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

造血干细胞来源的脂肪细胞中 ERα 的抑制通过犬尿氨酸和芳基烃受体增加肥胖

• 批准号: 10712611
• 负责人: Dwight J Klemm
• 金额: $ 29.55万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712611
• 关键词: Ablation; Adipocytes; Adipose tissue; Adoptive Transfer; Aging; Amino Acids; Aryl Hydrocarbon Receptor; Bioenergetics; Blood Vessels; Body Weight; Body fat; Bone Marrow; Brain; Cells; Cellularity; Centers of Research Excellence; Collaborations; Colorado; Data; Dioxygenases; Disease; Electrons; Energy Metabolism; Enzymes; Estrogen Receptor alpha; Estrogen Replacements; Estrogens; Event; Fatty acid glycerol esters; Female; Funding; Genetic; Gonadal Steroid Hormones; HIV; Health; Hematopoietic; Hematopoietic Cell Production; Hematopoietic stem cells; High Fat Diet; Human; Incidence; Inflammation; Insulin Resistance; Knockout Mice; Kynurenic Acid; Kynurenine; Laboratories; Leptin; Liver; Menopause; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mus; Myelogenous; Names; Nicotinamide adenine dinucleotide; Obesity; Ovariectomy; Pathway interactions; Patients; Perimenopause; Phenotype; Physical activity; Physiological; Play; Population; Postmenopause; Premenopause; Production; Regulation; Relaxation; Rheumatism; Role; Sex Differences; Signal Transduction; Skeletal Muscle; Specialized Center; System; T-Lymphocyte; Testing; Tryptophan; Tryptophan 2,3 Dioxygenase; Universities; Visceral; Weight Gain; Woman; abdominal fat; cardiometabolism; comorbidity; diet-induced obesity; gonad function; immunoregulation; indoleamine; knock-down; lymphocyte proliferation; male; metabolic phenotype; novel; prevent; response; subcutaneous; systemic inflammatory response; western diet

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.

更年期过渡是女性不可避免的与衰老相关的现象，伴随着 腹部肥胖和脂肪相关合并症的发生率增加，但 科罗拉多大学专业研究中心的项目 3 的潜在机制仍不确定。 性别差异卓越奖 (SCORE) 的前提是，性别差异的细胞组成发生了变化 脂肪组织是造成身体脂肪分布变化和代谢健康退化的原因 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。 人类是由造血干细胞而不是传统的间充质前体细胞产生的。 小鼠中，这些造血干细胞衍生的脂肪细胞（HSCDA）在 腹部脂肪库，表明在影响代谢健康方面发挥着关键作用。 α (ERa) 敲低或卵巢切除术显着增加了 HSCDA 的产生。 最近，两个实验室提供的证据表明，饮食引起的肥胖需要相互作用 代谢中间体犬尿氨酸 (Kyn) 和芳基烃受体 (AhR) 之间。 来自 Klemm 实验室的数据表明，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)，而 AhR 在 HSCDA 中的表达水平显着较高 因此，我们认为雌激素信号的丧失是通过 ER⍺ 促进 HSCDA 的产生以及随后 Kyn（通过 IDO1）和 AhR 的产生， 它促进体重增加、肥胖增加和相关的代谢功能障碍。 将解决这个假设：目标 1：测试 IDO1 或 AhR 的 HSCDA 靶向删除是否会抑制 由于 ERa 的敲低，导致体重、肥胖和其他脂肪组织相关终点的增加 脂肪细胞（与项目 2 合作）；目标 2：测试 HSCDA 的靶向消融是否会降低 Kyn、IDO1 和 AhR，并防止 ERa 敲低引起的体重、肥胖和其他参数的变化 （与项目2合作）；目标3：测试绝经前雌激素的产生是否受到抑制 女性会刺激 HSDCA 的产生以及 IDO1 和 AhR 的产生，但会被雌激素阻止 替代（与项目 1 合作）。成功完成这些目标将证明 HSCDA 是受 ERa 信号影响的体重和肥胖调节的主要中间体。 此外，这些研究将证明针对犬尿氨酸代谢的潜在益处 由于 HSCDA 是由造血细胞而不是间充质祖细胞产生的。 细胞，它们不仅提供调节全身新陈代谢的机会，还调节脂肪细胞代谢 与性激素产生变化相关的表型。