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.
Highlights
Obesity is a major contributor to non-communicable diseases, namely hyperlipidemia, type 2 diabetes and cancer.[1]
We have recently shown that a pan-proviral integration moloney murine leukaemia virus (Pim) kinase inhibitor SGI-1776 blocks adipogenesis in differentiating 3T3-L1 cells by reducing the expression and/or phosphorylation levels of CCAAT/enhancer-binding protein-a (C/EBP-a), peroxisome proliferator-activated receptor-c (PPAR-c), fatty acid synthase (FAS) and signal transducer and activator of transcription-3 (STAT-3).21 inhibition of Pim kinases could be a novel therapeutic path against obesity
In order to reposition AZD1208 as an anti-obesity alternative medicine, we investigated the drug’s anti-adipogenic and lipolytic effects on 3T3-L1 adipocytes
Summary
Obesity is a major contributor to non-communicable diseases, namely hyperlipidemia, type 2 diabetes and cancer.[1]. Recent evidence points to abnormal expansion of adipose tissue, closely linked to the development of obesity, is due to excessive adipocyte differentiation.[3,4]. We have recently shown that a pan-Pim kinase inhibitor SGI-1776 blocks adipogenesis in differentiating 3T3-L1 cells by reducing the expression and/or phosphorylation levels of C/EBP-a, PPAR-c, FAS and STAT-3.21 inhibition of Pim kinases could be a novel therapeutic path against obesity. Neither the anti-obesity effect nor the mode of action of AZD1208 in adipocytes is reported This is the first study reporting the antiadipogenic and lipolytic effects of AZD1208 on 3T3-L1 adipocytes through control of the expression and/or phosphorylation levels of C/EBP-a, PPAR-c, FAS, ACC, perilipin A, STAT-3, AMPK and HSL
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