AZD1208, a pan-Pim kinase inhibitor, inhibits adipogenesis and induces lipolysis in 3T3-L1 adipocytes.

Abstract

The proviral integration moloney murine leukaemia virus (Pim) kinases, consisting of Pim-1, Pim-2 and Pim-3, are involved in the control of cell growth, metabolism and differentiation. Pim kinases are emerging as important mediators of adipocyte differentiation. AZD1208 is a pan-Pim kinase inhibitor and is known for its anti-cancer activity. In this study, we investigated the effect of AZD1208 on adipogenesis and lipolysis in 3T3-L1 cells, a murine preadipocyte cell line. AZD1208 markedly suppressed lipid accumulation and reduced triglyceride contents in differentiating 3T3-L1 cells, suggesting the drug's anti-adipogenic effect. On mechanistic levels, AZD1208 reduced not only the expressions of 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 but also the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) in differentiating 3T3-L1 cells. Remarkably, AZD1208 increased cAMP-activated protein kinase (AMPK) and LKB-1 phosphorylation while decreased intracellular ATP contents in differentiating 3T3-L1 cells. Furthermore, in differentiated 3T3-L1 adipocytes, AZD1208 also partially promoted lipolysis and enhanced the phosphorylation of hormone-sensitive lipase (HSL), a key lipolytic enzyme, indicating the drug's HSL-dependent lipolysis. In summary, the findings show that AZD1208 has anti-adipogenic and lipolytic effects on 3T3-L1 adipocytes. These effects are mediated by the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, ACC, perilipin A, STAT-3, AMPK and HSL.

• Authors: Yu-Kyoung Park, Brice Wilfried Obiang-Obounou, Kyung-Bok Lee, Jong-Soon Choi, Byeong-Churl Jang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 22 Issue 4 Pg. 2488-2497 (04 2018) ISSN: 1582-4934 [Electronic] England
• PMID: 29441719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• AZD1208
• Biphenyl Compounds
• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, mouse
• Fas protein, mouse
• PPAR gamma
• Perilipin-1
• Pparg protein, mouse
• Protein Kinase Inhibitors
• Thiazolidines
• fas Receptor
• Proto-Oncogene Proteins c-pim-1
• proto-oncogene proteins pim

Topics

• 3T3-L1 Cells
• Adipocytes (drug effects)
• Adipogenesis (drug effects)
• Animals
• Biphenyl Compounds (pharmacology)
• CCAAT-Enhancer-Binding Proteins (genetics)
• Cell Differentiation (drug effects, genetics)
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Developmental (drug effects)
• Lipolysis (drug effects)
• Mice
• PPAR gamma (genetics)
• Perilipin-1 (genetics)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-pim-1 (antagonists & inhibitors)
• Thiazolidines (pharmacology)
• fas Receptor (genetics)