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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
Published on: June 3, 2016
Rifampicin impairs adipogenesis by suppressing NRF2-ARE activity in mice fed a high-fat diet
Tianchang Gao1, Miao Lai2, Xihe Zhu2
1Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China; The Fourth Affiliated Hospital, China Medical University, No. 4 Chongshan East Road, Huanggu Area, Shenyang, Liaoning 110032, PR China.
Abstract:
Prolonged treatment with rifampicin (RFP), a first-line antibacterial agent used in the treatment of drug-sensitive tuberculosis, may cause various side effects, including metabolic disorders. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, also known as NRF2) plays an essential regulatory role in cellular adaptive responses to stresses via the antioxidant response element (ARE). Our previous studies discovered that NRF2 regulates the expression of CCAAT-enhancer-binding protein β (Cebpb) and peroxisome proliferator-activated receptor gamma (Pparg) in the process of adipogenesis. Here, we found that prolonged RFP treatment in adult male mice fed a high-fat diet developed insulin resistance, but reduced fat accumulation and decreased expression of multiple adipogenic genes in white adipose tissues. In 3 T3-L1 preadipocytes, RFP reduced the induction of Cebpb, Pparg and Cebpa at mRNA and protein levels in the early and/or later stage of hormonal cocktail-induced adipogenesis. Mechanistic investigations demonstrated that RFP inhibits NRF2-ARE luciferase reporter activity and expression of NRF2 downstream genes under normal culture condition and in the early stage of adipogenesis in 3 T3-L1 preadipocytes, suggesting that RFP can disturb adipogenic differentiation via NRF2-ARE interference. Taken together, we demonstrate a potential mechanism that RFP impairs adipose function by which RFP likely inhibits NRF2-ARE pathway and thereby interrupts its downstream adipogenic transcription network.
Insights
Rifampicin (RFP) treatment impairs adipose function by disrupting the NRF2-ARE pathway, leading to insulin resistance and reduced fat accumulation. This study reveals a mechanism for RFP-induced metabolic disorders.
Area of Science:
- Metabolic disorders
- Cellular adaptive responses
- Adipogenesis
Background:
- Prolonged rifampicin (RFP) treatment, used for tuberculosis, can cause metabolic side effects.
- Nuclear factor (erythroid-derived 2)-like 2 (NRF2) regulates cellular stress responses via the antioxidant response element (ARE).
- NRF2 influences adipogenesis by regulating CCAAT-enhancer-binding protein β (Cebpb) and peroxisome proliferator-activated receptor gamma (Pparg).
Purpose of the Study:
- To investigate the mechanism by which prolonged RFP treatment affects adipose tissue function and metabolism.
- To determine the role of the NRF2-ARE pathway in RFP-induced metabolic changes.
- To elucidate how RFP interferes with adipogenic differentiation.
Main Methods:
- Adult male mice on a high-fat diet were treated with RFP.
- 3T3-L1 preadipocytes were induced to differentiate into adipocytes with RFP treatment.
- NRF2-ARE luciferase reporter assays and gene/protein expression analysis were performed.
Main Results:
- RFP treatment in mice led to insulin resistance, reduced fat accumulation, and decreased adipogenic gene expression.
- RFP inhibited Cebpb, Pparg, and Cebpa induction during adipogenesis in 3T3-L1 cells.
- RFP suppressed NRF2-ARE activity and downstream gene expression in preadipocytes.
Conclusions:
- RFP impairs adipose tissue function and promotes insulin resistance.
- RFP interferes with adipogenic differentiation by inhibiting the NRF2-ARE pathway.
- This disruption of the NRF2-ARE pathway and downstream adipogenic network is a potential mechanism for RFP-induced metabolic disorders.
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