2-Arachidonoylglycerol ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes
2-Arachidonoylglycerol ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes
复制标题
DOI：
10.1074/jbc.m116.767384
复制
发表时间：
2017-04-28
影响因子：
4.8
通讯作者：
Neumann, Dietbert
中科院分区：
文献类型：
--
作者：
Chanda, Dipanjan;Oligschlaeger, Yvonne;Neumann, Dietbert
一些研究已经将葡萄糖摄取受损和胰岛素抵抗(IR)与心脏功能损害联系起来。最近，内源性大麻素被认为与心血管疾病有关。然而，涉及内源性大麻素信号、葡萄糖摄取和心肌细胞IR的机制研究还不够深入。在这里，我们报道了内源性大麻素2-花生四烯基甘油(2-AG)通过刺激大麻素1型(CB1)受体和钙/钙调素依赖的蛋白激酶β，激活AMP激活的激酶(AMPK)，导致葡萄糖摄取增加。有趣的是，我们观察到糖尿病小鼠CB1和CB2受体的mRNA表达减少，表明糖尿病心脏中的内源性大麻素信号减少。我们进一步证实了肿瘤坏死因子α诱导心肌细胞的胰岛素抵抗。2-AG治疗可抑制肿瘤坏死因子α诱导的促炎标志物，改善胰岛素抵抗和葡萄糖摄取。相反，AMPK的药理抑制或敲除可减弱2-AG的抗炎和逆转IR的作用。此外，在用肿瘤坏死因子α或游离脂肪酸挑战的人胚胎干细胞来源的心肌细胞中，我们证明了2-AG改善了胰岛素敏感性和葡萄糖摄取。结论：在心肌细胞中，2-AG以AMPK依赖的方式减轻炎症反应，增加葡萄糖摄取，并克服IR。
Several studies have linked impaired glucose uptake and insulin resistance (IR) to functional impairment of the heart. Recently, endocannabinoids have been implicated in cardiovascular disease. However, the mechanisms involving endocannabinoid signaling, glucose uptake, and IR in cardiomyocytes are understudied. Here we report that the endocannabinoid 2-arachidonoylglycerol (2-AG), via stimulation of cannabinoid type 1 (CB1) receptor and Ca2+/calmodulin-dependent protein kinase beta, activates AMP-activated kinase (AMPK), leading to increased glucose uptake. Interestingly, we have observed that the mRNA expression of CB1 and CB2 receptors was decreased in diabetic mice, indicating reduced endocannabinoid signaling in the diabetic heart. We further establish that TNF alpha-induces IR in cardiomyocytes. Treatment with 2-AG suppresses TNF alpha-induced proinflammatory markers and improves IR and glucose uptake. Conversely, pharmacological inhibition or knockdown of AMPK attenuates the anti-inflammatory effect and reversal of IR elicited by 2-AG. Additionally, in human embryonic stem cell-derived cardiomyocytes challenged with TNF alpha or FFA, we demonstrate that 2-AG improves insulin sensitivity and glucose uptake. In conclusion, 2-AG abates inflammatory responses, increases glucose uptake, and overcomes IR in an AMPK-dependent manner in cardiomyocytes.