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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1869; no. 2; p. 130737
• Main Authors: Sawamoto, Atsushi, Itagaki, Ibuki, Okuyama, Satoshi, Nakajima, Mitsunari
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2025
• Subjects: 3T3-L1 Cells; Adipocytes - drug effects; Adipocytes - metabolism; Animals; C-Jun N-terminal kinase (JNK); Chemokine CCL2 - biosynthesis; Chemokine CCL2 - metabolism; Insulin resistance; JNK Mitogen-Activated Protein Kinases - metabolism; Lipopolysaccharides - pharmacology; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein 1 (MCP-1); Peroxisome proliferator-activated receptor gamma (PPARγ); PPAR gamma - agonists; PPAR gamma - genetics; PPAR gamma - metabolism; Preadipocytes; Rosiglitazone; Signal Transduction - drug effects; Silent information regulator 2 homolog 1 (SIRT1); Sirtuin 1 - metabolism; Thiazolidinediones - pharmacology; PBS; MCP-1; SVF; JNK; RSG; Preadipocytes; Monocyte chemoattractant protein 1 (MCP-1); WAT; C-Jun N-terminal kinase (JNK); LPS; BSA; DMEM; LDH; FBS; Silent information regulator 2 homolog 1 (SIRT1); Insulin resistance; Peroxisome proliferator-activated receptor gamma (PPARγ); SEM; ELISA
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130737

Obesity-induced monocyte chemoattractant protein 1 (MCP-1) production leads to the infiltration of monocytes/macrophages into white adipose tissue (WAT), which contributes to systemic insulin resistance. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are known to reduce MCP-1 production in both humans and mice; however, the underlying mechanism in WAT remains unclear. Here, we propose a novel mechanism for the reduction in MCP-1 production in preadipocytes. The PPARγ agonist rosiglitazone (RSG) reduced MCP-1 production and secretion in response to lipopolysaccharide (LPS) in 3T3-L1 preadipocytes and mouse stromal vascular fraction–derived primary preadipocytes. Both RSG and SP600125 (a c-Jun N-terminal kinase (JNK) inhibitor) inhibited LPS-induced degradation of silent information regulator 2 homolog 1 (SIRT1), a negative regulator of MCP-1 production in 3T3-L1 preadipocytes. Furthermore, RSG inhibited LPS-induced activation of nuclear factor-κB. These effects of RSG were abolished in 3T3-L1 preadipocytes transfected with Pparg siRNA. These findings highlight a novel mechanism by which PPARγ activation inhibits JNK/SIRT1 signaling in preadipocytes and contributes to the reduction in MCP-1 production, suggesting that preadipocytes could be a potential therapeutic target for the treatment of insulin resistance. •PPARγ is required for the reduction in LPS-induced MCP-1 production in 3T3-L1 and SVF-derived preadipocytes.•Rosiglitazone, a PPARγ agonist, inhibits the activation of JNK and degradation of SIRT1 in 3T3-L1 and SVF-derived preadipocytes.•Inhibition of the JNK/SIRT1 signaling pathway in preadipocytes may be a key mechanism underlying the reduction in MCP-1 production.