The Impact of Oleoylethanolamide on Glucagon-like Peptide-1 Receptor-Mediated Insulin Secretion and Anorectic Potential

项目摘要 肥胖症是一种流行病，网关疾病，显着增加患2型糖尿病的风险 （T2D）。本申请集中于描述油酰乙醇胺（OEA）作为免疫调节剂的增强剂的功能。 胰高血糖素样肽-1受体激动剂（Glp 1 RA）的促胰岛素和厌食作用。Glp 1 RA代表 一种新型T2 D药物，可改善胰岛素敏感性并促进减肥。因此，治疗 调节特异性Glp 1 RA信号传导事件的策略可以提供治疗T2 D的新方法， 肥胖OEA是一种内源性大麻素样脂质，最近显示与Glp 1结合并增加Glp 1- 介导的cAMP产生。我们比较了OEA对信号传导机制的影响， 胰岛素分泌和食物摄入抑制（cAMP产生、β-arrestin募集、细胞葡萄糖 在三种Glp 1 RA（Glp 1、Exendin-4 [Ex 4]和Liralgutide [里拉]）存在下，我们发现 OEA以Glp 1 RA特异性方式调节Glp 1 RA信号传导事件。首先，OEA增强Glp 1- 介导的cAMP产生和β-抑制蛋白募集。第二，OEA增强Glp 1和Ex 4介导的 糖酵解和线粒体呼吸。重要的是，我们证明了外周给药前- 与单独的Ex 4或OEA相比，混合的Ex 4-OEA更有效地抑制食欲。基于这些发现，我们 将使用体外和体内方法来确定Glp 1 RA-OEA相互作用对信号传导事件的影响 与增强的胰岛素分泌和抑制食物摄入有关， 端点本身。我们假设OEA与Glp 1 RA结合并调节Glp 1 R信号传导事件， 增强细胞葡萄糖代谢，导致胰岛素分泌增加， 与单独的Glp 1 RA或OEA相比的食物摄入量。目标1将侧重于确定相互作用动力学 Glp 1 RA和OEA之间的关系。目的2将鉴定与Glp 1 RA-OEA相关的分子特征 特别强调与胰岛素分泌和饱腹感相关的机制的组合（例如， 细胞葡萄糖代谢）。目的3将阐明Glp 1 RA-OEA给药对胰岛素的影响 分泌和食物摄入。从长远来看，我们寻求利用这些信息来识别 更有效的糖尿病和减肥疗法。

PROJECT SUMMARY Obesity is a pandemic, gateway disease that significantly increases the risk of developing type 2 diabetes (T2D). This application focuses on delineating the function of oleoylethanolamide (OEA) as an enhancer of the insulinotropic and anorectic effects of glucagon-like peptide-1 receptor agonists (Glp1RA). Glp1RA represent a new class of T2D drugs that improve insulin sensitivity and promote weight loss. Therefore, therapeutic strategies that modulate specific Glp1RA signaling events may provide a novel approach for treating T2D and obesity. OEA is an endocannabinoid-like lipid that was recently shown to bind to Glp1 and augment Glp1- mediated cAMP production. We compared the effects of OEA on signaling mechanisms associated with insulin secretion and suppression of food intake (cAMP production, -arrestin recruitment, cellular glucose metabolism) in the presence of three Glp1RA (Glp1, Exendin-4 [Ex4], and Liralgutide [Lira]). We discovered that OEA modulates Glp1RA signaling events in a Glp1RA-specific manner. First, OEA enhances Glp1- mediated cAMP production and β-arrestin recruitment. Second, OEA enhances Glp1- and Ex4-mediated glycolysis and mitochondrial respiration. Importantly, we demonstrate that peripheral administration of pre- mixed Ex4-OEA is more potently anorectic compared to either Ex4 or OEA alone. Based on these findings, we will use in vitro and in vivo approaches to define the impact of Glp1RA-OEA interactions on signaling events associated with enhanced insulin secretion and suppression of food intake and on these physiological endpoints themselves. We hypothesize that OEA binds to Glp1RA and modulates Glp1R signaling events that enhance cellular glucose metabolism, resulting in increased insulin secretion and more potent reductions in food intake compared to Glp1RA or OEA alone. Aim 1 will focus on determining the interaction dynamics between Glp1RA and OEA. Aim 2 will identify molecular signatures associated with Glp1RA-OEA combinations with a particular emphasis on mechanisms associated with insulin secretion and satiety (e.g., cellular glucose metabolism). Aim 3 will elucidate the impact of Glp1RA-OEA administration on insulin secretion and food intake. In the long-term, we seek to leverage this information towards the identification of more effective diabetes and weight loss therapies.