The Receptor Tyrosine Kinase c-Met Promotes Lipid Accumulation in 3T3-L1 Adipocytes.

Abstract

The receptor tyrosine kinase c-Met is elaborated in embryogenesis, morphogenesis, metabolism, cell growth, and differentiation. JNJ38877605 (JNJ) is an inhibitor of c-Met with anti-tumor activity. The c-Met expression and its role in adipocyte differentiation are unknown. Here, we investigated the c-Met expression and phosphorylation, knockdown (KD) effects, and pharmacological inhibition of c-Met by JNJ on fat accumulation in murine preadipocyte 3T3-L1 cells. During 3T3-L1 preadipocyte differentiation, strikingly, c-Met expression at the protein and mRNA levels and the protein phosphorylation on Y1234/1235 and Y1349 is crucial for inducing its kinase catalytic activity and activating a docking site for signal transducers were increased in a time-dependent manner. Of note, JNJ treatment at 20 μM that strongly inhibits c-Met phosphorylation without altering its total expression resulted in less lipid accumulation and triglyceride (TG) content with no cytotoxicity. JNJ further reduced the expression of adipogenic regulators, including CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and perilipin A. Moreover, JNJ treatment increased cAMP-activated protein kinase (AMPK) and liver kinase B-1 (LKB-1) phosphorylation but decreased ATP levels. Significantly, KD of c-Met suppressed fat accumulation and triglyceride (TG) quantity and reduced the expression of C/EBP-α, PPAR-γ, FAS, ACC, and perilipin A. Collectively, the present results demonstrate that c-Met is a novel, highly conserved mediator of adipogenesis regulating lipid accumulation in murine adipocytes.

• Authors: Yu-Kyoung Park, Byeong-Churl Jang
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 9 (Apr 29 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37175792 (Publication Type: Journal Article)

Chemical References

• CCAAT-Enhancer-Binding Protein-alpha
• Fatty Acid Synthases
• Lipids
• Perilipins
• Peroxisome Proliferator-Activated Receptors
• PPAR gamma
• Receptor Protein-Tyrosine Kinases
• Triglycerides

Topics

• Animals
• Mice
• 3T3-L1 Cells
• Adipocytes (metabolism)
• Adipogenesis (genetics)
• CCAAT-Enhancer-Binding Protein-alpha (metabolism)
• Cell Differentiation
• Fatty Acid Synthases (metabolism)
• Lipid Metabolism
• Lipids (pharmacology)
• Perilipins (metabolism)
• Peroxisome Proliferator-Activated Receptors (metabolism)
• PPAR gamma (metabolism)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Triglycerides (metabolism)