Inverse regulation of inflammation and mitochondrial function in adipose tissue defines extreme insulin sensitivity in morbidly obese patients.
Inverse regulation of inflammation and mitochondrial function in adipose tissue defines extreme insulin sensitivity in morbidly obese patients.
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作者：
Qatanani M;Tan Y;Dobrin R;Greenawalt DM;Hu G;Zhao W;Olefsky JM;Sears DD;Kaplan LM;Kemp DM
肥胖与胰岛素抵抗有关，胰岛素抵抗是2型糖尿病和心血管疾病的主要风险因素。然而，并不是所有的肥胖者都有胰岛素抵抗，这让我们对这些疾病之间的机制联系的理解变得混乱。我们对835名肥胖受试者进行了转录组分析，他们的平均BMI为48.8，我们之前已经报道了基因表达的遗传关联。在这里，我们选择了∼320非糖尿病(HbA1c<；7.0)受试者，并根据稳态模型评估-胰岛素抵抗将队列进一步分为胰岛素抵抗和胰岛素敏感亚组。一项无监督的信息学分析显示，在胰岛素极度敏感的肥胖者的大网膜脂肪组织中，免疫反应和炎症相关基因显著下调，而在皮下脂肪组织中的下调幅度要小得多。相比之下，与β氧化和柠檬酸循环相关的基因在胰岛素敏感型患者的脂肪中相对过度表达。通过询问我们公布的37名受试者的独立队列数据，证实了这些观察结果，这些受试者的皮下脂肪组织在使用噻唑烷二酮类药物治疗前后进行了采样。噻唑烷二酮处理下调免疫反应和炎症途径基因，上调β氧化和柠檬酸循环基因。这项工作强调了大网膜脂肪炎症通路在胰岛素抵抗的病理生理学中可能发挥的关键作用，而不是与体重无关。
Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes and cardiovascular disease. However, not all obese individuals are insulin resistant, which confounds our understanding of the mechanistic link between these conditions. We conducted transcriptome analyses on 835 obese subjects with mean BMI of 48.8, on which we have previously reported genetic associations of gene expression. Here, we selected ∼320 nondiabetic (HbA1c <7.0) subjects and further stratified the cohort into insulin-resistant versus insulin-sensitive subgroups based on homeostasis model assessment–insulin resistance. An unsupervised informatics analysis revealed that immune response and inflammation-related genes were significantly downregulated in the omental adipose tissue of obese individuals with extreme insulin sensitivity and, to a much lesser extent, in subcutaneous adipose tissue. In contrast, genes related to β-oxidation and the citric acid cycle were relatively overexpressed in adipose of insulin-sensitive patients. These observations were verified by querying an independent cohort of our published dataset of 37 subjects whose subcutaneous adipose tissue was sampled before and after treatment with thiazolidinediones. Whereas the immune response and inflammation pathway genes were downregulated by thiazolidinedione treatment, β-oxidation and citric acid cycle genes were upregulated. This work highlights the critical role that omental adipose inflammatory pathways might play in the pathophysiology of insulin resistance, independent of body weight.
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影响因子：
15.9
作者：
Kahn, BB;Flier, JS
通讯作者：
Flier, JS
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通讯作者：
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5.8
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16.2
作者：
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通讯作者：
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