Obesity and Metabolism Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.
Obesity (Silver Spring). 2010 Oct;18(10):1918-25. doi: 10.1038/oby.2010.1. Epub 2010 Jan 28.
The role of adaptive immunity in obesity-associated adipose tissue (AT) inflammation and insulin resistance (IR) is controversial. We employed flow cytometry and quantitative PCR to assess T-cell recruitment and activation in epididymal AT (eAT) of C57BL/6 mice during 4-22 weeks of a high-fat diet (HFD (60% energy)). By week 6, eAT mass and stromal vascular cell (SVC) number increased threefold in mice fed HFD, coincident with onset of IR. We observed no increase in the proportion of CD3(+) SVCs or in gene expression of CD3, interferon-γ (IFN-γ), or regulated upon activation, normal T-cell expressed and secreted (RANTES) during the first 16 weeks of HFD. In contrast, CD11c(+) macrophages (MΦ) were enriched sixfold by week 8 (P < 0.01). SVC enrichment for T cells (predominantly CD4(+) and CD8(+)) and elevated IFN-γ and RANTES gene expression were detected by 20-22 weeks of HFD (P < 0.01), coincident with the resolution of eAT remodeling. HFD-induced T-cell priming earlier in the obesity time course is suggested by (i) elevated (fivefold) interleukin-12 (IL-12)p40 gene expression in eAT by week 12 (P ≤ 0.01) and (ii) greater IFN-γ secretion from phorbol myristate acetate (PMA)/ionophore-stimulated eAT explants at week 6 (onefold, P = 0.08) and week 12 (fivefold, P < 0.001). In conclusion, T-cell enrichment and IFN-γ gene induction occur subsequent to AT macrophage (ATMΦ) recruitment, onset of IR and resolution of eAT remodeling. However, enhanced priming for IFN-γ production suggests the contribution of CD4(+) and/or CD8(+) effectors to cell-mediated immune responses promoting HFD-induced AT inflammation and IR.
适应性免疫在肥胖相关脂肪组织（AT）炎症和胰岛素抵抗（IR）中的作用存在争议。我们采用流式细胞术和定量 PCR 评估了 C57BL/6 小鼠在高脂肪饮食（HFD（60%能量））期间 4-22 周时附睾脂肪组织（eAT）中的 T 细胞募集和激活情况。在 HFD 喂养的第 6 周，eAT 质量和基质血管细胞（SVC）数量增加了三倍，同时出现了 IR。我们在 HFD 的前 16 周内没有观察到 CD3(+)SVC 比例的增加，也没有观察到 CD3、干扰素-γ（IFN-γ）或调节激活正常 T 细胞表达和分泌（RANTES）基因表达的增加。相比之下，在第 8 周时，CD11c(+)巨噬细胞（MΦ）富集了六倍（P < 0.01）。在 HFD 20-22 周时，检测到 SVC 中 T 细胞（主要是 CD4(+)和 CD8(+)）的富集以及 IFN-γ和 RANTES 基因表达的升高（P < 0.01），这与 eAT 重塑的解决同时发生。通过以下证据表明 HFD 在肥胖过程中的早期诱导 T 细胞启动：（i）第 12 周时 eAT 中白细胞介素-12（IL-12)p40 基因表达升高（五倍，P ≤ 0.01），（ii）第 6 周和第 12 周时佛波醇肉豆蔻酸酯（PMA）/离子霉素刺激的 eAT 外植体中 IFN-γ分泌增加（一倍，P = 0.08）和五倍（P < 0.001）。总之，T 细胞富集和 IFN-γ 基因诱导发生在 AT 巨噬细胞（ATMΦ）募集、IR 发作和 eAT 重塑解决之后。然而，增强 IFN-γ 产生的启动提示 CD4(+)和/或 CD8(+)效应器对细胞介导的免疫反应的贡献，促进 HFD 诱导的 AT 炎症和 IR。
