Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical College, Weihui, 453100, China.
Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical College, Weihui, 453100, China.
Biochem Biophys Res Commun. 2018 Sep 5;503(2):744-751. doi: 10.1016/j.bbrc.2018.06.070. Epub 2018 Aug 2.
Obesity and diabetes are associated with diabetic cardiomyopathy (DCM). However, the pathogenesis of DCM is not fully understood. Cannabinoid receptor gene (CNR1) has been a drug target for the treatment of obesity. Here, we reported that CNR1 expression was increased in high fat diet (HFD)-induced heart of mice. Following, the wild type (CNR1) and CNR1-knockout (CNR1) mice were employed and subjected to HFD treatments for 16 weeks to further investigate the effects of CNR1 on DCM. The results indicated that CNR1 knockout mice after HFD feeding exhibited a significant decrease of body weight and lipid accumulation in serum. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) analysis indicated that HFD-induced insulin resistance was attenuated by CNR1 deficiency. HFD-triggered cardiac dysfunction was also improved by CNR1 knockout using echocardiographic analysis. Further, CNR1 suppression increased expressions of genes promoting fatty acid oxidation, and mitochondrial biogenesis. Also, TUNEL staining showed that CNR1 inhibition markedly reduced apoptotic levels in heart tissue sections of HFD-fed mice. Importantly, HFD-induced insulin resistance was prevented by CNR1-knockout through decreasing p-IRS1 expressions, and increasing phosphorylated insulin receptor substrate 1 (p-IRS1), phospho-AMP-activated protein kinase α (AMPKα) and phospho-acetyl-CoA carboxylase α (ACCα) expressions in heart tissue samples. In addition, CNR1 knockout impeded endoplasmic reticulum (ER) stress caused by HFD via down-regulating phospho-protein kinase-like ER kinase (PERK), phospho-eukaryotic initiation factor-2α (eIF2α), activating transcription factor 4 (ATF4) and ATF6 in heart tissue samples. Of note, we found that CNR1 knockout-improved insulin resistance, ER stress and lipid accumulation was diminished by AMPKα suppression using its inhibitor, Compound C. Therefore, the results demonstrated that therapeutic CNR1 inhibition could alleviate the progression of DCM.
肥胖和糖尿病与糖尿病心肌病（DCM）有关。然而，DCM 的发病机制尚未完全阐明。大麻素受体基因（CNR1）一直是治疗肥胖的药物靶点。在这里，我们报道了高脂肪饮食（HFD）诱导的小鼠心脏中 CNR1 表达增加。随后，使用野生型（CNR1）和 CNR1 敲除（CNR1）小鼠，并进行 HFD 处理 16 周，以进一步研究 CNR1 对 DCM 的影响。结果表明，HFD 喂养后的 CNR1 敲除小鼠体重和血清脂质积累明显减少。口服葡萄糖耐量试验（OGTT）和胰岛素耐量试验（ITT）分析表明，CNR1 缺乏可减轻 HFD 诱导的胰岛素抵抗。超声心动图分析显示，CNR1 敲除也改善了 HFD 引发的心脏功能障碍。此外，CNR1 抑制增加了促进脂肪酸氧化和线粒体生物发生的基因表达。此外，TUNEL 染色显示，CNR1 抑制可显著降低 HFD 喂养小鼠心脏组织切片中的凋亡水平。重要的是，通过降低心脏组织样本中 p-IRS1 的表达和增加磷酸化胰岛素受体底物 1（p-IRS1）、磷酸化 AMP 激活的蛋白激酶 α（AMPKα）和磷酸化乙酰辅酶 A 羧化酶 α（ACCα）的表达，CNR1 敲除可预防 HFD 诱导的胰岛素抵抗。此外，CNR1 敲除通过下调心脏组织样本中磷酸化蛋白激酶样内质网激酶（PERK）、磷酸化真核起始因子 2α（eIF2α）、激活转录因子 4（ATF4）和 ATF6 来阻止 HFD 引起的内质网（ER）应激。值得注意的是，我们发现使用 AMPKα 抑制剂 Compound C 抑制 AMPKα 可减弱 CNR1 敲除改善胰岛素抵抗、ER 应激和脂质积累的作用。因此，这些结果表明，治疗性 CNR1 抑制可能缓解 DCM 的进展。
