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Reduction in MCP-1 production in preadipocytes is mediated by PPARγ activation and JNK/SIRT1 signaling

Atsushi Sawamoto1, Ibuki Itagaki1, Satoshi Okuyama1

  • 1Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.

Biochimica Et Biophysica Acta. General Subjects
|December 13, 2024
PubMed

Insights

PPARγ agonists like rosiglitazone reduce MCP-1 production in preadipocytes by inhibiting JNK/SIRT1 signaling. This discovery offers a new therapeutic target for treating insulin resistance associated with obesity.

Area of Science:

  • Metabolism
  • Cell Biology
  • Endocrinology

Background:

  • Obesity increases monocyte chemoattractant protein 1 (MCP-1) in white adipose tissue (WAT), driving inflammation and insulin resistance.
  • Peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduce MCP-1, but the mechanism in WAT is not fully understood.

Purpose of the Study:

  • To elucidate the novel mechanism by which PPARγ agonists reduce MCP-1 production in preadipocytes.
  • To investigate the role of JNK/SIRT1 signaling in PPARγ-mediated MCP-1 regulation.

Main Methods:

  • Utilized 3T3-L1 preadipocytes and primary mouse preadipocytes.
  • Administered lipopolysaccharide (LPS) with or without rosiglitazone (RSG) or SP600125 (JNK inhibitor).
  • Assessed MCP-1 production, SIRT1 degradation, and nuclear factor-κB activation; employed Pparg siRNA for gene knockdown.

Main Results:

  • RSG significantly reduced LPS-induced MCP-1 production and secretion in preadipocytes.
  • Both RSG and a JNK inhibitor blocked LPS-induced SIRT1 degradation.
  • RSG inhibited LPS-induced nuclear factor-κB activation, an effect dependent on PPARγ.

Conclusions:

  • PPARγ activation, via RSG, inhibits JNK/SIRT1 signaling and nuclear factor-κB activation in preadipocytes.
  • This novel mechanism reduces MCP-1 production, suggesting preadipocytes as a therapeutic target for obesity-related insulin resistance.
Keywords:
C-Jun N-terminal kinase (JNK)Insulin resistanceMonocyte chemoattractant protein 1 (MCP-1)Peroxisome proliferator-activated receptor gamma (PPARγ)PreadipocytesSilent information regulator 2 homolog 1 (SIRT1)

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