Role of GPER in Obesity and Lipid Metabolism.

项目总结/摘要 肥胖在美国是一个严重和恶化的公共健康问题， 最常见的可预防死亡原因仅次于吸烟。肥胖与发展为 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，称为E2）可以改善体重增加和多个方面 代谢紊乱的症状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），主要介导快速的“非- 基因组”信号。我们的初步结果表明，一个潜在的干预采用高度选择性GPER 激动剂，具有对抗肥胖的多种负面影响的有希望的结果。有机会雇用 GPER选择性激动剂G-1作为一种新型的肥胖治疗药物，了解GPER在肥胖中的直接作用， 脂肪细胞至关重要。长期目标是确定GPER的选择性激活剂，如G-1， 可以改善脂肪细胞中的脂质稳态、氧化应激和炎症。本报告的总体目标 建议是了解E2通过GPER介导的代谢调节作用的机制， 特别是脂肪细胞。有待检验的中心假设是GPER信号是否直接改善脂质代谢。 体内平衡、氧化应激、炎症和脂肪细胞中的线粒体功能。这些发现将 通过在我们对GPER在以下方面的作用的认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 用于治疗肥胖症。本提案的具体目标是：目标1：评估GPER在脂质中的作用 脂肪细胞的代谢。这一目标的工作假设是，GPER对肥胖的影响部分是 通过对脂肪细胞的脂质代谢的直接作用介导。目标2：确定GPER在以下方面的作用 脂肪细胞中的氧化应激、炎症和线粒体功能。对此的工作假设是 目的是GPER对氧化应激、炎症起直接保护作用，并改善 脂肪细胞中的线粒体功能。 该提案将研究GPER在脂肪细胞中对脂质稳态的直接影响， 氧化应激，炎症和线粒体功能，有可能显着推进研究 新的治疗方法来预防肥胖。

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.