Endocannabinoids And Energy Homeostasis

内源性大麻素和能量稳态

• 批准号: 7963844
• 负责人: GEORGE KUNOS
• 金额: $ 163.44万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7963844
• 关键词: 21 year old; Address; Adipocytes; Adipose tissue; Adverse effects; Affinity; Albumins; Alcohol consumption; Alcohols; Anabolism; Animals; Anxiety; Behavior; Bioavailable; Biological; Body Weight; Boston; Brain; CNR1 gene; Carbohydrates; Central obesity; Cholesterol; Clinical Trials; Collaborations; Conscious; Desire for food; Development; Diet; Disease; Double-Blind Method; Dyslipidemias; Endocannabinoids; Energy Intake; Energy Metabolism; Enzymes; Euglycemic Clamping; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Feeling suicidal; Food; Glucose; Glucose Clamp; Glucose Intolerance; Goals; Hand; Heavy Drinking; Hepatic; Hepatocellular Damage; Hepatocyte; Homeostasis; Hormonal; Human; Infusion procedures; Injection of therapeutic agent; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Leptin; Leptin resistance; Liver; Manuscripts; Marketing; Mediating; Metabolic; Metabolic syndrome; Modeling; Motor Activity; Mus; Obesity; Outpatients; Pathway interactions; Patients; Penetrance; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Placebos; Plasma; Play; Psychopharmacology; Publications; Regulation; Rewards; Rodent Model; Role; Safety; Self Administration; Serum; Skeletal Muscle; Structure of beta Cell of islet; System; Tissues; Tracer; Transgenic Mice; Triglycerides; Wild Type Mouse; Writing; adiponectin; alcohol exposure; anandamide; base; blood glucose regulation; depression; drinking; drug seeking behavior; feeding; glucose tolerance; glucose uptake; hospital laboratories; improved; insulin sensitivity; interest; lipid biosynthesis; medical schools; neuropsychiatry; novel; obesity treatment; oxidation; placebo controlled study; promoter; psychologic; receptor; receptor binding; receptor expression; response; rimonabant; social

The endocannabinoid system (ECS), which includes endogenous cannabinoids, their receptors, and the enzymes involved in the biosynthesis and degradation of endocannabinoids, plays an important role in the control of body weight and energy homeostasis. In several large clinical trials, the CB1 receptor (CB1R) blocking drug rimonabant had been found effective in reducing body weight and improving cardiometabolic abnormalities in patients with the metabolic syndrome, but was recently withdrawn from the market due to neuropsychiatric side effects, including depression, anxiety and suicidal ideation. We had earlier provided evidence that the liver is a major target of the metabolic effects of endocannabinoids in mice with diet-induced obesity (DIO)(JCI 115:1298, 2005). In a subsequent study using mice with liver-specific knockout of CB1R we have demonstrated that activation of hepatic CB1R contributes to steatosis, insulin and leptin resistance as well as dyslipidemias, but not to increased adiposity (JCI 118:3160-69, 2008). Functional CB1R are also present in adipocytes, skeletal muscle and pancreatic beta cells, raising the possibility that peripheral CB1 receptors may be targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order the minimize the neuropsychiatric side effects of non-selective CB1 blockade during the treatment of obesity-associated conditions. In a collaborative study with Alex Makriyannis (Northeastern Univ., Boston), we have developed a peripherally restricted CB1R antagonist. AM6545 is a novel, orally bioavailable CB1R neutral antagonist with high CB1R binding affinity similar to that of the brain-penetrant CB1R antagonist rimonabant. AM6545 has markedly reduced brain penetrance, with a brain to plasma ratio of 0.03 compared to 0.76 for rimonabant. Unlike rimonabant, AM6545 fails to inhibit central CB1R-mediated increases in locomotor activity or cataleptic behavior, and does not induce anxiety-related behaviors in mice. On the other hand, AM6545 has effects similar to rimonabant on hormonal/metabolic parameters in mice with diet-induced obesity (DIO). Treatment of DIO mice with 10 mg Kg-1 day-1 AM6545 for 28 days significantly reduced body weight without an overall effect on caloric intake, by shifting energy expenditure from carbohydrate to fat oxidation. Elevated serum leptin, glucose and insulin levels were significantly reduced or normalized, while adiponectin levels increased. AM6545 treatment ameliorated glucose tolerance and insulin sensitivity. Finally, AM6545 treatment fully reversed the diet-induced hepatic steatosis and hepatocellular damage, as well as CB1R-mediated de novo hepatic lipogenesis. Thus, selective blockade of peripheral CB1R is sufficient to improve the metabolic abnormalities associated with obesity, which suggests that non brain-penetrant CB1R antagonists may have value in the treatment of these disorders in humans. These findings have been written up for publication. Our earlier findings using hepatocyte-specific CB1R knockout mice indicated that hepatic CB1R are necessary for diet-induced steatosis, insulin and leptin resistance and dyslipidemias to develop in mice. To address the question whether activation of hepatic CB1R is sufficient for these effect, we have developed a rescue model, transgenic mice that express CB1R only in hepatocytes. This was achieved by transfecting fertilized egges of CB1R knockout mice with a construct of the mouse CB1R driven by the mouse albumin promoter. We have established several lines with variable degrees of CB1R expression in hepatocytes and verified the absence of CB1R in all other tissues. When fed a high fat diet, these mice remained lean, but developed glucose intolerance and insulin resistance. Also, glucose intolerance and insulin resistance can be acutely induced by the ip injection of the endocannabinoid anandamide in wild-type and liver CB1R transgenic mice, but not in CB1R-/- or hepatocyte-specific CB1R-/- (LCB1R-/-) mice. In collaboration with Christoph Buettner at Mount Sinai School of Medicine in NY, we performed hyperinsulinemic, euglycemic clamps in conscious wild-type, CB1R-/- and LCB1R-/- mice. High fat diet resulted in a marked suppression of the glucose infusion rate in wild-type mice but not in either knockout strain, with no change in tracer glucose uptake into adipose tissue or skeletal muscle. This indicates that high fat diet caused selective hepatic insulin resistance via activation of hepatic CB1R. Endocannabinoids and CB1 receptors are essential components of the mesolimbic dopaminergic reward pathway, and CB1 receptor blockade was found to disrupt drug-seeking behavior, including voluntary alcohol drinking in rodent models. Based on such findings in animal studies, including our own, we have completed a phase I/II clinical trial to assess the safety of rimonabant treatment in young, heavy drinking subjects and its efficacy to reduce their desire to drink. This was a double-blind, placebo controlled study involving forty heavy drinking subjects (consuming between 20 and 50 drinks per week) between the ages of 21 and 45 years who took rimonabant (20 mg/day) or placebo for two weeks, followed by an in-hospital laboratory drinking paradigm where their desire to drink as well as their physiological, psychological and hormonal response to exposure to alcohol and drinking was evaluated. Results from both the outpatient call-ins and the alcohol self-administration paradigm failed to show a statistically significant difference between those receiving rimonabant or placebo. This suggests that the daily administration of 20 mg rimonabant for two weeks has no effect on alcohol consumption in heavy social drinkers. A manuscript summarizing these results is under consideration for publication in Psychopharmacology.

内源性大麻素，其受体以及涉及内源性大麻素的生物合成和降解的酶，内源性大麻素，其受体以及内源性的酶在控制体重和能量稳态中起着重要作用。在几项大型临床试验中，发现CB1受体（CB1R）阻断药物rimonabant可有效减轻体重和改善代谢综合征患者的心脏代谢异常，但最近由于抑郁症，焦虑，焦虑和自杀感，最近由于神经精神副作用而从市场中撤出。我们早些时候提供了证据，表明肝脏是内源性大麻素在饮食诱导的肥胖症（DIO）（JCI 115：1298，2005）中的代谢作用的主要靶标。在随后使用CB1R肝特异性敲除小鼠的一项研究中，我们已经证明肝CB1R的激活有助于脂肪变性，胰岛素和瘦素耐药性以及血脂异常，但不能增加肥胖性（JCI 118：3160-69，2008）。 Functional CB1R are also present in adipocytes, skeletal muscle and pancreatic beta cells, raising the possibility that peripheral CB1 receptors may be targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order the minimize the neuropsychiatric side effects of non-selective CB1 blockade during the treatment of obesity-associated conditions. 在与Alex Makriyannis（波士顿东北大学）的合作研究中，我们开发了一个受周边限制的CB1R拮抗剂。 AM6545是一种新型的，口服的可生物利用的CB1R中性拮抗剂，具有高CB1R结合亲和力，类似于脑pentrant CB1R拮抗剂Rimonabant。 AM6545显着降低了大脑的渗透率，脑与血浆比为0.03，而Rimonabant则为0.76。与Rimonabant不同，AM6545无法抑制中央CB1R介导的运动活性或催化性行为的增加，并且不会诱导小鼠与焦虑相关的行为。另一方面，AM6545具有类似于饮食诱导肥胖症（DIO）小鼠的激素/代谢参数的rimonabant的作用。通过将能量消耗从碳水化合物转移到脂肪氧化，用10 mg kg-1第1天AM6545治疗28天的DIO小鼠，可显着降低体重，没有对热量摄入的总体影响。血清瘦素，葡萄糖和胰岛素水平升高显着降低或归一化，而脂联素水平升高。 AM6545治疗改善了葡萄糖耐受性和胰岛素敏感性。最后，AM6545治疗完全逆转了饮食引起的肝脏脂肪变性和肝细胞损伤，以及CB1R介导的从头肝脂肪生成。因此，对周围CB1R的选择性阻滞足以改善与肥胖相关的代谢异常，这表明非脑渗透剂CB1R拮抗剂可能在治疗人类的这些疾病方面具有价值。这些发现已写成出版。 我们使用肝细胞特异性CB1R基因敲除小鼠的早期发现表明，肝CB1R对于饮食诱导的脂肪变性，胰岛素和瘦素耐药性和血脂异性症在小鼠中发展是必需的。为了解决肝CB1R的激活是否足以满足这些作用，我们开发了一种仅在肝细胞中表达CB1R的转基因小鼠。这是通过用小鼠白蛋白启动子驱动的小鼠CB1R的构建体转染CB1R敲除小鼠的受精卵来实现的。我们已经在肝细胞中建立了几条CB1R表达度变化的线，并验证了所有其他组织中CB1R的不存在。当喂养高脂肪饮食时，这些小鼠保持苗条，但产生了葡萄糖不耐症和胰岛素抵抗。同样，葡萄糖不耐症和胰岛素抵抗可以通过在野生型和肝脏CB1R转基因小鼠中的内源性大麻素注射IP注射，但不能在CB1R - / - / - 或肝细胞特异性CB1R-/ - / - / - （LCB1R-/ - / - / - / - / - / - / - ）小鼠中诱导。在纽约州西奈山医学院的克里斯托夫·布特纳（Christoph Buettner）合作，我们在有意识的野生型，cb1r - / - 和lcb1r - / - 鼠标中进行了高胰岛素，尤利糖夹。高脂肪饮食导致野生型小鼠的葡萄糖输注率明显抑制，但在任何一种敲除菌株中都没有变化，示踪剂葡萄糖吸收到脂肪组织或骨骼肌中没有变化。这表明高脂肪饮食通过激活肝CB1R引起选择性肝胰岛素耐药性。 内源性大麻素和CB1受体是中断多巴胺能奖励途径的重要组成部分，发现CB1受体阻滞会破坏寻求药物的行为，包括啮齿动物模型中的自愿饮酒。根据包括我们自己在内的动物研究的这些发现，我们已经完成了I/II期临床试验，以评估年轻饮酒对象中的Rimonabant治疗的安全性及其减少饮酒愿望的功效。这是一项双盲，安慰剂对照的研究，涉及21至45岁之间的40名重型饮酒受试者（每周20至50饮料），他们服用了Rimonabant（20 mg/day）或安慰剂，持续了两个星期，随后是院内实验室饮酒范式，渴望喝酒，以及他们的物理学，心理学，饮酒，以便饮酒，以便饮酒，以便酒精饮酒。门诊呼叫和酒精自我管理范式的结果均未显示出接受Rimonabant或安慰剂的人之间的统计学意义差异。这表明，每天进行20毫克rimonabant两周的管理对大量社交饮酒者的饮酒没有影响。总结了这些结果的手稿正在考虑心理药理学上的出版。