ABSTRACT
Macrophage infiltration in the adipose tissue, and the interaction with adipocytes, is well documented to be involved in fat inflammation and obesity-associated complications. In this study, we isolated IκB kinase ε (IKKε) as a key adipocyte factor that is potentially affected by interaction with macrophages in adipose tissue in vivo. We showed that IKKε mRNA expression levels in white adipose tissue were increased in both genetic and diet-induced obese mouse. Furthermore, IKKε mRNA expression was decreased by the administration of vitamin B6, an anti-inflammatory vitamin, and that IKKε expression levels in adipose tissue were closely correlated with the numbers of infiltrating macrophages. In a co-culture system, we showed that IKKε expression in adipocytes was upregulated by interaction with activated macrophages. This study provides novel insight into IKKε, which is involved in adipose tissue inflammation during the development of obesity.
Subject(s)
Adipocytes/cytology , Adipocytes/metabolism , Cell Communication , I-kappa B Kinase/genetics , Macrophages/cytology , Up-Regulation , 3T3-L1 Cells , Animals , Cell Count , Macrophage Activation , Macrophages/immunology , Male , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Macrophage infiltration into adipose tissue is associated with obesity and the crosstalk between adipocytes and infiltrated macrophages has been investigated as an important pathological phenomenon during adipose tissue inflammation. Here, we sought to identify adipocyte mRNAs that are regulated by interaction with infiltrated macrophages in vivo. An anti-inflammatory vitamin, vitamin B6, suppressed macrophage infiltration into white adipose tissue and altered mRNA expression. We identified >3500 genes whose expression is significantly altered during the development of obesity in db/db mice, and compared them to the adipose tissue mRNA expression profile of mice supplemented with vitamin B6. We identified PTX3 and MMP3 as candidate genes regulated by macrophage infiltration. PTX3 and MMP3 mRNA expression in 3T3-L1 adipocytes was up-regulated by activated RAW264.7 cells and these mRNA levels were positively correlated with macrophage number in adipose tissue in vivo. Next, we screened adipose genes down-regulated by the interaction with macrophages, and isolated RASSF6 (Ras association domain family 6). RASSF6 mRNA in adipocytes was decreased by culture medium conditioned by activated RAW264.7 cells, and RASSF6 mRNA level was negatively correlated with macrophage number in adipose tissue, suggesting that adipocyte RASSF6 mRNA expression is down-regulated by infiltrated macrophages in vivo. Finally, this study also showed that decreased RASSF6 expression up-regulates mRNA expression of several genes, such as CD44 and high mobility group protein HMGA2. These data provide novel insights into the biological significance of interactions between adipocytes and macrophages in adipose tissue during the development of obesity.
Subject(s)
Adipocytes/metabolism , Adipose Tissue, White/metabolism , Macrophages/metabolism , Monomeric GTP-Binding Proteins/metabolism , Obesity/metabolism , RNA, Messenger/metabolism , Tumor Suppressor Proteins/metabolism , Adipocytes/drug effects , Adipocytes/pathology , Adipose Tissue, White/drug effects , Adipose Tissue, White/pathology , Animals , C-Reactive Protein/genetics , C-Reactive Protein/metabolism , Cell Communication/drug effects , Cell Line , Cell Movement/drug effects , Culture Media, Conditioned/pharmacology , Gene Expression Profiling , Gene Expression Regulation/drug effects , HMGA2 Protein/genetics , HMGA2 Protein/metabolism , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , Macrophages/drug effects , Macrophages/pathology , Male , Matrix Metalloproteinase 3/genetics , Matrix Metalloproteinase 3/metabolism , Mice , Mice, Transgenic , Monomeric GTP-Binding Proteins/antagonists & inhibitors , Monomeric GTP-Binding Proteins/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Obesity/genetics , Obesity/pathology , RNA, Messenger/genetics , Signal Transduction/drug effects , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/genetics , Vitamin B 6/pharmacologyABSTRACT
We previously demonstrated that vitamin B6 suppresses tumorigenesis in the colon of mice and exerts an anti-inflammatory effect through the inhibition of NF-κB activation. As these effects resemble the pharmacological properties of thiazolidinedione (TZD), a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) ligand, this study was designed to examine the effect of vitamin B6 on the activation of PPARγ and adipogenesis in 3T3-L1 adipocyte cells. Pyridoxal 5'-phosphate (PLP), one of the vitamin B6 derivatives, was shown to promote adipogenesis in the 3T3-L1 adipocytes. In addition, PLP specifically induced mRNA expression of PPARγ target genes in the 3T3-L1 adipocytes and enhanced the lipid accumulation and adipocyte fatty acid-binding protein (aP2) mRNA expression in NIH3T3 cells stably expressing PPARγ. Furthermore, the administration of vitamin B6 increased the expression of aP2 mRNA in mouse adipose tissues. Collectively, these observations suggest a novel function of vitamin B6 as an activator for PPARγ, which may contribute to the anti-tumor and anti-inflammatory effects of vitamin B6.
