Lindborg Katherine A, Jacob Stephan, Henriksen Erik J
Cardiorenal Med. 2011;1(1):31-44. doi: 10.1159/000322826. Epub 2011 Jan 17.
BACKGROUND/AIMS: Antagonism of the endocannabinoid receptor-1 (CB1R) directly improves whole-body metabolic parameters of insulin resistance. The present investigation determined the effects of chronic CB1R antagonism on whole-body and skeletal-muscle insulin action in insulin-sensitive lean and insulin-resistant obese Zucker rats.
Animals were either fed ad libitum or in pairs, or treated with SR141716 (10 mg/kg i.p. for 14 days).
Food intake was significantly reduced (p < 0.05) after initial SR141716 treatment and remained decreased in both lean and obese animals until day 13. Fasting plasma glucose decreased (24%) and insulin increased (43%) in lean SR141716-treated (24%) rats compared to lean ad libitum-fed controls, but not in the corresponding obese groups. Fasting plasma free fatty acids were reduced by CB1R antagonism in lean (21%) and obese (42%) animals. Whole-body insulin sensitivity was increased (36%) in obese SR141716-treated rats compared to obese ad libitum-fed controls, which was associated with reduced insulin secretion during an oral glucose tolerance test. Insulin-stimulated glucose transport activity in the soleus was greatest in the respective SR141716-treated lean and obese groups compared to the corresponding ad libitum- and pair-fed controls. Chronic SR141716 treatment did not induce alterations in signaling factors associated with the regulation of glucose transport [protein kinase B (Akt), glycogen synthase kinase-3β, 5'-AMP-dependent protein kinase, or p38 mitogen-activated protein kinase] in the soleus.
These results indicate that, while the chronic treatment with CB1R antagonism markedly diminished food intake in lean and obese Zucker rats, there are also significant metabolic improvements in whole-body and skeletal-muscle insulin action mediated by CB1R antagonism through mechanisms independent of reduced caloric intake.
背景/目的：内源性大麻素受体-1（CB1R）拮抗剂可直接改善胰岛素抵抗的全身代谢参数。本研究确定了慢性CB1R拮抗作用对胰岛素敏感的瘦型和胰岛素抵抗的肥胖型 Zucker 大鼠的全身及骨骼肌胰岛素作用的影响。
动物自由进食、成对饲养或用 SR141716（腹腔注射10mg/kg，共14天）处理。
初次 SR141716 处理后食物摄入量显著减少（p<0.05），且在瘦型和肥胖型动物中均持续减少直至第13天。与自由进食的瘦型对照大鼠相比，经 SR141716 处理的瘦型大鼠空腹血糖降低（24%），胰岛素升高（43%），但相应的肥胖组未出现此情况。CB1R 拮抗作用使瘦型（21%）和肥胖型（42%）动物的空腹血浆游离脂肪酸降低。与自由进食的肥胖对照大鼠相比，经 SR141716 处理的肥胖大鼠全身胰岛素敏感性增加（36%），这与口服葡萄糖耐量试验期间胰岛素分泌减少有关。与相应的自由进食和成对饲养的对照相比，经 SR141716 处理的瘦型和肥胖型比目鱼肌中胰岛素刺激的葡萄糖转运活性最高。慢性 SR141716 处理未引起比目鱼肌中与葡萄糖转运调节相关的信号因子[蛋白激酶 B（Akt）、糖原合酶激酶-3β、5'-AMP 依赖性蛋白激酶或 p38 丝裂原活化蛋白激酶]的改变。
这些结果表明，虽然 CB1R 拮抗剂的慢性治疗显著减少了瘦型和肥胖型 Zucker 大鼠的食物摄入量，但通过独立于热量摄入减少的机制，CB1R 拮抗作用在全身和骨骼肌胰岛素作用方面也有显著的代谢改善。
