Poitou Christine, Perret Claire, Mathieu François, Truong Vinh, Blum Yuna, Durand Hervé, Alili Rohia, Chelghoum Nadjim, Pelloux Véronique, Aron-Wisnewsky Judith, Torcivia Adriana, Bouillot Jean-Luc, Parks Brian W, Ninio Ewa, Clément Karine, Tiret Laurence
Institute of Cardiometabolism And Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Nutrition Department, F-75013, Paris, France; Sorbonne Universités, University Pierre et Marie Curie (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Nutriomics team, F-75005, Paris, France.
Institute of Cardiometabolism And Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Nutrition Department, F-75013, Paris, France; Sorbonne Universités, University Pierre et Marie Curie (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Genomics and Pathophysiology of Cardiovascular Diseases team, F-75013, Paris, France.
PLoS One. 2015 May 4;10(5):e0125718. doi: 10.1371/journal.pone.0125718. eCollection 2015.
Bariatric surgery is associated to improvements in obesity-associated comorbidities thought to be mediated by a decrease of adipose inflammation. However, the molecular mechanisms behind these beneficial effects are poorly understood.
METHODOLOGY/PRINCIPAL FINDINGS: We analyzed RNA-seq expression profiles in adipose tissue from 22 obese women before and 3 months after surgery. Of 15,972 detected genes, 1214 were differentially expressed after surgery at a 5% false discovery rate. Upregulated genes were mostly involved in the basal cellular machinery. Downregulated genes were enriched in metabolic functions of adipose tissue. At baseline, 26 modules of coexpressed genes were identified. The four most stable modules reflected the innate and adaptive immune responses of adipose tissue. A first module reflecting a non-specific signature of innate immune cells, mainly macrophages, was highly conserved after surgery with the exception of DUSP2 and CD300C. A second module reflected the adaptive immune response elicited by T lymphocytes; after surgery, a disconnection was observed between genes involved in T-cell signaling and mediators of the signal transduction such as CXCR1, CXCR2, GPR97, CCR7 and IL7R. A third module reflected neutrophil-mediated inflammation; after surgery, several genes were dissociated from the module, including S100A8, S100A12, CD300E, VNN2, TUBB1 and FAM65B. We also identified a dense network of 19 genes involved in the interferon-signaling pathway which was strongly preserved after surgery, with the exception of DDX60, an antiviral factor involved in RIG-I-mediated interferon signaling. A similar loss of connection was observed in lean mice compared to their obese counterparts.
CONCLUSIONS/SIGNIFICANCE: These results suggest that improvements of the inflammatory state following surgery might be explained by a disruption of immuno-inflammatory cascades involving a few crucial molecules which could serve as potential therapeutic targets.
减肥手术与肥胖相关合并症的改善有关，这些改善被认为是由脂肪炎症的减轻介导的。然而，这些有益作用背后的分子机制尚不清楚。
方法/主要发现：我们分析了22名肥胖女性术前及术后3个月脂肪组织中的RNA测序表达谱。在检测到的15972个基因中，有1214个基因在术后以5%的错误发现率存在差异表达。上调的基因大多参与基础细胞机制。下调的基因在脂肪组织的代谢功能中富集。在基线时，共鉴定出26个共表达基因模块。四个最稳定的模块反映了脂肪组织的先天性和适应性免疫反应。第一个模块反映先天性免疫细胞（主要是巨噬细胞）的非特异性特征，术后除双特异性磷酸酶2（DUSP2）和CD300C外高度保守。第二个模块反映了T淋巴细胞引发的适应性免疫反应；术后，观察到参与T细胞信号传导的基因与信号转导介质（如CXC趋化因子受体1（CXCR1）、CXC趋化因子受体2（CXCR2）、G蛋白偶联受体97（GPR97）、C-C趋化因子受体7（CCR7）和白细胞介素7受体（IL7R））之间出现脱节。第三个模块反映中性粒细胞介导的炎症；术后，几个基因与该模块分离，包括钙结合蛋白A8（S100A8）、钙结合蛋白A12（S100A12）、CD300E、香草基硫酸酯酶2（VNN2）、微管蛋白β1（TUBB1）和家族成员65B（FAM65B）。我们还鉴定出一个由19个参与干扰素信号通路的基因组成的密集网络，术后该网络除参与维甲酸诱导基因I（RIG-I）介导的干扰素信号传导的抗病毒因子解旋酶DDX60外强烈保留。与肥胖小鼠相比，瘦小鼠也观察到类似的连接丧失。
结论/意义：这些结果表明，术后炎症状态的改善可能是由于涉及一些关键分子的免疫炎症级联反应中断所致，这些分子可能是潜在的治疗靶点。
