Does GPR119 mediate the beneficial metabolic effects of THC?

GPR119 是否介导 THC 的有益代谢作用？

• 批准号: 9335512
• 负责人: Kenneth Mackie
• 金额: $ 19.64万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335512
• 关键词: Address; Affect; Agonist; Apoptosis; Arrestins; Beta Cell; Biological Assay; Body Weight decreased; Body mass index; CNR1 gene; Calcium; Cannabinoids; Cannabis; Cell Line; Cells; Chronic; Cognitive; Complement; Consumption; Cyclic AMP; Deposition; Drug Targeting; Enteroendocrine Cell; Fatty Liver; Fatty acid glycerol esters; Feeding behaviors; Food; G-Protein-Coupled Receptors; GPR119 receptor; GTP-Binding Protein alpha Subunits, Gs; Gastrointestinal tract structure; Glucose; High Fat Diet; Hormones; In Vitro; Incidence; Individual; Ingestion; Insulin; Knockout Mice; L Cells; Lead; Legal; Long-Term Effects; MAPK3 gene; Mediating; Metabolic; Metabolic syndrome; Metabolism; Modeling; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pancreas; Pathway interactions; Peptides; Physiological; Population; Prevalence; Risk; Role; Running; Series; Signal Pathway; Signal Transduction; Structure of beta Cell of islet; THC receptor; Testing; Tetrahydrocannabinol; Thinness; Weight; Work; base; drug development; endogenous cannabinoid system; epidemiology study; experimental study; feeding; glucagon-like peptide 1; in vivo; increased appetite; insulin secretion; insulin sensitivity; marijuana use; marijuana user; metabolic profile; pancreatic juice; phytocannabinoid; receptor; sex; theories

Cannabis use is prevalent in the US population, and its prevalence is likely to increase due to ongoing legalization efforts. Thus, understanding the implications (both beneficial and harmful) of long-term cannabis use is imperative. While the long-term cognitive and psychiatric sequelae of cannabis use have been intensely investigated, few studies have investigated the metabolic effects of long-term cannabis use. Metabolism is a likely target for cannabis as several of the compounds abundant in cannabis (e.g., delta-9- tetrahydrocannabinol, THC) directly affect feeding behaviors and/or metabolism. Interestingly, despite the popular view that cannabis ingestion enhances consumption of calorically dense food, which might lead to increased obesity, the metabolic syndrome, and type II diabetes among chronic cannabis users, most epidemiological studies have found the opposite. Thus, chronic cannabis use is associated with decreased body mass index, decreased incidence of metabolic syndrome, and a decreased risk for developing type II diabetes. The mechanism for this is unclear—stimulation of CB1 cannabinoid receptors by THC would be expected to increase consumption of calorically rich foods and increase fat deposition, thus it is likely that THC may target other receptor(s) involved in metabolism and whose engagement by THC leads to more beneficial metabolic effects. The proposed work will address the hypothesis that activation of GPR119 beneficial metabolic consequences. GPR119 is a G protein-coupled receptor expressed in pancreatic beta cells as well as K and L enteroendocrine cells in the gastrointestinal tract. Its activation increases insulin secretion from the pancreas, secretion of the incretins GIP and GLP-1, as well as PYY, from the gut, and may protect beta cells from apoptosis. Cumulatively, GPR119 activation is expected to lead to a favorable metabolic profile, which has made GPR119 activation a target for drug development. In preliminary studies investigating GPR119 signaling, we made the surprising observation that THC is a GPR119 agonist. Further studies found that chronic administration of THC or a GPR119 agonist decreased weight in obese mice to the same extent. In the proposed R21 CEBRA we will complete two specific aims to better understand the consequences of THC signaling through GPR119. Aim 1. Fully characterize the signaling of THC and other cannabinoids at GPR119 using cell lines natively expressing GPR119. Aim 2. Determine if THC-induced weight loss in obese mice requires GPR119. Completion of these two specific aims will greatly advance our understanding of the potential role of GPR119 in mediating the apparent metabolic benefits of THC.

大麻的使用在美国人口中很普遍，并且由于持续的影响，其流行率可能会增加 因此，对长期大麻的理解（有益和有害）的影响。 使用大麻势在必行，而使用大麻会造成严重的长期认知和精神后遗症。 调查显示，很少有研究调查长期使用大麻对代谢的影响。 大麻的可能目标，因为大麻中富含多种化合物（例如 delta-9- 四氢大麻酚（THC）直接影响进食行为和/或新陈代谢。 流行的观点认为，大麻的摄入会增加热量密集食物的消耗，这可能会导致 慢性大麻使用者中肥胖、代谢综合征和二型糖尿病的增加，大多数 流行病学研究发现相反的情况，因此，长期使用大麻与减少有关。 体重指数、代谢综合征发生率降低以及罹患 II 型疾病的风险降低 其机制尚不清楚——THC 会刺激 CB1 大麻素受体。 预计会增加高热量食物的消耗并增加脂肪沉积，因此 THC 很可能 可能会针对参与新陈代谢的其他受体，并且 THC 的参与会带来更有益的效果 拟议的工作将解决 GPR119 激活有益的假设。 GPR119 是一种 G 蛋白偶联受体，也在胰腺 β 细胞中表达。 作为胃肠道中的 K 和 L 肠内分泌细胞，它的激活会增加胰岛素的分泌。 胰腺，从肠道分泌肠促胰岛素 GIP 和 GLP-1 以及 PYY，并可能保护 β 细胞 累积地，GPR119 激活预计会产生有利的代谢特征，从而产生良好的代谢特征。 在调查 GPR119 的初步研究中，已将 GPR119 激活作为药物开发的目标。 进一步的研究发现，THC 是一种 GPR119 激动剂。 长期服用 THC 或 GPR119 激动剂可以同样程度地减轻肥胖小鼠的体重。 拟议的 R21 CEBRA 我们将完成两个具体目标，以更好地了解 THC 的后果 通过 GPR119 发送信号。 目标 1. 使用天然细胞系全面表征 GPR119 上 THC 和其他大麻素的信号传导 表达GPR119。 目标 2. 确定 THC 诱导的肥胖小鼠体重减轻是否需要 GPR119。 这两个具体目标的完成将极大地增进我们对GPR119潜在作用的理解 调节 THC 的明显代谢益处。