The Role of Estrogen-Related Receptors in Energy Homeostasis

雌激素相关受体在能量稳态中的作用

• 批准号: 8534114
• 负责人: Anastasia Kralli
• 金额: $ 44.35万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-20 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534114
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Affect; Biogenesis; Brown Fat; Cardiovascular Diseases; Cells; Data; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Energy Intake; Energy Metabolism; Environment; Exposure to; Family; Future; Gene Expression; Genes; Goals; Grant; Homeostasis; Immune system; Lead; Ligands; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Orphan Receptor; Nuclear Receptors; Nutrient; Obesity; Obesity associated disease; Pathway interactions; Patients; Physical activity; Physiological; Post-Translational Protein Processing; Protein Isoforms; Proteins; Publishing; Relative (related person); Reporting; Research; Resistance; Role; Signal Transduction; Temperature; Testing; Therapeutic Intervention; Time; Transcriptional Regulation; Work; adrenergic; base; cell type; energy balance; estrogen-related receptor; feeding; genome-wide; in vivo; insight; insulin sensitivity; meetings; member; novel; programs; receptor; response; small molecule; stressor

DESCRIPTION (provided by applicant): Obesity is a major contributing factor to several diseases, including type 2 diabetes, dyslipidemias and cardiovascular disease. Obesity is caused by an excess of caloric intake compared to energy expenditure. Thus, elucidation of the mechanisms that regulate energy expenditure may lead to novel and safe approaches for treating obesity and associated diseases. The family of estrogen-related receptors (ERR?, ERR? and ERR?) regulates energy homeostasis pathways. Notably, mice lacking ERR? may lead to novel and safe approaches for treating obesity and associated diseases. are lean and resistant to diet-induced obesity. As members of the nuclear receptor family, ERRs have pockets that accommodate synthetic ligands and can thus be targeted therapeutically. In support of this notion, a ligand that inhibits ERR? has been reported to decrease adiposity and increase insulin sensitivity in mice. However, the mechanisms by which loss or inhibition of ERR? results into protection from obesity are not known. Moreover, the specific roles of the different ERRs in adipose tissue are far from understood and appear surprisingly diverse, with ERR?, ERR? and ERR? activating similarly many genes that support mitochondrial oxidative capacity, but working antagonistically at others. In the proposed work, we will elucidate the specific functions and relative contributions of ERR?, ERR? and ERR?, and of the novel ERR coregulator Gadd45? to energy homeostasis. We will use genetically modified mice and primary cultures derived from such mice to elucidate shared and unique roles of the different ERR isoforms in primary adipocytes and in adipose tissues in vivo. We will also test the extent to which the ERR coregulator Gadd45? regulates adaptive responses in brown adipose tissue. We expect our studies to elucidate how ERRs affect whole body energy balance, and establish their potential as targets for small molecules that could benefit patients with obesity and obesity related diseases.

描述（由申请人提供）：肥胖是导致多种疾病的主要因素，包括2型糖尿病、血脂异常和心血管疾病。肥胖是由于热量摄入超过能量消耗造成的。因此，阐明调节能量消耗的机制可能会带来治疗肥胖及相关疾病的新颖且安全的方法。雌激素相关受体家族（ERR？、ERR？和ERR？）调节能量稳态途径。值得注意的是，小鼠缺乏 ERR？可能会带来治疗肥胖及相关疾病的新颖且安全的方法。身材苗条，对饮食引起的肥胖具有抵抗力。作为核受体家族的成员，ERR 具有容纳合成配体的口袋，因此可以作为治疗目标。为了支持这一观点，抑制 ERR 的配体？据报道可以减少小鼠的肥胖并增加胰岛素敏感性。然而，ERR 丢失或抑制的机制是什么？预防肥胖的结果尚不清楚。此外，脂肪组织中不同 ERR 的具体作用尚不清楚，而且表现出令人惊讶的多样性，如 ERR？、ERR？和错误？激活类似的许多支持线粒体氧化能力的基因，但对其他基因起拮抗作用。在拟议的工作中，我们将阐明 ERR?、ERR? 的具体功能和相对贡献。和 ERR？，以及新型 ERR 核心调节器 Gadd45？达到能量稳态。我们将使用转基因小鼠和源自此类小鼠的原代培养物来阐明不同 ERR 亚型在原代脂肪细胞和体内脂肪组织中的共同和独特作用。我们还将测试ERR核心调节器Gadd45的程度？调节棕色脂肪组织的适应性反应。我们希望我们的研究能够阐明 ERR 如何影响全身能量平衡，并确定它们作为小分子靶标的潜力，从而使肥胖和肥胖患者受益 相关疾病。