Cansby Emmelie, Nerstedt Annika, Amrutkar Manoj, Durán Esther Nuñez, Smith Ulf, Mahlapuu Margit
The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Mol Cell Endocrinol. 2014 Aug 5;393(1-2):143-51. doi: 10.1016/j.mce.2014.06.014. Epub 2014 Jun 26.
Interleukin-6 (IL-6) induces hepatic inflammation and insulin resistance, and therapeutic strategies to counteract the IL-6 action in liver are of high interest. In this study, we demonstrate that acute treatment with AMP-activated protein kinase (AMPK) agonists AICAR and metformin efficiently repressed IL-6-induced hepatic proinflammatory gene expression and activation of STAT3 in a mouse model of diet-induced type 2 diabetes, bringing it back to basal nonstimulated level. Surprisingly, the inflammatory response in liver induced by IL-6 administration in vivo was markedly blunted in the mice fed a high-fat diet, compared to lean chow-fed controls, while this difference was not replicated in vitro in primary hepatocytes derived from these two groups of mice. In summary, our work reveals that partial hepatic IL-6 resistance develops in the mouse model of type 2 diabetes, while the anti-inflammatory action of AMPK is maintained. Systemic factors, rather than differences in intracellular IL-6 receptor signaling, are likely mediating the relative impairment in IL-6 effect.
白细胞介素-6（IL-6）可引发肝脏炎症和胰岛素抵抗，因此对抗IL-6在肝脏中作用的治疗策略备受关注。在本研究中，我们证明，在饮食诱导的2型糖尿病小鼠模型中，用AMP激活的蛋白激酶（AMPK）激动剂AICAR和二甲双胍进行急性治疗可有效抑制IL-6诱导的肝脏促炎基因表达和STAT3的激活，使其恢复到基础非刺激水平。令人惊讶的是，与喂食普通饲料的瘦小鼠对照组相比，在体内给予IL-6诱导的肝脏炎症反应在喂食高脂肪饮食的小鼠中明显减弱，而在源自这两组小鼠的原代肝细胞中，这种差异在体外并未重现。总之，我们的研究表明，在2型糖尿病小鼠模型中会出现部分肝脏IL-6抵抗，而AMPK的抗炎作用得以维持。全身因素而非细胞内IL-6受体信号传导的差异可能介导了IL-6效应的相对损害。
