Sex Hormones Differentially Regulate Production of a Distinct Adipocyte Population

项目3：项目总结 更年期转变是女性不可避免的与衰老有关的现象，伴随着更年期的增加 腹型肥胖症与脂肪相关并发症的伴随发生率。尽管之前的研究 主要集中在身体脂肪的分布上，我们已经产生了证据表明 脂肪组织(AT)定义每个储存库的表型，确定其对新陈代谢的整体影响 健康。前提是性腺激素的丧失会改变AT的细胞性，从而导致身体的变化 脂肪分布和恶化的新陈代谢健康。我们之前发现了一种新的脂肪细胞谱系 小鼠和人的主要白色脂肪库来源于造血细胞的骨髓源细胞 血统而不是传统的间充质前体细胞。在小鼠中，骨髓源性脂肪细胞(BMDA) 在腹部脂肪库中检测到更多，并显示炎性细胞因子增加，但 降低瘦素和线粒体脂质氧化基因的表达，表明在影响 新陈代谢健康。此外，卵巢切除(OVX)显著增加了BMDA的产生，这是 通过雌二醇(E2)替代而减弱。除了雌激素水平下降外，更年期(或OVX)也是一个特征 通过提高卵泡刺激素(FSH)水平。最近的研究质疑， 更年期传统上归因于卵巢E2的特异性丢失，而不是以前的 卵泡刺激素水平意外升高。在这里，我们对之前的观察结果进行扩展，以检验中心假设 雌二醇和卵泡刺激素对BMDA的产生有不同的调节作用，从而改变脂肪的细胞组成 并导致代谢和炎症表型的显著变化。三个具体目标 将解决这一假设：目标1：确定E2和/或FSH信号是否调节BMDA的产生 雌性小鼠，目标2(与项目2相互作用)：测试雌性小鼠是否靶向消耗BMDAs 减少OVX引起的能量肥胖、能量平衡、炎症和代谢健康的变化 3(与项目1的相互作用)：测试循环中FSH和E2水平变化对脂肪细胞前体的影响 女性皮下脂肪组织的亚群蓄积。成功完成这些研究 将确定E2和FSH在控制BMDA生产中的作用，这可能有助于 绝经后代谢病理学。这些数据具有突出BMDA生产的巨大潜力 作为一个新的治疗靶点，为预防更年期和衰老相关的慢性疾病提供新的策略 疾病风险。

PROJECT 3: PROJECT SUMMARY The menopausal transition, an unavoidable aging related phenomenon in females, is accompanied by increased abdominal adiposity and the concomitant incidence of adipose-related comorbidities. Although previous research has primarily focused on body fat distribution, we have generated evidence that the cellular composition of adipose tissue (AT) defines the phenotype of each individual depot, determining its overall influence on metabolic health. The premise is that the loss of gonadal hormones alters the cellularity of AT, leading to changes in body fat distribution and worsening metabolic health. We previously discovered a novel lineage of adipocytes in the major white adipose depots of mice and humans generated from bone marrow derived cells of the hematopoietic lineage rather than conventional mesenchymal precursors. In mice, bone marrow-derived adipocytes (BMDAs) were detected in greater numbers in abdominal fat depots and displayed increased inflammatory cytokine but decreased leptin and mitochondrial lipid oxidation gene expression, suggesting a critical role in influencing metabolic health. Furthermore, ovariectomy (OVX) significantly increased BMDA production, which was attenuated by estradiol (E2) replacement. In addition to declines in E2, menopause (or OVX) is also characterized by rising follicle stimulating hormone (FSH) levels. Recent research questions whether the consequences of menopause traditionally attributed to the specific loss of ovarian E2 may instead be resultant to the previously unappreciated rise in FSH. Here we expand on our previous observations to test the central hypothesis that E2 and FSH differentially regulate the production of BMDAs, altering the cellular composition of adipose tissue and resulting in significant changes in metabolic and inflammatory phenotype. Three specific aims will address this hypothesis: Aim 1: Determine whether E2 and/or FSH signaling regulate BMDA production in female mice, Aim 2 (Interaction with Project 2): Test whether targeted depletion of BMDAs in female mice reduces OVX-induced changes in energy adiposity, energy balance, inflammation and metabolic health and Aim 3 (Interaction with Project 1): Test the effects of altered circulating FSH and E2 levels on adipocyte precursor sub-population accumulation in subcutaneous adipose tissue of women. Successful completion of these studies will define the role of E2 and FSH in controlling the production of BMDAs, which may contribute to postmenopausal metabolic pathology. These data have the tremendous potential to highlight BMDA production as a new therapeutic target providing novel strategies for the prevention of menopausal and aging related chronic disease risk.