Sultan Ariane, Strodthoff Daniela, Robertson Anna-Karin, Paulsson-Berne Gabrielle, Fauconnier Jeremy, Parini Paolo, Rydén Mikael, Thierry-Mieg Nicolas, Johansson Maria E, Chibalin Alexander V, Zierath Juleen R, Arner Peter, Hansson Göran K
Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Circ Res. 2009 Apr 24;104(8):961-8. doi: 10.1161/CIRCRESAHA.108.190280. Epub 2009 Mar 19.
Obesity is associated with chronic inflammation in adipose tissue. Proinflammatory cytokines including tumor necrosis factor-alpha and interleukin-6 secreted by adipose tissue during the metabolic syndrome are proposed to cause local and general insulin resistance and promote development of type 2 diabetes. We have used a compound mutant mouse, Apoe(-/-)xCD4dnTGFbR, with dysregulation of T-cell activation, excessive production of proinflammatory cytokines, hyperlipidemia, and atherosclerosis, to dissect the role of inflammation in adipose tissue metabolism. These mice are lean, which avoids confounding effects of concomitant obesity. Expression and secretion of a set of proinflammatory factors including tumor necrosis factor-alpha, interferon-gamma, and monocyte chemoattractant protein-1 was increased in adipose tissue of Apoe(-/-)xCD4dnTGFbR mice, as was the enzyme 11beta-hydroxysteroid dehydrogenase type 1, which converts cortisone to bioactive cortisol. Interleukin-6, which has an inhibitory glucocorticoid response element in its promoter, was not upregulated. In spite of intense local inflammation, insulin sensitivity was not impaired in adipose tissue of Apoe(-/-)xCD4dnTGFbR mice unless exogenous interleukin-6 was administered. In conclusion, T-cell activation causes inflammation in adipose tissue but does not lead to insulin resistance in this tissue in the absence of interleukin-6.
肥胖与脂肪组织中的慢性炎症相关。在代谢综合征期间，脂肪组织分泌的包括肿瘤坏死因子-α和白细胞介素-6在内的促炎细胞因子被认为会导致局部和全身胰岛素抵抗，并促进2型糖尿病的发展。我们使用了一种复合突变小鼠Apoe(-/-)xCD4dnTGFbR，其T细胞活化失调、促炎细胞因子过度产生、高脂血症和动脉粥样硬化，以剖析炎症在脂肪组织代谢中的作用。这些小鼠很瘦，避免了伴随肥胖带来的混杂影响。在Apoe(-/-)xCD4dnTGFbR小鼠的脂肪组织中，包括肿瘤坏死因子-α、干扰素-γ和单核细胞趋化蛋白-1在内的一组促炎因子的表达和分泌增加，将可的松转化为生物活性皮质醇的11β-羟基类固醇脱氢酶1型酶也是如此。白细胞介素-6在其启动子中有一个抑制性糖皮质激素反应元件，并未上调。尽管存在强烈的局部炎症，但除非给予外源性白细胞介素-6，Apoe(-/-)xCD4dnTGFbR小鼠脂肪组织中的胰岛素敏感性并未受损。总之，T细胞活化会导致脂肪组织炎症，但在没有白细胞介素-6的情况下不会导致该组织的胰岛素抵抗。
