keap1KD:AdNICD; black line: Nrf2KO:Keap1KD:AdNICD with n = 9, n = 7, and n = 3, respectively) over a period of 72 hours. (G) Percentage increase in RER in dark vs. light cycle (based on indirect calorimetry data from 72 hours). All data represent mean ± SEM. *P < 0.05 compared with control mice; #P < 0.05 compared with Keap1KD:AdNICD mice, 1-way ANOVA.

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