Department of Molecular Medicine and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan.
Diabetes. 2011 Mar;60(3):819-26. doi: 10.2337/db10-0864. Epub 2011 Jan 31.
We have provided evidence that saturated fatty acids, which are released from adipocytes via macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for the Toll-like receptor (TLR) 4 complex in macrophages, thereby aggravating obesity-induced adipose tissue inflammation. The aim of this study was to identify the molecule(s) activated in adipose tissue macrophages in obesity.
We performed a cDNA microarray analysis of coculture of 3T3-L1 adipocytes and RAW264 macrophages. Cultured adipocytes and macrophages and the adipose tissue of obese mice and humans were used to examine mRNA and protein expression.
We found that macrophage-inducible C-type lectin (Mincle; also called Clec4e and Clecsf9), a type II transmembrane C-type lectin, is induced selectively in macrophages during the interaction between adipocytes and macrophages. Treatment with palmitate, a major saturated fatty acid released from 3T3-L1 adipocytes, induced Mincle mRNA expression in macrophages at least partly through the TLR4/nuclear factor (NF)-κB pathway. Mincle mRNA expression was increased in parallel with macrophage markers in the adipose tissue of obese mice and humans. The obesity-induced increase in Mincle mRNA expression was markedly attenuated in C3H/HeJ mice with defective TLR4 signaling relative to control C3H/HeN mice. Notably, Mincle mRNA was expressed in bone-marrow cell (BMC)-derived proinflammatory M1 macrophages rather than in BMC-derived anti-inflammatory M2 macrophages in vitro.
Our data suggest that Mincle is induced in adipose tissue macrophages in obesity at least partly through the saturated fatty acid/TLR4/NF-κB pathway, thereby suggesting its pathophysiologic role in obesity-induced adipose tissue inflammation.
我们已经证明，脂肪细胞通过巨噬细胞诱导的脂肪细胞脂解释放的饱和脂肪酸，作为巨噬细胞中 Toll 样受体（TLR）4 复合物的天然配体，从而加剧肥胖诱导的脂肪组织炎症。本研究旨在鉴定肥胖时脂肪组织巨噬细胞中被激活的分子。
我们对 3T3-L1 脂肪细胞和 RAW264 巨噬细胞的共培养进行了 cDNA 微阵列分析。我们使用培养的脂肪细胞和巨噬细胞以及肥胖小鼠和人类的脂肪组织来检测 mRNA 和蛋白质表达。
我们发现，巨噬细胞诱导型 C 型凝集素（Mincle；也称为 Clec4e 和 Clecsf9），一种 II 型跨膜 C 型凝集素，在脂肪细胞与巨噬细胞相互作用过程中，在巨噬细胞中被选择性诱导。棕榈酸（3T3-L1 脂肪细胞释放的主要饱和脂肪酸）处理至少部分通过 TLR4/核因子（NF）-κB 途径诱导巨噬细胞中 Mincle mRNA 表达。在肥胖小鼠和人类的脂肪组织中，Mincle mRNA 表达与巨噬细胞标志物平行增加。在 TLR4 信号传导有缺陷的 C3H/HeJ 小鼠中，与对照 C3H/HeN 小鼠相比，肥胖诱导的 Mincle mRNA 表达增加明显减弱。值得注意的是，Mincle mRNA 在体外骨髓细胞（BMC）衍生的促炎 M1 巨噬细胞中表达，而不在 BMC 衍生的抗炎 M2 巨噬细胞中表达。
我们的数据表明，Mincle 在肥胖时的脂肪组织巨噬细胞中至少部分通过饱和脂肪酸/TLR4/NF-κB 途径被诱导，从而提示其在肥胖诱导的脂肪组织炎症中的病理生理作用。
