Navia B, Ferrer B, Giralt M, Comes G, Carrasco J, Molinero A, Quintana A, Leclerc J, Viollet B, Señarís R M, Hidalgo J
Department of Physiology, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.
Acta Physiol (Oxf). 2014 Aug;211(4):585-96. doi: 10.1111/apha.12328. Epub 2014 Jul 1.
Interleukin-6 (IL-6) is a major cytokine controlling body weight and metabolism, but because many types of cells can synthesize and respond to IL-6 considerable uncertainty still exists about the mechanisms underlying IL-6 effects. Therefore, the aim of this study was to analyse the effects of tissue-specific deletion of IL-6 using a fatty acid binding protein (aP2) promoter-Cre inducible system (aP2-Cre-ERT2).
Tissue-specific IL-6 KO mice (aP2-IL-6 KO mice) were produced upon tamoxifen administration and were fed a high-fat diet (HFD, 58.4% kcal from fat) or a control diet (18%) for 14 weeks.
aP2-IL-6 KO female mice on a HFD gained less weight and adiposity than littermate wild-type mice, but these effects were not observed in males. Hypothalamic factors such as NPY and AgRP showed a pattern of expression consistent with this sex-specific phenotype. PGC-1α expression was increased in several tissues in aP2-IL-6 KO female mice, which is compatible with increased energy expenditure. Serum leptin, insulin, glucose, cholesterol and triglycerides levels were increased by HFD, and in females IL-6 deficiency reversed this effect in the case of insulin and cholesterol. HFD induced impaired responses to insulin and glucose tolerance tests, but no significant differences between genotypes were observed.
The present results demonstrate that deletion of IL-6 driven by aP2-Cre regulates body weight, body fat and metabolism in a sex-specific fashion.
白细胞介素-6（IL-6）是控制体重和新陈代谢的主要细胞因子，但由于多种类型的细胞均可合成并对IL-6产生反应，IL-6作用的潜在机制仍存在相当大的不确定性。因此，本研究旨在利用脂肪酸结合蛋白（aP2）启动子-Cre诱导系统（aP2-Cre-ERT2）分析组织特异性缺失IL-6的影响。
给予他莫昔芬后制备组织特异性IL-6基因敲除小鼠（aP2-IL-6基因敲除小鼠），并给予高脂饮食（HFD，58.4%的热量来自脂肪）或对照饮食（18%）14周。
高脂饮食喂养的aP2-IL-6基因敲除雌性小鼠比同窝野生型小鼠体重增加和脂肪堆积更少，但在雄性小鼠中未观察到这些影响。下丘脑因子如神经肽Y（NPY）和刺鼠相关肽（AgRP）的表达模式与这种性别特异性表型一致。aP2-IL-6基因敲除雌性小鼠的多个组织中过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）表达增加，这与能量消耗增加相一致。高脂饮食使血清瘦素、胰岛素、葡萄糖、胆固醇和甘油三酯水平升高，在雌性小鼠中，IL-6缺乏逆转了胰岛素和胆固醇方面的这种影响。高脂饮食导致胰岛素和葡萄糖耐量试验反应受损，但未观察到不同基因型之间的显著差异。
目前的结果表明，由aP2-Cre驱动的IL-6缺失以性别特异性方式调节体重、体脂和新陈代谢。
