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Published on: March 28, 2013
Inhibition of STAT3 enhances UCP1 expression and mitochondrial function in brown adipocytes
Lini Song1, Xi Cao1, Wenyi Ji1
1Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Abstract:
Extensive studies have shown that the increasing brown adipose tissue (BAT) mass/activity possesses a strong ability to prevent obesity and its related complications. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal pathway is known to play a role in adipocyte differentiation and development. However, its impact on thermogenic properties of mature brown adipocytes has not yet been clarified. Nifuroxazide (NFX), a potent inhibitor of STAT3, has received widespread attention due to its alternative anti-tumor and anti-inflammatory effects. Herein, we report that NFX induces lipolysis with subsequent downregulation of ACCα and FAS, while ATGL and pHSL levels are elevated in mature brown adipocytes. Furthermore, NFX treatment promotes the mitochondrial respiration of mature brown adipocytes, as evidenced by increased expression of thermogenic transcriptional factors and mitochondrial content. In addition, it also alleviates the IL-6 and TNFα inhibition on brown thermogenic programming via suppressing the STAT3/NF-κB/IL-6 signaling pathway. In general, these findings suggest that the blockade of the JAK/STAT3 pathway by NFX has a pro-thermogenic effect on mature brown adipocytes which opens new perspectives for NFX repurposing and potential therapeutic route to counteract obesity and related metabolic disorders.
Insights
Nifuroxazide (NFX) enhances brown adipose tissue (BAT) thermogenesis by blocking the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. This promotes fat breakdown and mitochondrial respiration, offering a potential strategy against obesity.
Area of Science:
- Metabolic research
- Adipose tissue biology
- Pharmacology
Background:
- Increased brown adipose tissue (BAT) mass and activity are linked to obesity prevention.
- The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway influences adipocyte development.
- The role of JAK/STAT signaling in mature brown adipocyte thermogenesis remains unclear.
Purpose of the Study:
- To investigate the effect of Nifuroxazide (NFX), a STAT3 inhibitor, on the thermogenic properties of mature brown adipocytes.
- To explore the underlying molecular mechanisms of NFX action in brown adipocytes.
Main Methods:
- Treatment of mature brown adipocytes with Nifuroxazide (NFX).
- Assessment of lipolysis, gene/protein expression (ACCα, FAS, ATGL, pHSL, thermogenic factors, mitochondrial content).
- Analysis of inflammatory signaling pathways (STAT3, NF-κB, IL-6, TNFα).
Main Results:
- NFX induced lipolysis, decreasing ACCα and FAS while increasing ATGL and pHSL levels.
- NFX promoted mitochondrial respiration and increased thermogenic gene/protein expression.
- NFX suppressed the STAT3/NF-κB/IL-6 pathway, counteracting inflammatory inhibition of brown thermogenic programming.
Conclusions:
- Blocking the JAK/STAT3 pathway with NFX exerts a pro-thermogenic effect on mature brown adipocytes.
- NFX demonstrates potential for repurposing as a therapeutic agent against obesity and metabolic disorders.
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