Abstract
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.
Highlights
The metabolic syndrome is linked to visceral obesity and is a major risk factor for insulin resistance, type2 diabetes, and cardiovascular disease [1,2]
We noticed that dietary vitamin B6 decreased mRNA expression of EGF-like module-containing mucin-like hormone receptor-like 1 (Emr1), macrophage scavenger receptor 1 (Msr1), macrophage galactose N-acetyl-galactosamine specific lectin 1 (Mgl1), macrophage expressed gene 1 (Mpeg1) and Cd86, which are considered markers of infiltrated macrophages (Table 1)
This study showed that vitamin B6 supplementation significantly decreased tumor necrosis factor-a (TNFa), serum amyloid protein (SAA) and MCP-1/CCL2 mRNA levels in adipose tissue compared with the 1 mg PN HCl/kg diet group (Fig. 1F–H)
Summary
The metabolic syndrome is linked to visceral obesity and is a major risk factor for insulin resistance, type diabetes, and cardiovascular disease [1,2]. Adipose tissues respond to nutrient excess through increases in adipocyte size (hypertrophy) and cell number (hyperplasia). Adipocyte hypertrophy and hyperplasia can both lead to adipose tissue expansion and a variety of effects, including hypoxia, adipocyte cell death and enhanced secretion of a large number of bioactive substances, adipocytokines [3,4]. Obese adipose tissue is characterized by dynamic alterations in cellular composition and function, and chronic low-grade inflammation [3,4,5,6,7]. Dramatic changes in stromal cell number and cell type in adipose tissue point to a pathological role for immune cells as a contributor to chronic inflammation, including macrophages, T lymphocytes and mast cells [3,4,5,6,7]. Recent reports emphasize macrophage accumulation in expanding adipose tissue as a key phenomenon [5,8] and raise important questions about the molecular mechanisms underlying macrophage infiltration and the influence of adipose tissue macrophages on energy homeostasis and inflammatory responses related to obesity-induced insulin resistance [1,2,9]
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