Inhibition of Lipid Accumulation and Cyclooxygenase-2 Expression in Differentiating 3T3-L1 Preadipocytes by Pazopanib, a Multikinase Inhibitor.

Abstract

Pazopanib is a multikinase inhibitor with anti-tumor activity. As of now, the anti-obesity effect and mode of action of pazopanib are unknown. In this study, we investigated the effects of pazopanib on lipid accumulation, lipolysis, and expression of inflammatory cyclooxygenase (COX)-2 in differentiating and differentiated 3T3-L1 cells, a murine preadipocyte. Of note, pazopanib at 10 µM markedly decreased lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, pazopanib inhibited not only expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), and perilipin A but also phosphorylation of signal transducer and activator of transcription (STAT)-3 during 3T3-L1 preadipocyte differentiation. In addition, pazopanib treatment increased phosphorylation of cAMP-activated protein kinase (AMPK) and its downstream effector ACC during 3T3-L1 preadipocyte differentiation. However, in differentiated 3T3-L1 adipocytes, pazopanib treatment did not stimulate glycerol release and hormone-sensitive lipase (HSL) phosphorylation, hallmarks of lipolysis. Moreover, pazopanib could inhibit tumor necrosis factor (TNF)-α-induced expression of COX-2 in both 3T3-L1 preadipocytes and differentiated cells. In summary, this is the first report that pazopanib has strong anti-adipogenic and anti-inflammatory effects in 3T3-L1 cells, which are mediated through regulation of the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT-3, ACC, perilipin A, AMPK, and COX-2.

• Authors: Anil Kumar Yadav, Byeong-Churl Jang
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 9 (May 05 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34063048 (Publication Type: Journal Article)

Chemical References

• CCAAT-Enhancer-Binding Protein-alpha
• Indazoles
• Leptin
• PPAR gamma
• Perilipin-1
• Protein Kinase Inhibitors
• Pyrimidines
• RNA, Messenger
• Resistin
• STAT3 Transcription Factor
• Sulfonamides
• Triglycerides
• Tumor Necrosis Factor-alpha
• pazopanib
• Cyclooxygenase 2
• Fatty Acid Synthases
• Adenylate Kinase
• Sterol Esterase
• Glycerol

Topics

• 3T3-L1 Cells
• Adenylate Kinase (metabolism)
• Adipocytes (cytology, drug effects, metabolism)
• Adipogenesis (drug effects)
• Animals
• CCAAT-Enhancer-Binding Protein-alpha (metabolism)
• Cell Death (drug effects)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (metabolism)
• Fatty Acid Synthases (metabolism)
• Glycerol (metabolism)
• Indazoles (pharmacology)
• Leptin (metabolism)
• Lipid Metabolism (drug effects)
• Mice
• PPAR gamma (metabolism)
• Perilipin-1 (metabolism)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Resistin (metabolism)
• STAT3 Transcription Factor (metabolism)
• Sterol Esterase (metabolism)
• Sulfonamides (pharmacology)
• Triglycerides (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)