The role of the endocannabinoid system in regulating hepatic glucose fluxes

内源性大麻素系统在调节肝葡萄糖通量中的作用

• 批准号: 7751805
• 负责人: CHRISTOPH BUETTNER
• 金额: $ 8.39万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751805
• 关键词: Abbreviations; Adipocytes; Adipose tissue; Affect; Body Weight decreased; Brain; CNR1 gene; Clinical Research; Complications of Diabetes Mellitus; Diabetes Mellitus; Diazoxide; Endocannabinoids; Euglycemic Clamping; Excision; Fatty acid glycerol esters; Functional disorder; Glucose; Glucose Clamp; Hepatic; Homeostasis; Hormones; Human; Hypothalamic structure; Infusion procedures; Insulin; Insulin Resistance; Intake; JAK2 gene; Janus kinase 2; Lead; Leptin; Leptin resistance; Lipids; Liver; Metabolic syndrome; Metabolism; Modeling; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Pathway interactions; Peripheral; Phosphatidylinositols; Phosphoenolpyruvate Carboxylase; Phosphotransferases; Play; Postsynaptic Membrane; Potassium Channel; Pyruvate Kinase; Rattus; Regulation; Risk; Role; STAT protein; STAT3 gene; Signal Transduction; Source; Sprague-Dawley Rats; Synaptic Transmission; System; Triglycerides; Visceral; Weight Gain; aged; anandamide; base; blood glucose regulation; cannabinoid receptor; glucose metabolism; glucose production; glycemic control; improved; insulin signaling; lipid biosynthesis; lipid metabolism; mind control; neurotransmission; presynaptic; receptor

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.

描述（由申请人提供）： 内源性大麻素（Endocannabinoid，EC）信号通路在代谢综合征中起重要作用。在肥胖和胰岛素抵抗中，下丘脑和外周器官如肝脏和脂肪组织中的EC水平增加。2型糖尿病（2型DM）患者的临床研究结果表明，药物大麻素受体（CB）1阻断可改善葡萄糖稳态。EC参与葡萄糖稳态调节的机制尚不清楚，但被认为涉及中枢、下丘脑作用和/或直接作用于靶器官如肝脏和脂肪组织。在神经元中，EC具有作为逆行信使的能力，通过激活突触前CB 1受体来抑制递质释放。在外周中，CB 1活化已显示诱导肝脏和脂肪组织中的脂肪生成。我们最近发现，EC张力在脂肪组织中被下丘脑瘦素信号抑制，这表明增加EC张力在肥胖症和2型糖尿病是一个结果，中央瘦素抵抗。下丘脑中底核在肝脏葡萄糖生成的脑调节中起着关键作用.胰岛素和瘦素等循环激素通过MBH中各自的受体发出信号。这反过来又导致下行途径的激活，从而抑制肝脏葡萄糖产生和调节脂质代谢。我们已经发现，在短期（3天）过度喂养诱导的胰岛素抵抗的模型中，输注到MBH中的胰岛素失去其抑制肝葡萄糖产生的能力，而胰岛素信号传导在该模型的肝脏和下丘脑中是完整的。因此，我们推测下丘脑中EC的增加对胰岛素诱导的神经元传递产生抑制作用。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，并对2。研究下丘脑EC水平是否可以由源自脂肪组织的EC调节。这些研究应该促进我们理解为什么过量的营养摄入会导致EC张力增加和脂肪组织和肝脏代谢的大脑控制受损。肥胖与2型糖尿病之间存在着密切的关系。体重增加有助于血糖控制，相反，体重减轻可以改善血糖控制，从而降低糖尿病并发症的风险。在这里，我们希望了解如何发挥重要作用的激素，在能量稳态，瘦素和EC控制葡萄糖稳态推进我们的理解的病理生理和治疗糖尿病。