Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes
Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes
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急性过度活跃的内源性大麻素信号传导诱导葡萄糖不耐受、肝脂肪变性和新型大麻素受体 1 反应基因
作者：
Maxwell A. Ruby;Daniel K. Nomura;Carolyn S. S. Hudak;A. Barber;J. Casida;R. Krauss
内源性大麻素通过刺激大麻素受体1 （CB1）调节能量平衡和脂质代谢。基因缺失和药理拮抗表明，CB1信号是肥胖和相关代谢紊乱发生的必要条件。然而，内源性产生的内源性大麻素是否足以引起肝脏脂质积累和胰岛素抵抗，而不依赖于食物摄入，尚未得到证实。本研究表明，单次给药异丙基十二烷基氟膦酸盐（IDFP）可能是内源性大麻素降解最有效的药理学抑制剂，可增加小鼠肝脏甘油三酯（TG）并诱导胰岛素抵抗。这些影响包括CB1信号的增加，因为CB1拮抗剂（AM251）和CB1敲除小鼠可以减轻CB1信号的增加。尽管CB1对肝脏脂质和葡萄糖代谢有很强的生理作用，但对这些作用的下游靶点知之甚少。为了阐明CB1信号的转录靶点，我们对DMSO（对照组）、IDFP和AM251/IDFP处理小鼠的肝脏RNA进行了微阵列检测。分泌糖蛋白脂载蛋白2 （lcn2）的基因与肥胖和胰岛素抵抗有关，是对CB1信号改变最敏感的基因之一。在层次聚类分析中，从DMSO小鼠中分离出的IDFP小鼠的表达模式和AM251预给药使大多数（533只中的303只）IDFP诱导的改变减少（bbb50 %）。通路分析显示，IDFP以cb1依赖的方式改变了参与脂质、脂肪酸和类固醇代谢、急性期反应和氨基酸代谢的基因的表达。PCR证实了多个独立实验中关键靶基因的阵列结果。总的来说，我们发现急性IDFP治疗诱导肝脏TG积累和胰岛素抵抗，至少部分通过CB1受体，并鉴定出新的大麻素反应基因。
Endocannabinoids regulate energy balance and lipid metabolism by stimulating the cannabinoid receptor type 1 (CB1). Genetic deletion and pharmacological antagonism have shown that CB1 signaling is necessary for the development of obesity and related metabolic disturbances. However, the sufficiency of endogenously produced endocannabinoids to cause hepatic lipid accumulation and insulin resistance, independent of food intake, has not been demonstrated. Here, we show that a single administration of isopropyl dodecylfluorophosphonate (IDFP), perhaps the most potent pharmacological inhibitor of endocannabinoid degradation, increases hepatic triglycerides (TG) and induces insulin resistance in mice. These effects involve increased CB1 signaling, as they are mitigated by pre-administration of a CB1 antagonist (AM251) and in CB1 knockout mice. Despite the strong physiological effects of CB1 on hepatic lipid and glucose metabolism, little is known about the downstream targets responsible for these effects. To elucidate transcriptional targets of CB1 signaling, we performed microarrays on hepatic RNA isolated from DMSO (control), IDFP and AM251/IDFP-treated mice. The gene for the secreted glycoprotein lipocalin 2 (lcn2), which has been implicated in obesity and insulin resistance, was among those most responsive to alterations in CB1 signaling. The expression pattern of IDFP mice segregated from DMSO mice in hierarchal cluster analysis and AM251 pre-administration reduced (>50%) the majority (303 of 533) of the IDFP induced alterations. Pathway analysis revealed that IDFP altered expression of genes involved in lipid, fatty acid and steroid metabolism, the acute phase response, and amino acid metabolism in a CB1-dependent manner. PCR confirmed array results of key target genes in multiple independent experiments. Overall, we show that acute IDFP treatment induces hepatic TG accumulation and insulin resistance, at least in part through the CB1 receptor, and identify novel cannabinoid responsive genes.
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DOI：
10.1073/pnas.96.10.5780
发表时间：
1999-05-11
影响因子：
11.1
作者：
Zimmer, A;Zimmer, AM;Bonner, TI
通讯作者：
Bonner, TI
影响因子：
--
作者：
Long JZ;Nomura DK;Cravatt BF
通讯作者：
Cravatt BF
anandamide（一种假定的内源性大麻素）在小鼠中的药理活性。
DOI：
--
发表时间：
1994
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Smith,PB;Compton,DR;Welch,SP;Razdan,RK;Mechoulam,R;Martin,BR
通讯作者：
Martin,BR
影响因子：
15.9
作者：
Tam, Joseph;Vemuri, V. Kiran;Kunos, George
通讯作者：
Kunos, George
影响因子：
15.9
作者：
Osei-Hyiaman, Douglas;Liu, Jie;Kunos, George
通讯作者：
Kunos, George