Enhanced Nrf2 Activity Worsens Insulin Resistance, Impairs Lipid Accumulation in Adipose Tissue, and Increases Hepatic Steatosis in Leptin-Deficient Mice

Authors

Jialin Xu, University of Rhode Island
Supriya R. Kulkarni, University of Rhode Island
Ajay C. Donepudi, University of Rhode Island
Vijay R. More, University of Rhode Island
Angela L. Slitt, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

2012

Department

Biomedical and Pharmaceutical Sciences

Abstract

The study herein determined the role of nuclear factor erythoid 2–related factor 2 (Nrf2) in the pathogenesis of hepatic steatosis, insulin resistance, obesity, and type 2 diabetes. Lep^ob/ob-Keap1-knockdown (KD) mice, which have increased Nrf2 activity, were generated. Markers of obesity and type 2 diabetes were measured in C57Bl/6J, Keap1-KD, Lep^ob/ob, and Lep^ob/ob-Keap1-KD mice. Lep^ob/ob-Keap1-KD mice exhibited less lipid accumulation, smaller adipocytes, decreased food intake, and reduced lipogenic gene expression. Enhanced Nrf2 activity impaired insulin signaling, prolonged hyperglycemia in response to glucose challenge, and induced insulin resistance in Lep^ob/ob background. Nrf2 augmented hepatic steatosis and increased lipid deposition in liver. Next, C57Bl/6J and Keap1-KD mice were fed a high-fat diet (HFD) to determine whether Keap1 and Nrf2 impact HFD-induced obesity. HFD-induced obesity and lipid accumulation in white adipose tissue was decreased in Keap1-KD mice. Nrf2 activation via Keap1-KD or sulforaphane suppressed hormone-induced differentiation and decreased peroxisome proliferator–activated receptor-γ, CCAAT/enhancer–binding protein α, and fatty acid–binding protein 4 expression in mouse embryonic fibroblasts. Constitutive Nrf2 activation inhibited lipid accumulation in white adipose tissue, suppressed adipogenesis, induced insulin resistance and glucose intolerance, and increased hepatic steatosis in Lep^ob/ob mice.

Citation/Publisher Attribution

Xu, J., Kulkarni, S. R., Donepudi, A. C., More, V. R., & Slitt, A. L. (2012). Enhanced Nrf2 Activity Worsens Insulin Resistance, Impairs Lipid Accumulation in Adipose Tissue, and Increases Hepatic Steatosis in Leptin-Deficient Mice. Diabetes, 61(12), 3208-3218. doi: 10.2337/db11-1716

Available at: https://doi.org/10.2337/db11-1716

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.