The role of the endocannabinoid system in regulating hepatic glucose fluxes

描述(由申请人提供)： 内源性大麻素(EC)信号在代谢综合征中起重要作用。在肥胖和胰岛素抵抗中，下丘脑以及肝脏和脂肪组织等外围器官中的EC水平会增加。对人类2型糖尿病(2型DM)的临床研究结果表明，药理上的大麻素受体(CB)1阻断可以改善血糖稳态。内皮细胞参与糖稳态调节的机制尚不清楚，但被认为涉及中枢、下丘脑和/或对肝脏和脂肪组织等靶器官的直接影响。在神经元中，内皮细胞有能力作为逆行信使，通过激活突触前CB1受体来抑制递质释放。在外周，CB1的激活已经被证明可以诱导肝脏和脂肪组织中的脂肪生成。我们最近发现脂肪组织中的EC张力受到下丘脑瘦素信号的抑制，这表明肥胖和2型糖尿病的EC张力增加是中枢性瘦素抵抗的结果。下丘脑中基底核(MBH)在大脑调节肝脏葡萄糖生成中起着关键作用。循环中的激素，如胰岛素和瘦素，通过它们各自的MBH受体传递信号。这反过来又导致下行通路的激活，从而抑制肝脏葡萄糖的产生和调节脂肪代谢。我们发现，在短期(3天)过量喂养诱导的胰岛素抵抗模型中，注入MBH的胰岛素失去了抑制肝脏葡萄糖产生的能力，而该模型的肝脏和下丘脑中的胰岛素信号是完整的。因此，我们推测，下丘脑中内皮细胞的增加对胰岛素诱导的神经元传递具有抑制作用。这一建议的两个目的是：1.阐明中枢EC信号在调节肝脏葡萄糖生成中的作用；2.研究来源于脂肪组织的EC是否可以调节下丘脑EC水平。这些研究应该会促进我们理解为什么过量的营养摄入会导致EC张力增加，并损害大脑对脂肪组织和肝脏新陈代谢的控制。众所周知，肥胖和2型糖尿病之间存在着密切的关系。体重增加会恶化血糖控制，相反，体重减轻会改善血糖控制，从而降低糖尿病并发症的风险。在这里，我们希望了解在能量稳态中起重要作用的激素、瘦素和EC是如何控制血糖稳态的，以促进我们对糖尿病的病理生理和治疗的理解。

DESCRIPTION (provided by applicant): Endocannabinoid (EC) signaling has recently been recognized to play an important role in the metabolic syndrome. In obesity and insulin resistance, EC levels are increased in the hypothalamus and in peripheral organs like liver and adipose tissue. Results from clinical studies in humans with type 2 diabetes mellitus (type2 DM) indicate that pharmacologic cannabinoid receptor (CB) 1 blockade improves glucose homeostasis. The mechanisms by which ECs participate in the regulation of glucose homeostasis are poorly defined, but are thought to either involve central, hypothalamic effects and/or direct effects in target organs like liver and adipose tissue. In neurons ECs have the ability to act as retrograde messengers to suppress transmitter release via activation of presynaptic CB1 receptors. In the periphery CB1 activation has been shown to induce lipogenesis in liver and adipose tissue. We have recently shown that EC tone in adipose tissue is suppressed by hypothalamic leptin signaling, suggesting that the increased EC tone in obesity and type 2 DM is a consequence of central leptin resistance. The medio- basal hypothalamus (MBH) plays a pivotal role in the brain regulation of hepatic glucose production. Circulating hormones like insulin and leptin signal through their respective receptors in the MBH. This in turn leads to the activation of descending pathways that result in the suppression of hepatic glucose production and the modulation of lipid metabolism. We have found that in a model of short term (3 days) overfeeding induced insulin resistance, insulin infused into the MBH looses its ability to suppress hepatic glucose production, while insulin signaling is intact in liver and the hypothalamus of this model. Thus, we speculate that increased ECs in the hypothalamus exert an inhibitory effect on insulin induced neuronal transmission. The two aims of this proposal are to 1. Delineate the role of central EC signaling in the regulation of hepatic glucose production and to 2. Investigate if hypothalamic EC levels can be modulated by ECs that originate from adipose tissue. These studies should advance our understanding of why excessive nutrient intake leads to increased EC tone and impaired brain control of metabolism in adipose tissue and liver. It is well established that a tight relationship exists between obesity and type 2 diabetes. Weight gain worsens glucose control and conversely, weight loss improves glycemic control and thereby decreases the risk of diabetic complications. Here we wish to understand how hormones that play important roles in energy homeostasis, leptin and EC control glucose homeostasis advancing our understanding of pathophysiology and treatment of diabetes.