The Role of Estrogen-Related Receptors in Energy Homeostasis

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。肥胖是由于摄入的热量超过了消耗的热量。因此，阐明调节能量消耗的机制可能会导致治疗肥胖和相关疾病的新颖和安全的方法。雌激素相关受体家族(ERR？,呃?和ERR?)调节能量稳态途径。值得注意的是，缺乏ERR？可能导致新的和安全的方法来治疗肥胖和相关疾病。精瘦，对饮食引起的肥胖有抵抗力。作为核受体家族的成员，ERRs具有容纳合成配体的口袋，因此可以靶向治疗。为了支持这一观点，抑制ERR的配体？据报道可以减少老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，不同ERR在脂肪组织中的具体作用还远未被理解，并且表现出惊人的多样性。,呃?和犯错?类似地激活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。在建议的工作中，我们将阐明ERR的具体功能和相关贡献。,呃?和犯错?以及新型ERR协同调节剂Gadd45？能量稳态。我们将使用转基因小鼠和来源于这些小鼠的原代培养来阐明不同ERR异构体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ERR共同调控因子Gadd45？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

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.