Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9413, USA.
Gastroenterology. 2012 May;142(5):1218-1228.e1. doi: 10.1053/j.gastro.2012.01.032. Epub 2012 Jan 31.
BACKGROUND & AIMS: Obesity-related insulin resistance contributes to cardiovascular disease. Cannabinoid receptor-1 (CB(1)) blockade improves insulin sensitivity in obese animals and people, suggesting endocannabinoid involvement. We explored the role of hepatic CB(1) in insulin resistance and inhibition of insulin signaling pathways.
Wild-type mice and mice with disruption of CB(1) (CB(1)(-/-) mice) or with hepatocyte-specific deletion or transgenic overexpression of CB(1) were maintained on regular chow or a high-fat diet (HFD) to induce obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp analysis was used to analyze the role of the liver and hepatic CB(1) in HFD-induced insulin resistance. The cellular mechanisms of insulin resistance were analyzed in mouse and human isolated hepatocytes using small interfering or short hairpin RNAs and lentiviral knockdown of gene expression.
The HFD induced hepatic insulin resistance in wild-type mice, but not in CB(1)(-/-) mice or mice with hepatocyte-specific deletion of CB(1). CB(1)(-/-) mice that overexpressed CB(1) specifically in hepatocytes became hyperinsulinemic as a result of reduced insulin clearance due to down-regulation of the insulin-degrading enzyme. However, they had increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance; this was further increased by the HFD. In mice with hepatocytes that express CB(1), the HFD or CB(1) activation induced the endoplasmic reticulum stress response via activation of the Bip-PERK-eIF2α protein translation pathway. In hepatocytes isolated from human or mouse liver, CB(1) activation caused endoplasmic reticulum stress-dependent suppression of insulin-induced phosphorylation of akt-2 via phosphorylation of IRS1 at serine-307 and by inducing the expression of the serine and threonine phosphatase Phlpp1. Expression of CB(1) was up-regulated in samples from patients with nonalcoholic fatty liver disease.
Endocannabinoids contribute to diet-induced insulin resistance in mice via hepatic CB(1)-mediated inhibition of insulin signaling and clearance.
肥胖相关的胰岛素抵抗可导致心血管疾病。大麻素受体-1（CB1）阻断可改善肥胖动物和人类的胰岛素敏感性，表明内源性大麻素参与其中。我们探索了肝 CB1 在胰岛素抵抗和抑制胰岛素信号通路中的作用。
野生型小鼠和 CB1 敲除（CB1（-/-）小鼠）或肝特异性 CB1 缺失或过表达的转基因小鼠维持在正常饮食或高脂肪饮食（HFD）以诱导肥胖和胰岛素抵抗。使用高胰岛素-正葡萄糖钳夹分析来分析肝和肝 CB1 在 HFD 诱导的胰岛素抵抗中的作用。使用小干扰 RNA 或短发夹 RNA 以及基因表达的慢病毒敲低，在小鼠和人分离的肝细胞中分析胰岛素抵抗的细胞机制。
HFD 诱导野生型小鼠的肝胰岛素抵抗，但在 CB1（-/-）小鼠或肝特异性 CB1 缺失的小鼠中没有诱导。由于胰岛素降解酶下调导致胰岛素清除减少，特异性在肝细胞中过表达 CB1 的 CB1（-/-）小鼠变得高胰岛素血症，由于糖原分解增加，导致肝葡萄糖产生增加，表明肝胰岛素抵抗；这进一步因 HFD 而增加。在表达 CB1 的肝细胞中，HFD 或 CB1 激活通过激活 Bip-PERK-eIF2α 蛋白翻译途径诱导内质网应激反应。在从人或鼠肝分离的肝细胞中，CB1 激活通过 IRS1 丝氨酸 307 磷酸化和诱导丝氨酸和苏氨酸磷酸酶 Phlpp1 的表达，导致内质网应激依赖性抑制胰岛素诱导的 akt-2 磷酸化，从而引起内质网应激。非酒精性脂肪性肝病患者的样本中 CB1 的表达上调。
内源性大麻素通过肝 CB1 介导的抑制胰岛素信号和清除作用，促进小鼠饮食诱导的胰岛素抵抗。
