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

油酰乙醇酰胺对胰高血糖素样肽-1 受体介导的胰岛素分泌和厌食电位的影响

• 批准号: 9415800
• 负责人: Jacob Brown
• 金额: $ 0.09万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9415800
• 关键词: Address; Affect; Affinity; Agonist; Albumins; Appetite Depressants; Arrestins; Binding; Body Weight; Body Weight decreased; Cardiovascular Diseases; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Diabetes Mellitus; Dipeptidyl-Peptidase IV; Disease; Eating; Endocannabinoids; Enhancers; Event; Foundations; Future; GLP-I receptor; Glucose; Glycolysis; Goals; Half-Life; In Vitro; Insulin; Ligands; Lipids; MAP Kinase Gene; Mediating; Metabolic Pathway; Mitochondria; Modification; Molecular; Molecular Profiling; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathway interactions; Patients; Peptides; Peripheral; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Physiological; Play; Production; Property; Proteins; Proteomics; Receptor Signaling; Recruitment Activity; Respiration; Risk; Role; Satiation; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Weight; base; beta-arrestin; blood glucose regulation; diabetes mellitus therapy; drug development; exenatide; experience; glucagon-like peptide 1; glucose metabolism; improved; in vivo; insulin secretion; insulin sensitivity; liraglutide; mimetics; novel; novel strategies; oleoylethanolamide; oxidation; pandemic disease; receptor; therapeutic target; trend

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.

项目概要 肥胖是一种流行病，会显着增加患 2 型糖尿病的风险 （T2D）。该应用的重点是描述油酰乙醇酰胺 (OEA) 作为增强剂的功能 胰高血糖素样肽 1 受体激动剂 (Glp1RA) 的促胰岛素和减食欲作用。 Glp1RA代表 一类新型 T2D 药物，可提高胰岛素敏感性并促进减肥。因此，治疗 调节特定 Glp1RA 信号传导事件的策略可能为治疗 T2D 和 肥胖。 OEA 是一种内源性大麻素样脂质，最近被证明可以与 Glp1 结合并增强 Glp1- 介导的 cAMP 产生。我们比较了 OEA 对相关信号机制的影响 胰岛素分泌和食物摄入抑制（cAMP 产生、-抑制蛋白募集、细胞葡萄糖 代谢）在三种 Glp1RA（Glp1、Exendin-4 [Ex4] 和 Liralgutide [Lira]）存在的情况下。我们发现 OEA 以 Glp1RA 特异性方式调节 Glp1RA 信号传导事件。首先，OEA 增强 Glp1- 介导的 cAMP 产生和 β-抑制蛋白募集。其次，OEA 增强 Glp1 和 Ex4 介导的 糖酵解和线粒体呼吸。重要的是，我们证明了预外周给药 与单独的 Ex4 或 OEA 相比，混合的 Ex4-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 Glp1RA-OEA 相互作用对信号事件的影响 与增强胰岛素分泌和抑制食物摄入以及这些生理学有关 端点本身。我们假设 OEA 与 Glp1RA 结合并调节 Glp1R 信号传导事件 增强细胞葡萄糖代谢，导致胰岛素分泌增加和更有效地减少 与单独的 Glp1RA 或 OEA 相比，食物摄入量。目标 1 将侧重于确定交互动态 Glp1RA 和 OEA 之间。目标 2 将识别与 Glp1RA-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）。目标 3 将阐明 Glp1RA-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。