The impact of ERalpha on mitochondrial function in macrophages

雌激素受体（ER）β表达的减少与代谢功能障碍有关， 妇女和男子的患病风险增加。然而，代谢功能障碍背景下ERα水平降低的因果机制以及赋予ERα介导的代谢、炎症和胰岛素作用效应的特定组织仍未充分确定。我们已经证明，代谢综合征的各个方面，包括胰岛素抵抗、组织炎症和肥胖，在全身Esr 1-/-小鼠（Esr 1编码ERα）中重现。我们随后进行了组织解剖方法，以了解ERα作用对炎症和代谢稳态的细胞特异性影响。由于巨噬细胞（MΦ）是调节组织代谢的关键细胞类型，并且参与心脏代谢相关疾病的病理生物学，因此本文建议探究ERα调节MΦ功能的机制，特别关注M Φ线粒体代谢和mtDNA复制。在目标1中，我们将使用Esr 1（ERαMyeTg）表达缺失（MACER）和获得（ERαMyeTg）方法选择性调节雄性和雌性小鼠骨髓谱系中的ERα。我们将研究 ERα表达对高脂饮食喂养引起的代谢稳态的影响，并确定全身Esr 1-/-小鼠模型骨髓细胞中ERα的恢复是否可以逆转肥胖和胰岛素抵抗表型。由于我们是第一个确定ER α调节肌细胞和脂肪细胞中线粒体动力学和mtDNA复制的人，并且线粒体被视为调节免疫代谢的中心信号枢纽，因此在目的2中，我们将探讨ERα在控制裂变/融合/线粒体自噬动力学和聚合酶γ Polg 1（催化亚基）的mtDNA复制中的作用。由于我们的研究显示不同细胞类型中ERα缺失的分子结果存在差异，因此本提案的主要目标是更好地了解ERα在控制线粒体功能（特别是在MΦ中）中的作用，以及确定受损的ERα作用如何驱动炎症和代谢功能障碍与心脏代谢疾病易感性相关，特别是在绝经过渡期的女性中。

Reductions in estrogen receptor (ER) expression are associated with metabolic dysfunction and heightened disease risk in women and men. However, the causal mechanisms underlying reduced ERα levels in the context of metabolic dysfunction and the specific tissue(s) conferring ERα-mediated effects on metabolism, inflammation, and insulin action remain inadequately defined. We have shown that aspects of the metabolic syndrome including insulin resistance, tissue inflammation, and obesity are recapitulated in whole body Esr1-/- mice (Esr1 encodes ERα). We have subsequently performed a tissue dissection approach to understand the cell-specific impact of ERα action on inflammation and metabolic homeostasis. Because macrophages (MΦ) are a key cell type regulating tissue metabolism, and are involved in the pathobiology of cardiometabolic-related diseases, herein we propose to interrogate the mechanisms by which ERα modulates MΦ function with a specific focus on M mitochondrial metabolism and mtDNA replication. In Aim 1 we will use loss- (MACER) and gain-of-Esr1 (ERαMyeTg) expression approaches to selectively modulate ERα in the myeloid lineage of male and female mice. We will examine the impact of ERα expression on metabolic homeostasis in response to high fat diet feeding and determine whether restoration of ERα in myeloid cells of the whole body Esr1-/- mouse model can reverse the obesity and insulin resistance phenotype. Since we were the first to identify that ER regulates mitochondrial dynamics and mtDNA replication in myocytes and adipocytes, and since mitochondria are viewed as central signaling hubs regulating immunometabolism, in Aim 2 we will interrogate the role of ERα in controlling fission/fusion/mitophagy dynamics and mtDNA replication by polymerase γ, Polg1 (catalytic subunit). Since our research shows contrasting molecular outcomes to ERα deletion in different cell types, a primary goal of this proposal is to better understand the role of ERα in controlling mitochondrial function specifically in MΦ, as well as determine how impaired ERα action drives inflammation and metabolic dysfunction with relevance to cardiometabolic disease susceptibility, especially in women during the menopausal transition.