Does GPR119 mediate the beneficial metabolic effects of THC?

大麻的使用在美国人口中很普遍，而且由于目前的情况，大麻的流行率可能会增加 合法化努力。因此，了解长期大麻的影响(有益的和有害的) 使用势在必行。虽然长期使用大麻的认知和精神后遗症一直很强烈 在调查中，很少有研究调查长期使用大麻对新陈代谢的影响。新陈代谢是一个 可能成为大麻的目标，因为有几种化合物富含大麻(例如，Delta-9- 四氢大麻酚(THC)直接影响摄食行为和/或新陈代谢。有趣的是，尽管 流行的观点认为，吸食大麻会增加高热量食物的摄入量，这可能会导致 长期吸食大麻者中肥胖、代谢综合征和II型糖尿病增加，大多数 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有关。 体重指数，代谢综合征发生率降低，II型发病风险降低 糖尿病。其机制尚不清楚--THC对CB1大麻素受体的刺激可能是 预计会增加高热量食物的消费并增加脂肪沉积，因此THC很可能 可能以其他参与代谢的受体(S)为靶点，其参与THC的作用会带来更多好处 新陈代谢影响。拟议的工作将解决以下假设：激活GPR119有益 新陈代谢后果。GPR119是一种G蛋白偶联受体，也在胰岛β细胞中表达 如K和L等人的胃肠道内分泌细胞。它的激活增加了胰岛素的分泌 胰腺，肠道分泌的胰岛素GIP和GLP-1，以及PYY，可能保护β细胞 来自于细胞凋亡。总体而言，GPR119的激活有望导致有利的代谢谱，这 使GPR119激活成为药物开发的目标。在研究GPR119的初步研究中 作为信号，我们令人惊讶地观察到THC是一种GPR119激动剂。进一步的研究发现， 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。在……里面 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。 目的1.利用天然细胞系充分研究THC和其他大麻素在GPR119上的信号转导 表达GPR119。 目的2.确定THC诱导的肥胖小鼠的体重减轻是否需要GPR119。 这两个具体目标的完成将极大地促进我们对GPR119潜在作用的理解 在调节THC的明显代谢益处方面。

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.