Role of GPER in Obesity and Lipid Metabolism.

GPER 在肥胖和脂质代谢中的作用。

• 批准号: 10680278
• 负责人: Randy Ko
• 金额: $ 4.43万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680278
• 关键词: Adipocytes; Adult; Agonist; Anti-Inflammatory Agents; Atherosclerosis; Biological Assay; Biological Models; Body Weight; CRISPR/Cas technology; Cardiovascular Diseases; Caring; Cell Line; Cell Survival; Cells; Chronic; Complex; Desire for food; Diabetes Mellitus; Disease; Disease Progression; Estradiol; Estrogen Nuclear Receptor; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exhibits; Fatty acid glycerol esters; Female; GPER gene; Gene Expression; Generations; Genes; Genus Hippocampus; Goals; Homeostasis; Hormones; Hydrogen Peroxide; Hyperlipidemia; Hypertension; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Intervention; Knock-out; Knockout Mice; Knowledge; Laboratories; Ligands; Lipase; Lipids; Lipolysis; Liver diseases; Mediating; Medical; Membrane; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Mus; National Health and Nutrition Examination Survey; Obese Mice; Obesity; Outcome; Overweight; Oxidative Stress; Pathway interactions; Physiological; Physiological Processes; Play; Public Health; Receptor Activation; Receptor Signaling; Regulation; Respiration; Risk; Role; Signal Transduction; Smoking; Stress Tests; Supplementation; Systems Development; TNF gene; Testing; Therapeutic; Time; Tissues; United States; Weight Gain; Western Blotting; Wild Type Mouse; adipokines; aged; antagonist; antioxidant enzyme; body system; comorbidity; cost; cytokine; drug development; improved; in vivo; inflammatory marker; inhibitor; lipid biosynthesis; lipid metabolism; male; non-genomic; novel therapeutics; obesity treatment; preventable death; protein expression; receptor expression; reproductive development; therapeutic development; treatment strategy

PROJECT SUMMARY/ABSTRACT Obesity poses as a serious and worsening public health issue in the United States and is the second most common cause of preventable death behind smoking. Obesity is associated with the risk of developing additional comorbidities, such as hypertension, atherosclerosis, and diabetes. Estrogens (primarily 17β-estradiol, referred to as E2) can ameliorate weight gain and multiple aspects of metabolic dysfunction. The effects of estrogens are mediated through multiple estrogen receptors (ERs), including the classical nuclear ERs (ERα and ERβ), which traditionally regulate gene expression, and the 7- transmembrane G protein-coupled estrogen receptor (GPER), which predominantly mediates rapid “non- genomic” signaling. Our preliminary results suggest a potential intervention employing a highly selective GPER agonist, with promising outcomes against multiple negative effects of obesity. With the opportunity to employ the GPER-selective agonist G-1 as a novel therapeutic for obesity, understanding the direct effects of GPER in adipocytes is critical. The long-term goal is to determine whether selective activators of GPER, such as G-1, can improve lipid homeostasis, oxidative stress, and inflammation in adipocytes. The overall objective of this proposal is to understand the mechanisms of E2-mediated effects via GPER in metabolic regulation, specifically in adipocytes. The central hypothesis to be tested is whether GPER signaling directly improves lipid homeostasis, oxidative stress, inflammation, and mitochondrial function in adipocytes. These findings will inform drug development by making significant advancements in our knowledge regarding the role of GPER in obesity and lipid metabolism, ultimately advancing the current insufficient therapeutic treatment options available for obesity. The specific aims of this proposal are: Aim 1: Evaluate the roles of GPER in lipid metabolism of adipocytes. The working hypothesis for this aim is that GPER’s effects on obesity are in part mediated by direct actions on lipid metabolism on adipocytes. Aim 2: Determine the role of GPER in oxidative stress, inflammation, and mitochondrial function in adipocytes. The working hypothesis for this aim is that GPER plays a direct protective role against oxidative stress, inflammation, and improves mitochondrial function in adipocytes. This proposal will investigate the direct effects of GPER in adipocytes pertaining to lipid homeostasis, oxidative stress, inflammation, and mitochondrial function, with the potential to significantly advance the study of novel therapeutics protecting against obesity.

项目概要/摘要 肥胖在美国已成为一个严重且日益恶化的公共卫生问题，是第二大公共卫生问题 吸烟之后最常见的可预防死亡原因。肥胖与罹患以下疾病的风险相关 其他合并症，如高血压、动脉粥样硬化和糖尿病。 雌激素（主要是17β-雌二醇，简称E2）可以改善体重增加等多个方面 代谢功能障碍。雌激素的作用是通过多种雌激素受体（ER）介导的， 包括传统上调节基因表达的经典核 ER（ERα 和 ERβ），以及 7- 跨膜 G 蛋白偶联雌激素受体 (GPER)，主要介导快速“非 基因组”信号。我们的初步结果表明，采用高度选择性的 GPER 进行潜在的干预 激动剂，对对抗肥胖的多种负面影响具有良好的效果。有了就业机会 GPER 选择性激动剂 G-1 作为一种新型肥胖疗法，了解 GPER 对肥胖的直接影响 脂肪细胞至关重要。长期目标是确定 GPER 的选择性激活剂（例如 G-1）是否 可以改善脂肪细胞的脂质稳态、氧化应激和炎症。本次活动的总体目标 建议是了解 E2 通过 GPER 在代谢调节中介导的作用机制， 特别是在脂肪细胞中。要测试的中心假设是 GPER 信号传导是否直接改善脂质 脂肪细胞中的稳态、氧化应激、炎症和线粒体功能。这些发现将 通过在我们关于 GPER 在药物中的作用方面的知识方面取得重大进展，为药物开发提供信息 肥胖和脂质代谢，最终推进目前不足的治疗选择 可用于肥胖症。该提案的具体目标是： 目标 1：评估 GPER 在脂质中的作用 脂肪细胞的代谢。该目标的工作假设是 GPER 对肥胖的影响部分是由于 通过对脂肪细胞脂质代谢的直接作用介导。目标 2：确定 GPER 在 脂肪细胞中的氧化应激、炎症和线粒体功能。对此的工作假设 目的是 GPER 对氧化应激、炎症发挥直接保护作用，并改善 脂肪细胞中的线粒体功能。 该提案将研究 GPER 对脂肪细胞中与脂质稳态有关的直接影响， 氧化应激、炎症和线粒体功能，有可能显着推进研究 预防肥胖的新疗法。