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，由于持续的药物滥用，其流行率可能会增加。 合法化的努力。因此，了解长期大麻的影响（有益和有害） 使用是必要的。虽然大麻使用的长期认知和精神后遗症一直受到强烈关注， 尽管对长期使用大麻的代谢影响进行了调查，但很少有研究调查长期使用大麻的代谢影响。新陈代谢是一种 可能是大麻的目标，因为大麻中丰富的几种化合物（例如，δ-9- 四氢大麻酚，THC）直接影响进食行为和/或代谢。有趣的是，尽管 流行的观点认为，吸食大麻会增加热量密集的食物的消费，这可能会导致 慢性大麻使用者中肥胖、代谢综合征和II型糖尿病的增加， 流行病学研究发现了相反的情况。因此，长期使用大麻与减少 体重指数，降低代谢综合征的发病率，降低II型糖尿病的风险 糖尿病其机制尚不清楚-THC对CB 1大麻素受体的刺激可能是 预计会增加热量丰富的食物的消费，增加脂肪沉积，因此THC很可能 可能靶向参与代谢的其他受体，并且其与THC的结合导致更有益的 代谢效应拟议的工作将解决这一假设，激活GPR 119有利于 代谢的后果。GPR 119也是在胰腺β细胞中表达的G蛋白偶联受体 如胃肠道中的K和L肠内分泌细胞。它的激活增加了胰岛素分泌， 胰腺，肠促胰岛素GIP和GLP-1以及PYY从肠道分泌，并可保护β细胞 从细胞凋亡。累积而言，预期GPR 119活化会导致有利的代谢特征， 使GPR 119活化成为药物开发的目标。在研究GPR 119的初步研究中， 在信号传导中，我们做出了令人惊讶的观察，即THC是GPR 119激动剂。进一步的研究发现， THC或GPR 119激动剂的长期给药以相同的程度降低了肥胖小鼠的体重。在 在拟议的R21 CEBRA中，我们将完成两个具体目标，以更好地了解THC的后果 通过GPR 119进行信号传导。 目标1。使用天然细胞系充分表征THC和其他大麻素在GPR 119处的信号传导 表达GPR 119。 目标2.确定THC诱导的肥胖小鼠体重减轻是否需要GPR 119。 这两个具体目标的完成将极大地推进我们对GPR 119潜在作用的理解 在介导THC的明显代谢益处方面。