Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Diabetes. 2011 Apr;60(4):1055-62. doi: 10.2337/db10-0962.
The endocannabinoid (EC) system has been implicated as an important regulator of energy homeostasis. In obesity and type 2 diabetes, EC tone is elevated in peripheral tissues including liver, muscle, fat, and also centrally, particularly in the hypothalamus. Cannabinoid receptor type 1 (CB₁) blockade with the centrally and peripherally acting rimonabant induces weight loss and improves glucose homeostasis while also causing psychiatric adverse effects. The relative contributions of peripheral versus central EC signaling on glucose homeostasis remain to be elucidated. The aim of this study was to test whether the central EC system regulates systemic glucose fluxes.
We determined glucose and lipid fluxes in male Sprague-Dawley rats during intracerebroventricular infusions of either WIN55,212-2 (WIN) or arachidonoyl-2'-chloroethylamide (ACEA) while controlling circulating insulin and glucose levels through hyperinsulinemic, euglycemic clamp studies. Conversely, we fed rats a high-fat diet for 3 days and then blocked central EC signaling with an intracerebroventricular infusion of rimonabant while assessing glucose fluxes during a clamp.
Central CB₁ activation is sufficient to impair glucose homeostasis. Either WIN or ACEA infusions acutely impaired insulin action in both liver and adipose tissue. Conversely, in a model of overfeeding-induced insulin resistance, CB₁ antagonism restored hepatic insulin sensitivity.
Thus central EC tone plays an important role in regulating hepatic and adipose tissue insulin action. These results indicate that peripherally restricted CB₁ antagonists, which may lack psychiatric side effects, are also likely to be less effective than brain-permeable CB₁ antagonists in ameliorating insulin resistance.
内源性大麻素（EC）系统被认为是能量平衡的重要调节因子。在肥胖和 2 型糖尿病中，外周组织（包括肝脏、肌肉、脂肪）和中枢组织（尤其是下丘脑）中的 EC 张力升高。用中枢和外周作用的利莫那班阻断大麻素受体 1（CB₁）可诱导体重减轻和改善葡萄糖稳态，同时也引起精神不良影响。外周与中枢 EC 信号对葡萄糖稳态的相对贡献仍有待阐明。本研究旨在测试中枢 EC 系统是否调节全身葡萄糖通量。
我们在雄性 Sprague-Dawley 大鼠中进行了脑室内输注 WIN55,212-2（WIN）或 arachidonoyl-2'-chloroethylamide（ACEA），同时通过高胰岛素-正常血糖钳夹研究控制循环胰岛素和葡萄糖水平，以确定葡萄糖和脂质通量。相反，我们让大鼠连续 3 天进食高脂肪饮食，然后通过脑室内输注利莫那班阻断中枢 EC 信号，在钳夹期间评估葡萄糖通量。
中央 CB₁ 激活足以损害葡萄糖稳态。WIN 或 ACEA 输注均可急性损害肝脏和脂肪组织中的胰岛素作用。相反，在过食诱导的胰岛素抵抗模型中，CB₁ 拮抗作用恢复了肝胰岛素敏感性。
因此，中枢 EC 张力在调节肝脏和脂肪组织胰岛素作用方面起着重要作用。这些结果表明，外周限制的 CB₁ 拮抗剂，可能缺乏精神副作用，也可能不如脑渗透性 CB₁ 拮抗剂在改善胰岛素抵抗方面有效。
