Molecular mechanisms mediating metabolic benefits of glucagon-like peptide-1 receptor agonists

介导胰高血糖素样肽 1 受体激动剂代谢益处的分子机制

• 批准号: 10583838
• 负责人: Julio E Ayala
• 金额: $ 55.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583838
• 关键词: Adipocytes; Adrenergic Receptor; Affect; Agonist; Appetite Depressants; Assessment tool; Binding; Blood Glucose; Body Weight; Body Weight decreased; Brain; Cell physiology; Cells; Chinese Hamster Ovary Cell; Closure by clamp; Complex; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Dose; Drug Side Effects; Effectiveness; Energy Intake; Event; FRAP1 gene; Future; GLP-I receptor; Glucose; Glycolysis; Homeostasis; Human; Hyperglycemia; Hypothalamic structure; Hypoxia Inducible Factor; Impairment; Individual; Knock-in Mouse; Knowledge; Measures; Mediating; Metabolic; Molecular; Molecular Target; Morphology; Mus; Mutation; Neurons; Nutrient; Obesity; Outcome; Pancreas; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological; Physiology; Predisposition; Pro-Opiomelanocortin; Proteins; Publishing; Receptor Activation; Receptor Signaling; Regulation; Resistance; Role; Signal Transduction; Test Result; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Variant; Weight; cardiometabolism; cell type; clinical effect; clinically relevant; design; detection of nutrient; drug action; energy balance; genetic regulatory protein; glucagon-like peptide 1; glucose tolerance; hypoxia inducible factor 1; improved; in vivo; insulin secretion; islet; liraglutide; metabolic phenotype; mouse model; mutant; novel; personalized medicine; protein activation; receptor; reduced food intake; response; sensor; temporal measurement; transcription factor

PROJECT SUMMARY Although the ability of glucagon-like peptide-1 receptor (Glp1r) agonists to stimulate insulin secretion and reduce caloric intake has been recognized for over two decades, surprisingly little is known about the molecular mechanisms behind these effects. We have previously shown that activation of the hypothalamic Glp1r reduces food intake by engaging key nutrient sensing mechanisms such as mechanistic Target of Rapamycin Complex-1 (mTORC1). Since mTORC1 is also an important regulatory component of -cell function, this suggests that elucidating how Glp1r agonists regulate mTORC1 and its downstream targets will address a key knowledge gap about the mechanism of action of an important class of diabetes and obesity drugs. We have identified a novel interaction stimulated by the clinically relevant Glp1r agonist liraglutide (Lira) whereby the canonical target of Glp1r signaling, cAMP-dependent protein kinase A (PKA), phosphorylates the mTORC1 regulatory protein Raptor resulting in increased mTORC1 signaling. We have also identified the transcription factor Hypoxia- Inducible Factor (HIF) as a target of Glp1r signaling. This is relevant since HIF stimulates glycolysis, a mechanism necessary for the anorectic and insulinotropic effects of Glp1r agonists, and increased HIF expression in the hypothalamus and -cells reduces food intake and stimulates insulin secretion, respectively. We also provide preliminary data showing that Lira no longer reduces body weight or glucose levels in novel knockin mice replacing endogenous Raptor with a PKA-resistant Raptor. Our preliminary data, therefore, lead us to hypothesize that a Glp1r-PKA-mTORC1-HIF-glycolysis axis in the hypothalamus and -cells mediates the ability of Lira to reduce body weight (Aim 1) and stimulate insulin secretion (Aim 2), respectively. The clinical relevance of this is further emphasized by our preliminary data showing that two variants of the Glp1r found in humans that are associated with improved cardiometabolic outcomes and improved responsiveness to Lira also stimulate mTORC1 signaling to a greater degree than wild-type Glp1r. We will, therefore, use mice expressing these human Glp1r variants to test the hypothesis that Lira promotes greater weight loss and improved glucose tolerance in these mice via enhanced mTORC1 signaling (Aim 3). We will complete these Aims by leveraging our extensive expertise in assessing metabolic phenotypes in mice, including real-time measurements of energy balance parameters as well as pancreatic function in isolated islets and in vivo using hyperglycemic clamps. We will apply these approaches to a suite of novel mouse models that allow us to modulate or measure the expression and activity of target proteins in specific cell types. Accomplishing these Aims will delineate specific molecular mechanisms that can be leveraged towards either the improvement of the effectiveness of Lira or the design of more efficient weight-lowering drugs.

项目摘要 虽然胰高血糖素样肽-1受体（GLP1R）激动剂刺激胰岛素分泌的能力 并且减少热量摄入量已被认可了二十年，令人惊讶的是知之甚少 这些作用背后的分子机制。我们以前已经表明激活 下丘脑GLP1R通过参与关键营养感应机制（例如 雷帕霉素复合物1（MTORC1）的机械靶标。由于mtorc1也是一个重要的 细胞函数的调节成分，这表明阐明GLP1R激动剂如何调节 MTORC1及其下游目标将解决有关行动机制的关键知识差距 一类重要的糖尿病和肥胖药物。我们已经确定了一种刺激的新型相互作用 通过临床相关的GLP1R激动剂Liraglutide（Lira），GLP1R信号的规范目标， cAMP依赖性蛋白激酶A（PKA），磷酸化MTORC1调节蛋白猛禽 导致MTORC1信号的增加。我们还确定了转录因子缺氧 - 诱导因子（HIF）作为GLP1R信号的目标。这很重要，因为HIF刺激糖酵解，一个 GLP1R激动剂的厌食和胰岛素效应所需的机制，并增加了HIF 在下丘脑和细胞中的表达可减少食物摄入并刺激胰岛素分泌， 分别。我们还提供了初步数据，表明里拉不再降低体重或 新型敲蛋白小鼠中的葡萄糖水平用抗PKA猛禽代替内源性猛禽。我们的 因此，初步数据导致我们假设GLP1R-PKA-PKA-MTORC1-HIF-糖酵解轴 下丘脑和细胞介导了里拉降低体重的能力（AIM 1）并刺激 胰岛素分泌（AIM 2）。我们的临床相关性进一步强调了 初步数据表明，在人类中发现的两个变体与 改善了心脏代谢结果和提高对里拉的响应能力也刺激了MTORC1 比野生型GLP1R更高的信号传导。因此，我们将使用表达这些人的小鼠 GLP1R变体以检验LIRA促进更大的体重减轻并改善葡萄糖的假设 通过增强的MTORC1信号传导在这些小鼠中的耐受性（AIM 3）。我们将通过 利用我们广泛的专业知识来评估小鼠的代谢表型，包括实时 孤立胰岛中能量平衡参数以及胰腺功能的测量 使用高血糖夹的体内。我们将把这些方法应用于一套新型鼠标模型 这使我们能够调节或测量特定细胞类型中靶蛋白的表达和活性。 实现这些目标将描述可以利用的特定分子机制 LIRA的有效性或更有效的减肥药物的设计提高。