The Role of Estrogen-Related Receptors in Energy Homeostasis

描述（由申请人提供）：肥胖是多种疾病的主要促成因素，包括2型糖尿病、血脂异常和心血管疾病。肥胖症是由于热量摄入超过能量消耗而引起的。因此，阐明调节能量消耗的机制可能导致治疗肥胖和相关疾病的新的和安全的方法。雌激素相关受体家族（ERR？，错误？（错误？）调节能量稳态途径。值得注意的是，缺乏ERR的小鼠？可能为治疗肥胖症和相关疾病带来新的安全方法。都很瘦而且能抵抗饮食引起的肥胖。作为核受体家族的成员，ERR具有容纳合成配体的口袋，因此可以在治疗上靶向。为了支持这一观点，抑制ERR的配体？据报道可减少小鼠的肥胖并增加胰岛素敏感性。然而，损失或抑制ERR的机制？预防肥胖的结果尚不清楚。此外，脂肪组织中不同ERRs的具体作用远未被理解，并且似乎令人惊讶地多样化，错误？而ER？类似地激活许多支持线粒体氧化能力的基因，但在其他方面起拮抗作用。在拟议的工作中，我们将阐明ERR的具体功能和相对贡献，嗯？而ER？和新的ERR共调节子Gadd45？能量平衡我们将使用转基因小鼠和来自这样的小鼠的原代培养物来阐明不同ERR亚型在体内原代脂肪细胞和脂肪组织中的共同和独特作用。我们还将测试在何种程度上的ERR共调节Gadd45？调节褐色脂肪组织的适应性反应。我们希望我们的研究能够阐明ERRs如何影响全身能量平衡，并确定它们作为小分子靶点的潜力，从而使肥胖和肥胖患者受益。 相关疾病。

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.