Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia
Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia
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DOI：
10.1210/jc.2005-2679
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发表时间：
2006-08-01
影响因子：
5.8
通讯作者：
Di Marzo, Vincenzo
中科院分区：
文献类型：
--
作者：
Matias, Isabel;Gonthier, Marie-Paule;Di Marzo, Vincenzo
内容：大麻素CB 1受体阻断剂可以降低肥胖动物和人类的体重和高胰岛素血症，其方式与食物摄入量无关。目的：本研究的目的是研究脂肪细胞和胰腺β细胞中内源性大麻素系统的调节和功能。设计、设置和患者：小鼠3 T3-F442 A脂肪细胞和大鼠胰岛素瘤RIN-m5 F β细胞，饮食诱导肥胖小鼠的胰腺和脂肪，体重指数等于或大于30 kg/m2患者的内脏和皮下脂肪（2），主要结果测量：内源性大麻素酶和脂肪细胞蛋白表达，以及内源性大麻素和胰岛素水平被测量。结果：内源性大麻素存在于脂肪细胞中，其水平在分化前达到峰值，并且存在于RIN-m5 F β细胞中，在那里它们处于胰岛素的阴性控制下。用胰岛素长期治疗脂肪细胞伴随着内源性大麻素信号传导的永久性升高，而在高葡萄糖中培养RIN-m5 F β细胞将内源性大麻素水平的胰岛素下调转化为上调。饮食诱导肥胖小鼠的附睾脂肪和胰腺比瘦小鼠含有更高的内源性大麻素水平。与相应的对照组相比，2型糖尿病引起的肥胖或高血糖患者在内脏脂肪或血清中分别显示出更高浓度的内源性大麻素。CB 1受体刺激增加脂滴，降低脂联素在脂肪细胞中的表达，它增加细胞内钙和胰岛素的释放RIN-m5 F β-cells保持在高glucose.Conclusions：外周内源性大麻素过度可能解释为什么CB 1受体阻滞剂导致减肥独立减少脂肪生成，低脂联素血症，高胰岛素血症在肥胖的动物和人类。
Context: Cannabinoid CB1 receptor blockade decreases weight and hyperinsulinemia in obese animals and humans in a way greatly independent from food intake.Objective: The objective of this study was to investigate the regulation and function of the endocannabinoid system in adipocytes and pancreatic beta-cells.Design, Setting, and Patients: Mouse 3T3-F442A adipocytes and rat insulinoma RIN-m5F beta-cells, pancreas and fat from mice with diet-induced obesity, visceral and sc fat from patients with body mass index equal to or greater than 30 kg/m(2), and serum from normoglycemic and type 2 diabetes patients were studied.Main Outcome Measure: Endocannabinoid enzyme and adipocyte protein expression, and endocannabinoid and insulin levels were measured.Results: Endocannabinoids are present in adipocytes with levels peaking before differentiation, and in RIN-m5F beta-cells, where they are under the negative control of insulin. Chronic treatment of adipocytes with insulin is accompanied by permanently elevated endocannabinoid signaling, whereas culturing of RIN-m5F beta-cells in high glucose transforms insulin down-regulation of endocannabinoid levels into up-regulation. Epididymal fat and pancreas from mice with diet-induced obesity contain higher endocannabinoid levels than lean mice. Patients with obesity or hyperglycemia caused by type 2 diabetes exhibit higher concentrations of endocannabinoids in visceral fat or serum, respectively, than the corresponding controls. CB1 receptor stimulation increases lipid droplets and decreases adiponectin expression in adipocytes, and it increases intracellular calcium and insulin release in RIN-m5F beta-cells kept in high glucose.Conclusions: Peripheral endocannabinoid overactivity might explain why CB1 blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.