Adipose Tissue-Derived Stem Cells From Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation
Adipose Tissue-Derived Stem Cells From Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation
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DOI：
10.2337/db15-0162
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发表时间：
2015-07-01
期刊：
影响因子：
7.7
通讯作者：
Pirola, Luciano
中科院分区：
文献类型：
--
作者：
Eljaafari, Assia;Robert, Maud;Pirola, Luciano
肥胖，通过低度炎症，可以导致胰岛素抵抗和2型糖尿病。虽然单核细胞（MNCs）浸润脂肪组织（AT）在肥胖中已经确立，但这些相互作用的功能后果尚不清楚。在此，我们将肥胖个体的人脂肪来源干细胞（ASCs）与跨国公司共培养，并分析了它们的相互行为。ASCs的存在1)增强Th17细胞分泌白细胞介素(IL)-17A, 2)抑制Th1细胞分泌-干扰素和肿瘤坏死因子，3)增加单核细胞介导的IL-1分泌。IL-17A的分泌也发生在肥胖而非瘦弱个体的间质血管中。Th17极化主要依赖于ASCs和mncs之间的物理接触，细胞内粘附分子-1的贡献，并通过激活炎性体和磷脂酰肌醇3-激酶途径发生。ASCs倾向于STAT3而不是STAT5转录因子结合IL-17A/F基因位点上的STAT结合位点。最后，活化ASC-MNC共培养的条件培养基抑制脂肪细胞分化mRNA标记物，并损害胰岛素介导的Akt磷酸化和脂肪分解抑制。总之，我们报道肥胖而非瘦源性ASCs诱导Th17促进和单核细胞活化。这种促炎环境反过来又抑制脂肪生成和脂肪细胞胰岛素反应。asc - th17单核细胞轴的发现揭示了肥胖期间AT中发生的一种新的促炎过程，并确定了新的假定治疗靶点。
Obesity, through low-grade inflammation, can drive insulin resistance and type 2 diabetes. While infiltration of adipose tissue (AT) with mononuclear cells (MNCs) is well established in obesity, the functional consequences of these interactions are less understood. Herein, we cocultured human adipose-derived stem cells (ASCs) from obese individuals with MNCs and analyzed their reciprocal behavior. Presence of ASCs 1) enhanced interleukin (IL)-17A secretion by Th17 cells, 2) inhibited -interferon and tumor necrosis factor secretion by Th1 cells, and 3) increased monocyte-mediated IL-1 secretion. IL-17A secretion also occurred in stromal vascular fractions issued from obese but not lean individuals. Th17 polarization mostly depended on physical contacts between ASCs and MNCswith a contribution of intracellular adhesion molecule-1and occurred through activation of the inflammasome and phosphatidylinositol 3-kinase pathways. ASCs favored STAT3 over STAT5 transcription factor binding on STAT binding sites within the IL-17A/F gene locus. Finally, conditioned media from activated ASC-MNC cocultures inhibited adipocyte differentiation mRNA markers and impaired insulin-mediated Akt phosphorylation and lipolysis inhibition. In conclusion, we report that obese- but not lean-derived ASCs induce Th17 promotion and monocyte activation. This proinflammatory environment, in turn, inhibits adipogenesis and adipocyte insulin response. The demonstration of an ASC-Th17-monocyte cell axis reveals a novel proinflammatory process taking place in AT during obesity and defines novel putative therapeutic targets.