Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart.
Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart.
复制标题
营养应激通过抑制心脏中 AMP 激活的蛋白激酶来激活炎症并降低葡萄糖代谢。
作者：
Ko HJ;Zhang Z;Jung DY;Jun JY;Ma Z;Jones KE;Chan SY;Kim JK
心力衰竭是糖尿病患者死亡的主要原因，可能与代谢改变有因果关系。最近的报道表明炎症在外周胰岛素抵抗中起作用，但炎症对心脏代谢的影响尚不清楚。我们研究了饮食性肥胖对小鼠心脏炎症和糖代谢的影响。雄性C57BL/6小鼠饲喂高脂饮食（HFD） 6周，取心脏样本测量胰岛素敏感性、糖代谢和炎症。在急性白介素(IL)-6或脂质输注C57BL/6小鼠和HFD后IL-6敲除小鼠的心脏样本也被检查。饮食诱导的肥胖降低了心脏糖代谢、GLUT和amp活化的蛋白激酶（AMPK）水平，这与心脏中巨噬细胞、toll样受体4、细胞因子信号3抑制因子（SOCS3）和细胞因子水平的增加有关。IL-6的急性生理升高通过增加SOCS3以及SOCS3介导的胰岛素受体底物(IRS)-1和可能的AMPK的抑制，抑制糖代谢并引起胰岛素抵抗。在IL-6敲除小鼠中，饮食诱导的炎症和糖代谢缺陷减弱，暗示IL-6在肥胖相关的心脏炎症中的作用。急性脂质输注引起炎症并升高局部巨噬细胞、C-C基序趋化因子受体2、SOCS3和细胞因子水平。脂质诱导的心脏炎症抑制AMPK，提示脂质作为营养应激触发炎症的作用。我们的研究发现，营养应激激活心脏炎症，IL-6通过抑制AMPK和IRS-1抑制心肌糖代谢，强调炎症在糖尿病心脏发病机制中的重要作用。
Heart failure is a major cause of mortality in diabetes and may be causally associated with altered metabolism. Recent reports indicate a role of inflammation in peripheral insulin resistance, but the impact of inflammation on cardiac metabolism is unknown. We investigated the effects of diet-induced obesity on cardiac inflammation and glucose metabolism in mice. Male C57BL/6 mice were fed a high-fat diet (HFD) for 6 weeks, and heart samples were taken to measure insulin sensitivity, glucose metabolism, and inflammation. Heart samples were also examined following acute interleukin (IL)-6 or lipid infusion in C57BL/6 mice and in IL-6 knockout mice following an HFD. Diet-induced obesity reduced cardiac glucose metabolism, GLUT, and AMP-activated protein kinase (AMPK) levels, and this was associated with increased levels of macrophages, toll-like receptor 4, suppressor of cytokine signaling 3 (SOCS3), and cytokines in heart. Acute physiological elevation of IL-6 suppressed glucose metabolism and caused insulin resistance by increasing SOCS3 and via SOCS3-mediated inhibition of insulin receptor substrate (IRS)-1 and possibly AMPK in heart. Diet-induced inflammation and defects in glucose metabolism were attenuated in IL-6 knockout mice, implicating the role of IL-6 in obesity-associated cardiac inflammation. Acute lipid infusion caused inflammation and raised local levels of macrophages, C-C motif chemokine receptor 2, SOCS3, and cytokines in heart. Lipid-induced cardiac inflammation suppressed AMPK, suggesting the role of lipid as a nutrient stress triggering inflammation. Our findings that nutrient stress activates cardiac inflammation and that IL-6 suppresses myocardial glucose metabolism via inhibition of AMPK and IRS-1 underscore the important role of inflammation in the pathogenesis of diabetic heart.