Obesity and Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA.
Diabetes. 2010 May;59(5):1171-81. doi: 10.2337/db09-1402. Epub 2010 Feb 25.
To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Phis) during high-fat diet (HFD)-induced obesity.
Male C57BL/6 mice were fed an HFD (60% fat kcal) or low-fat diet (LFD) (10% fat kcal) for 8 or 12 weeks. eATMPhis (F4/80(+) cells) were characterized by in vivo fluorescent labeling, immunohistochemistry, fluorescence-activated cell sorting, and quantitative PCR.
Recruited interstitial macrophage galactose-type C-type lectin (MGL)1(+)/CD11c(-) and crown-like structure-associated MGL1(-)/CD11c(+) and MGL1(med)/CD11c(+) eATMPhis were identified after 8 weeks of HFD. MGL1(med)/CD11c(+) cells comprised approximately 65% of CD11c(+) eATMPhis. CD11c(+) eATMPhis expressed a mixed M1/M2 profile, with some M1 transcripts upregulated (IL-12p40 and IL-1beta), others downregulated (iNOS, caspase-1, MCP-1, and CD86), and multiple M2 and matrix remodeling transcripts upregulated (arginase-1, IL-1Ra, MMP-12, ADAM8, VEGF, and Clec-7a). At HFD week 12, each eATMPhi subtype displayed an enhanced M2 phenotype as compared with HFD week 8. CD11c(+) subtypes downregulated IL-1beta and genes mediating antigen presentation (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-1alpha) and adipogenesis (MMP-2). MGL1(med)/CD11c(+) eATMPhis upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-alpha). MGL1(med)/CD11c(+) ATMPhis expressing elevated PGC-1alpha, PPAR-alpha, and Ym-1 transcripts were selectively enriched in eAT of obese mice fed pioglitazone for 6 days, confirming the M2 features of the MGL1(med)/CD11c(+) eATMPhi transcriptional profile and implicating PPAR activation in its elicitation.
These results 1) redefine the phenotypic potential of CD11c(+) eATMPhis and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMPhis in the development of obesity and its complications.
在高脂饮食（HFD）诱导肥胖期间，鉴定附睾脂肪组织（eAT）巨噬细胞（Phis）的位置并确定其 M1/M2 极化。
雄性 C57BL/6 小鼠用 HFD（60%脂肪卡路里）或低脂饮食（LFD）（10%脂肪卡路里）喂养 8 或 12 周。通过体内荧光标记、免疫组织化学、荧光激活细胞分选和定量 PCR 对 eATMPhis（F4/80(+) 细胞）进行了表征。
在 HFD 8 周后，鉴定出募集的间质巨噬细胞半乳糖型 C 型凝集素（MGL）1(+) / CD11c(-)和冠层状结构相关的 MGL1(-) / CD11c(+)和 MGL1(med) / CD11c(+) eATMPhis。MGL1(med) / CD11c(+)细胞约占 CD11c(+) eATMPhis 的 65%。CD11c(+) eATMPhis 表达混合的 M1/M2 表型，一些 M1 转录本上调（IL-12p40 和 IL-1beta），其他转录本下调（iNOS、caspase-1、MCP-1 和 CD86），并且上调了多个 M2 和基质重塑转录本（精氨酸酶-1、IL-1Ra、MMP-12、ADAM8、VEGF 和 Clec-7a）。在 HFD 第 12 周，与 HFD 第 8 周相比，每种 eATMPhi 亚型均表现出增强的 M2 表型。CD11c(+)亚型下调 IL-1beta 和介导抗原呈递的基因（I-a、CD80），上调 M2 标志物 Ym-1 和促进氧化代谢（PGC-1alpha）和脂肪生成（MMP-2）的基因。MGL1(med) / CD11c(+) eATMPhis 上调了其他 M2 基因（IL-13、SPHK1、CD163、LYVE-1 和 PPAR-alpha）。在接受吡格列酮治疗 6 天的肥胖小鼠的 eAT 中，高表达 PGC-1alpha、PPAR-alpha 和 Ym-1 转录本的 MGL1(med) / CD11c(+) ATMPhis 被选择性富集，证实了 MGL1(med) / CD11c(+) eATMPhi 转录谱的 M2 特征，并暗示了 PPAR 激活在其诱导中的作用。
这些结果 1）重新定义了 CD11c(+) eATMPhis 的表型潜力，2）表明在肥胖及其并发症的发展中，人和鼠类 ATMPhis 之间存在以前未被认识到的表型和功能共性。
