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.

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.