Suppression of ERalpha in Hematopoietic Stem Cell-Derived Adipocytes Increases Adiposity via Kynurenine and the Aryl Hydrocarbon Receptor

更年期转变是女性不可避免的与衰老有关的现象，伴随着 腹部肥胖和与脂肪相关的并发症的伴随发生率增加，但 潜在的机制仍不确定。科罗拉多大学专业研究中心项目3 性别差异方面的卓越表现(分数)是基于这样一个前提，即细胞组成的变化 脂肪组织是导致体内脂肪分布转移和代谢健康恶化的原因 更年期。我们之前在小鼠的主要白色脂肪库中发现了一种新的脂肪细胞谱系 而人类是从造血干细胞而不是传统的间充质前体细胞产生的。在……里面 在小鼠中，这些造血干细胞来源的脂肪细胞(HSCDA)在 腹部脂肪堆积，表明在影响新陈代谢健康方面起着关键作用。此外，雌激素受体 α(Era)基因敲除或卵巢切除显著增加了HSCDA的产生。 最近，两个实验室提出了饮食诱导的肥胖需要相互作用的证据。 在代谢中间体犬尿氨酸(Kyn)和芳香烃受体(AhR)之间。初步 Klemm实验室的数据显示，催化犬尿氨酸产生的酶，吲哚胺 脂肪组织中的双加氧酶1(IDO1)和AhR在HSCDA中的表达水平显著高于HSCDA 而不是其他脂肪细胞群体。因此，我们假设雌激素信号的丢失是通过 ER⍺促进HSCDA的生产及其随后的Kyn(通过IDO1)和AhR的生产， 这会增加体重，增加肥胖，以及相关的代谢功能障碍。三个具体目标 将解决这一假设：目标1：测试HSCDA靶向删除IDO1或AhR是否会抑制 体重、肥胖和其他与脂肪组织相关的终点增加，原因是Era基因被敲除 脂肪细胞(与项目2合作)；目标2：测试靶向消融HSCDA是否降低Kyn，IDO1 和AhR，并防止Era基因敲除引起的体重、肥胖和其他参数的变化 (与项目2合作)；和目标3：测试绝经前雌激素生成是否受到抑制 女性刺激HSDCA的产生及其IDO1和AhR的产生，并被雌激素阻止 替换(与项目1协作)。这些目标的成功实现将证明HSCDA 是受ERA信号影响的体重和肥胖调节的主要中间体。 此外，这些研究将证明靶向犬尿氨酸代谢在 性腺老化的背景。由于HSCDA是由造血祖细胞而不是间充质祖细胞产生的 细胞，它们不仅提供了调节全身新陈代谢的机会，而且还提供了调节脂肪细胞代谢的机会 与性激素产生变化相关的表型。

The menopausal transition, an unavoidable aging-related phenomenon in women, is accompanied by increased abdominal adiposity and the concomitant incidence of adipose-related comorbidities, but the underlying mechanisms remain uncertain. Project 3 of the University of Colorado Specialized Center of Research Excellence on Sex Differences (SCORE) is based on the premise that alterations in the cellular composition of adipose tissue are responsible for the shift in body fat distribution and worsening metabolic health observed after menopause. We previously discovered a novel lineage of adipocytes in the major white adipose depots of mice and humans generated from hematopoietic stem cells rather than conventional mesenchymal precursors. In mice, these hematopoietic stem cell-derived adipocytes (HSCDAs) were detected in greater numbers in abdominal fat depots, suggesting a critical role in influencing metabolic health. Furthermore, estrogen receptor alpha (ERa) knockdown or ovariectomy significantly increased HSCDA production. Recently, two laboratories have presented evidence that diet-induced obesity requires the interaction between the metabolic intermediate, kynurenine (Kyn) and the aryl hydrocarbon receptor (AhR). Preliminary data from the Klemm laboratory shows that the enzyme that catalyzes kynurenine production, indoleamine dioxygenase 1 (IDO1) in adipose tissue, and the AhR are expressed at significantly higher levels in HSCDAs than other adipocyte populations. Thus, we hypothesize that the loss of estrogen signaling via ER⍺ promotes the production of HSCDAs and their subsequent production of Kyn (via IDO1) and AhR, which promotes weight gain, increased adiposity, and related metabolic dysfunction. Three specific aims will address this hypothesis: Aim 1: test whether HSCDA-targeted deletion of IDO1 or AhR will suppress increases in body weight, adiposity, and other adipose tissue-related endpoints due to knockdown of ERa in adipocytes (collaboration with Project 2); Aim 2: test whether targeted ablation of HSCDAs decreases Kyn, IDO1 and AhR and prevents changes in body weight, adiposity and other parameters induced by ERa knockdown (collaboration with Project 2); and Aim 3: test whether suppression of estrogen production in premenopausal women stimulates HSDCA production and their production of IDO1 and AhR, and is prevented by estrogen replacement (collaboration with Project 1). Successful completion of these aims will demonstrate that HSCDAs are a primary intermediate in the regulation of body weight and adiposity influenced by ERa signaling. Additionally, these studies will demonstrate the potential benefits of targeting kynurenine metabolism in the context of gonadal aging. Since HSCDAs are produced from hematopoietic rather than mesenchymal progenitor cells, they offer the opportunity to modulate not only body-wide metabolism, but also adipocyte metabolic phenotypes associated with changes in sex hormone production.