Role of GPER in Obesity and Lipid Metabolism.

GPER 在肥胖和脂质代谢中的作用。

基本信息

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
项目类别：
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

项目摘要

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与罹患肥胖症的风险有关。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，具有对抗肥胖多种负面影响的良好效果，并有机会使用。 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的长期目标是确定 GPER 的选择性激活剂（例如 G-1）是否具有选择性。可以改善脂肪细胞的脂质稳态、氧化应激和炎症。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。这些发现将影响脂肪细胞的稳态、氧化应激、炎症和线粒体功能。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该提案的具体目标是：目标 1：评估 GPER 在脂质中的作用。该目标的工作假设是 GPER 对肥胖的部分影响。通过对脂肪细胞脂质代谢的直接作用介导。目标 2：确定 GPER 在脂肪细胞中的作用。脂肪细胞中的氧化应激、炎症和线粒体功能。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。