Defining the molecular roles of peripheral CB1 and CB2 cannabinoid receptors in age-induced changes in energy and metabolic homeostasis.

定义外周 CB1 和 CB2 大麻素受体在年龄引起的能量和代谢稳态变化中的分子作用。

• 批准号: BB/N002342/1
• 负责人: Hari Hundal
• 金额: $ 42.73万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN002342%2F1
• 关键词: Defining; molecular; roles; peripheral; CB1

There is immense interest at present in targeting the action of a class of compounds, termed cannabinoids, in the treatment of obesity and metabolic-related disorders. Cannabinoids are present in cannabis, but our bodies naturally create cannabinoid-like chemicals, known as endocannabinoids that lock-on to protein molecules found on the surface of cells called cannabinoid receptors (i.e. CB1 and CB2). During obesity, diabetes and, as we have recently discovered, during ageing the CB1 is notably over-activated by endocannabinoids produced by the body resulting in impaired insulin action and dysregulation of energy balance in metabolically important tissues such as muscle, fat and liver. CB1 over-activation has been linked strongly with development of insulin resistance and increased adiposity. In contrast, emerging data indicates that CB2 may confer a protective physiological effect. In line with this idea, we find that CB2 inhibitors (antagonists) augment the insulin-desensitising effects of the endocannabinoid, anandamide (AEA) in muscle cells, whereas CB2 activators (agonists) ameliorate the loss in insulin signalling. Moreover, it is noteworthy that whilst CB1 expression is enhanced in ageing muscle that of CB2 is significantly decreased, consistent with the reduced insulin sensitivity that prevails in ageing skeletal muscle. Intriguingly, CB1 antagonists (e.g. rimonabant) promote glucose tolerance, stimulate energy expenditure and reduce body weight in obese animals by mechanisms independent of their appetite-reducing effect. Consistent with such findings, we find rimonabant ameliorates age-related tissue insulin resistance and fat mass gain in older animals. Precisely how CB1 antagonism elicits these beneficial effects is unclear, but our recent work indicates that CB1 blockade induces activation of AMPK - a molecule that not only senses cellular energy but promotes the breakdown and burning of fat in mitochondria (the cell's energy factory). The molecular events linking CB1 blockade to AMPK activation and the effect of the latter on enzymes involved in fat breakdown/burning and mitochondrial dynamics remain poorly understood. The proposed studies will utilise cultured muscle and fat cells to understand how CB1 inhibition or CB2 activation impacts upon molecules implicated in insulin action, energy balance and mitochondrial function and integrity. Our molecular analyses will involve biochemical and state-of-the-art imaging techniques for visualising mitochondrial staining in muscle and fat cells. These cell-based studies will be complemented with analysis of tissues from young and old mice genetically deficient in CB2 or experiments in young and aged mice administered a pharmacologically active dose of a CB1 antagonist or CB2 agonist for two weeks. During this period we will monitor food intake, glucose tolerance, energy expenditure, physical activity and fat mass before sampling blood/tissue for experimental analyses designed to dissect the mechanisms by which CB1 blockade or CB2 activation improves the metabolic status of aged animals. We also aim to test the effects of exercise in aged animals given that physical activity is known to help sustain tissue sensitivity to anabolic hormones such as insulin and preserve tissue functionality during aging. These studies will help unveil whether exercise curtails age-related changes in tissue CB1 and CB2 expression and, if so, whether these correlate favourably with measures of whole body energetics (i.e. body fat, glucose tolerance and energy expenditure). The proposed research will specifically expand our fundamental understanding of how modulating peripheral CB receptor activity influences energy balance and insulin action. The findings that will emerge will advance our knowledge of these key issues and prove invaluable in designing therapies that selectively target the peripheral ECS for treatment of age and obesity-related metabolic disorders.

目前，人们对靶向一类称为大麻素的化合物在治疗肥胖症和代谢相关疾病中的作用产生了极大的兴趣。大麻素存在于大麻中，但我们的身体会自然产生大麻素样化学物质，称为内源性大麻素，它锁定在称为大麻素受体（即CB 1和CB 2）的细胞表面上发现的蛋白质分子上。在肥胖、糖尿病期间，以及我们最近发现的衰老期间，CB 1被身体产生的内源性大麻素显著过度激活，导致胰岛素作用受损和代谢重要组织（如肌肉、脂肪和肝脏）中的能量平衡失调。CB 1过度激活与胰岛素抵抗和肥胖增加的发展密切相关。相反，新出现的数据表明，CB 2可能赋予保护性生理作用。根据这一想法，我们发现CB 2抑制剂（拮抗剂）增强了内源性大麻素anandamide（AEA）在肌肉细胞中的胰岛素脱敏作用，而CB 2激活剂（激动剂）改善了胰岛素信号传导的损失。此外，值得注意的是，虽然CB 1的表达在老化肌肉中增强，但CB 2的表达显著降低，这与老化骨骼肌中普遍存在的胰岛素敏感性降低一致。有趣的是，CB 1拮抗剂（例如利莫那班）通过独立于其食欲降低作用的机制促进肥胖动物的葡萄糖耐量，刺激能量消耗并减轻体重。与这些发现一致，我们发现利莫那班改善老年动物与年龄相关的组织胰岛素抵抗和脂肪量增加。确切地说，CB 1拮抗作用如何发挥这些有益作用尚不清楚，但我们最近的工作表明，CB 1阻断诱导AMPK的激活-AMPK是一种不仅能感知细胞能量，还能促进线粒体（细胞的能量工厂）中脂肪分解和燃烧的分子。将CB 1阻断与AMPK激活联系起来的分子事件以及后者对参与脂肪分解/燃烧和线粒体动力学的酶的影响仍然知之甚少。拟议的研究将利用培养的肌肉和脂肪细胞来了解CB 1抑制或CB 2激活如何影响与胰岛素作用、能量平衡和线粒体功能和完整性有关的分子。我们的分子分析将涉及生物化学和最先进的成像技术，用于可视化肌肉和脂肪细胞中的线粒体染色。这些基于细胞的研究将通过对遗传性CB 2缺陷的年轻和老年小鼠的组织分析或对给予活性剂量的CB 1拮抗剂或CB 2激动剂两周的年轻和老年小鼠的实验进行补充。在此期间，我们将监测食物摄入、葡萄糖耐量、能量消耗、体力活动和脂肪量，然后采集血液/组织进行实验分析，旨在剖析CB 1阻断或CB 2激活改善老年动物代谢状态的机制。我们还旨在测试运动对老年动物的影响，因为已知体力活动有助于维持组织对胰岛素等合成代谢激素的敏感性，并在衰老过程中保持组织功能。这些研究将有助于揭示运动是否会减少组织CB 1和CB 2表达中与年龄相关的变化，如果是这样，这些变化是否与全身能量学（即体脂，葡萄糖耐量和能量消耗）的测量有利相关。拟议的研究将特别扩大我们对调节外周CB受体活性如何影响能量平衡和胰岛素作用的基本理解。即将出现的研究结果将推进我们对这些关键问题的认识，并证明在设计选择性靶向外周ECS治疗年龄和肥胖相关代谢疾病的治疗方法方面是非常宝贵的。

项目成果

Is REDD1 a Metabolic Éminence Grise?

• DOI: 10.1016/j.tem.2016.08.005
• 发表时间: 2016-12
• 期刊: TRENDS IN ENDOCRINOLOGY AND METABOLISM
• 影响因子: 10.9
• 作者: Lipina, Christopher;Hundal, Harinder S.
• 通讯作者: Hundal, Harinder S.

CDK7 is a component of the integrated stress response regulating SNAT2 (SLC38A2)/System A adaptation in response to cellular amino acid deprivation.

CDK7 是调节 SNAT2 (SLC38A2)/系统 A 适应以响应细胞氨基酸剥夺的综合应激反应的一个组成部分。

• DOI: 10.1016/j.bbamcr.2019.03.002
• 发表时间: 2019
• 期刊: Biochimica et biophysica acta. Molecular cell research
• 作者: Stretton C

CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction.

• DOI: 10.1111/acel.12438
• 发表时间: 2016-04
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Lipina C;Vaanholt LM;Davidova A;Mitchell SE;Storey-Gordon E;Hambly C;Irving AJ;Speakman JR;Hundal HS
• 通讯作者: Hundal HS

Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1.

• DOI: 10.1016/j.cellsig.2016.01.014
• 发表时间: 2016-05
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Watson A;Lipina C;McArdle HJ;Taylor PM;Hundal HS
• 通讯作者: Hundal HS

The endocannabinoid system: 'NO' longer anonymous in the control of nitrergic signalling?

• DOI: 10.1093/jmcb/mjx008
• 发表时间: 2017-04-01
• 期刊: Journal of molecular cell biology
• 影响因子: 5.5
• 作者: Lipina C;Hundal HS
• 通讯作者: Hundal HS