Deficiency in Nrf2 transcription factor decreases adipose tissue mass and hepatic lipid accumulation in leptin‐deficient mice

Authors

Jialin Xu, University of Rhode Island
Ajay C. Donepudi, University of Rhode Island
Vijay R. More, University of Rhode Island
Supriya R. Kulkarni, University of Rhode Island
Liya Li, University of Rhode Island
Liangran Guo, University of Rhode Island
Bingfang Yan, University of Rhode IslandFollow
Tapan Chatterjee
Neal Weintraub
Angela L. Slitt, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

2015

Department

Biomedical and Pharmaceutical Sciences

Abstract

Objective: To evaluate whether Nrf2 deficiency impacts insulin resistance and lipid accumulation in liver and white adipose tissue.

Methods: Lep^ob/ob mice (OB) with targeted Nrf2 deletion (OB‐Nrf2KO) were generated. Pathogenesis of obesity and type 2 diabetes was measured in C57BL/6J, Nrf2KO, OB, and OB‐Nrf2KO mice. Hepatic lipid content, lipid clearance, and very low‐density lipoprotein (VLDL) secretion were determined between OB and OB‐Nrf2KO mice.

Results: OB‐Nrf2KO mice exhibited decreased white adipose tissue mass and decreased adipogenic and lipogenic gene expression compared with OB mice. Nrf2 deficiency prolonged hyperglycemia in response to glucose challenge, which was paralleled by reduced insulin‐stimulated Akt phosphorylation. In OB mice, Nrf2 deficiency decreased hepatic lipid accumulation, decreased peroxisome proliferator‐activated receptor γ expression and nicotinamide adenine dinucleotide phosphate (NADPH) content, and enhanced VLDL secretion. However, this observation was opposite in lean mice. Additionally, OB‐Nrf2KO mice exhibited increased plasma triglyceride content, decreased HDL‐cholesterol content, and enhanced apolipoprotein B expression, suggesting Nrf2 deficiency caused dyslipidemia in these mice.

Conclusions: Nrf2 deficiency in Lep^ob/ob mice reduced white adipose tissue mass and prevented hepatic lipid accumulation but induced insulin resistance and dyslipidemia. This study indicates a dual role of Nrf2 during metabolic dysregulation—increasing lipid accumulation in liver and white adipose tissue but preventing lipid accumulation in obese mice.

Citation/Publisher Attribution

Xu, J. , Donepudi, A. C., More, V. R., Kulkarni, S. R., Li, L. , Guo, L. , Yan, B. , Chatterjee, T. , Weintraub, N. and Slitt, A. L. (2015), Deficiency in Nrf2 transcription factor decreases adipose tissue mass and hepatic lipid accumulation in leptin‐deficient mice. Obesity, 23: 335-344. doi: 10.1002/oby.20929 Available at: https://doi.org/10.1002/oby.20929