Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093, USA.
Diabetes Obes Metab. 2010 Aug;12(8):722-30. doi: 10.1111/j.1463-1326.2010.01227.x.
We determined the direct effects of modulating the endocannabinoid-1 (CB1) receptor on the glucose transport system in isolated skeletal muscle from insulin-sensitive lean Zucker and insulin-resistant obese Zucker rats.
Soleus strips were incubated in the absence or presence of insulin, without or with various concentrations of the CB1 receptor antagonist SR141716 or with the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA).
CB1 receptor protein expression in visceral adipose (57%), soleus (40%) and myocardial (36%) tissue was significantly (p < 0.05) decreased in obese compared to lean animals, with a trend for a reduction (17%, p = 0.079) in the liver. In isolated soleus muscle from both lean and obese Zucker rats, CB1 receptor antagonism directly improved glucose transport activity in a dose-dependent manner. Basal glucose transport activity was maximally enhanced between 100 and 200 nM SR141716 in lean (26-28%) and obese (22-31%) soleus. The maximal increase in insulin-stimulated glucose transport for lean muscle ( approximately 30%) was achieved at 50 nM SR141716 and for obese muscle ( approximately 30%) at 100 nM SR141716. In contrast, CB1 receptor antagonism did not alter hypoxia-stimulated glucose transport activity. CB1 receptor agonism (1 mM ACEA) significantly decreased both basal (15%) and insulin-stimulated (22%) glucose transport activity in isolated lean soleus. This effect was reversed by 200 nM SR141716. In both lean and obese muscle, the functionality of key signalling proteins (insulin receptor beta-subunit, Akt, glycogen synthase kinase-3beta (GSK-3beta), AMP-dependent protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK)) was not altered by either CB1 receptor agonism or antagonism.
These results indicate that the engagement of CB1 receptor can negatively modulate both basal and insulin-dependent glucose transport activity in lean and obese skeletal muscles, and that these effects are not mediated by the engagement of elements of the canonical pathways regulating this process in mammalian skeletal muscle.
我们旨在确定调节内源性大麻素-1（CB1）受体对来自胰岛素敏感的瘦 Zucker 和胰岛素抵抗肥胖 Zucker 大鼠的分离骨骼肌葡萄糖转运系统的直接影响。
在不存在或存在胰岛素的情况下，将比目鱼肌条在各种浓度的 CB1 受体拮抗剂 SR141716 或 CB1 受体激动剂花生四烯酸-2-氯乙基酰胺（ACEA）下孵育。
与瘦 Zucker 动物相比，肥胖 Zucker 动物内脏脂肪（57%）、比目鱼肌（40%）和心肌（36%）组织中的 CB1 受体蛋白表达显著（p < 0.05）降低，而在肝脏中呈降低趋势（17%，p = 0.079）。在来自瘦 Zucker 和肥胖 Zucker 大鼠的分离比目鱼肌中，CB1 受体拮抗作用以剂量依赖性方式直接改善葡萄糖转运活性。在瘦 Zucker（26-28%）和肥胖 Zucker（22-31%）比目鱼肌中，100-200 nM SR141716 之间最大程度地增强了基础葡萄糖转运活性。瘦肌肉中胰岛素刺激的葡萄糖转运的最大增加（约 30%）发生在 50 nM SR141716，肥胖肌肉中（约 30%）发生在 100 nM SR141716。相比之下，CB1 受体拮抗作用不会改变缺氧刺激的葡萄糖转运活性。CB1 受体激动剂（1 mM ACEA）显著降低了分离的瘦 Zucker 比目鱼肌中的基础（15%）和胰岛素刺激（22%）葡萄糖转运活性。这种作用被 200 nM SR141716 逆转。在瘦 Zucker 和肥胖 Zucker 肌肉中，CB1 受体激动或拮抗作用均未改变关键信号蛋白（胰岛素受体β亚基、Akt、糖原合酶激酶-3β（GSK-3β）、AMP 依赖蛋白激酶（AMPK）、p38 丝裂原激活蛋白激酶（p38 MAPK））的功能。
这些结果表明，CB1 受体的参与可以负向调节瘦 Zucker 和肥胖 Zucker 骨骼肌中的基础和胰岛素依赖性葡萄糖转运活性，并且这些作用不是通过调节哺乳动物骨骼肌中该过程的经典途径的元素介导的。
