Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes
Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes
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DOI：
10.1210/en.2006-0536
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发表时间：
2006-11-01
期刊：
影响因子：
4.8
通讯作者：
McIntosh, Michael K.
中科院分区：
文献类型：
--
作者：
Chung, Soonkyu;LaPoint, Kathleen;McIntosh, Michael K.
最近的数据表明，脂肪组织分泌的促炎细胞因子导致与肥胖相关的发病率。然而，参与炎症的细胞类型的特征以及这些细胞如何促进人类脂肪细胞的胰岛素抵抗尚不清楚。我们使用内毒素脂多糖（LPS）模拟急性炎症，以确定非脂肪细胞在人类脂肪细胞原代培养物中的作用。 LPS 对促炎细胞因子（例如 IL-6、TNF-α 和 IL-1β）和趋化因子（例如 IL-8、单核细胞趋化蛋白-1）mRNA 水平的诱导主要发生在新分化的人类脂肪细胞的非脂肪细胞部分中。非脂肪细胞根据其丰富的前脂肪细胞标记物前脂肪细胞因子 1 和脂肪细胞增强蛋白 1 的 mRNA 水平以及仅痕量水平的巨噬细胞和肌细胞标记物被定性为前脂肪细胞。通过调节培养物的分化程度从约 0 - 90% 证实了前脂肪细胞在炎症中的重要作用。 LPS 诱导的促炎细胞因子/趋化因子表达以及核因子-κ B 和 MAPK 信号传导随着分化的增加而减少。 LPS 诱导的前脂肪细胞中的细胞因子/趋化因子表达与以下因素相关：1) 脂肪形成基因表达减少，2) 配体诱导的过氧化物酶体增殖物激活受体 (PPAR)-γ 报告构建体的激活减少，PPAR γ 磷酸化增加，3) 胰岛素刺激的葡萄糖摄取减少。总的来说，这些数据表明，LPS 主要在前脂肪细胞中诱导核因子 kappa B 和 MAPK 依赖性促炎细胞因子/趋化因子表达，从而触发人脂肪细胞中 PPAR γ 活性和胰岛素反应性的抑制。
Recent data suggest that proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. However, characterization of the cell types involved in inflammation and how these cells promote insulin resistance in human adipocytes are unclear. We simulated acute inflammation using the endotoxin lipopolysaccharide (LPS) to define the roles of nonadipocytes in primary cultures of human adipocytes. LPS induction of the mRNA levels of proinflammatory cytokines (e. g. IL-6, TNF-alpha, and IL-1 beta) and chemokines (e.g. IL-8, monocyte chemoattractant protein-1) occurred primarily in the nonadipocyte fraction of newly differentiated human adipocytes. Nonadipocytes were characterized as preadipocytes based on their abundant mRNA levels of preadipocyte markers preadipocyte factor-1 and adipocyte enhancer protein-1 and only trace levels of markers for macrophages and myocytes. The essential role of preadipocytes in inflammation was confirmed by modulating the degree of differentiation in the cultures from approximately 0 - 90%. LPS-induced proinflammatory cytokine/chemokine expression and nuclear factor-kappa B and MAPK signaling decreased as differentiation increased. LPS-induced cytokine/chemokine expression in preadipocytes was associated with: 1) decreased adipogenic gene expression, 2) decreased ligand-induced activation of a peroxisome proliferator activated receptor ( PPAR)-gamma reporter construct and increased phosphorylation of PPAR gamma, and 3) decreased insulin-stimulated glucose uptake. Collectively, these data demonstrate that LPS induces nuclear factor-kappa B- and MAPK-dependent proinflammatory cytokine/chemokine expression primarily in preadipocytes, which triggers the suppression of PPAR gamma activity and insulin responsiveness in human adipocytes.