Diminished Sex Hormone Levels Stimulate Production of Inflammatory Bone Marrow-Derived Adipocytes

更年期在所有女性中都是正常发生的，而且是一个渐进的过程，开始于 生活。更年期的特征是卵巢激素的丧失，最终导致许多 合并症包括体重增加，脂肪从臀部、腰部和臀部重新分布到腹部，以及 代谢活性降低。美国女退伍军人是全球增长最快的患者 退伍军人管理局医疗保健系统，其中超过三分之一的患者是在 目前处于更年期。然而，更年期卵巢激素变化的机制 生产调节体内脂肪含量和代谢是VA研究中一个未被探索的领域。 我们在小鼠和人类的脂肪库中发现了一种脂肪细胞亚群 来自造血干细胞，称为骨髓源性脂肪细胞(BMDA)。这些细胞是在 足以影响脂肪组织功能的数量，其产量因性腺的丧失而增加 模拟女性更年期的小鼠模型中的性激素。这些观察结果值得注意。 由于BMDA不同于传统的脂肪细胞，具有潜在的有害表型， 以炎性细胞因子的产生增加为特征的。 最近的初步数据表明，BMDA是由脂肪组织基质细胞产生的， 表达髓系和间充质标记物，我们称之为“髓系脂肪细胞前体细胞”或 地图。由于支持成熟脂肪细胞增殖的证据仍然存在争议，因此 调节BMDA丰度的性腺激素可归因于产生和/或增殖 地图。这个项目将检验雌激素和卵泡刺激素不同的假设 调节MAP(和BMDA)的产生，改变脂肪和蛋白质的细胞组成 导致代谢和炎症表型发生明显变化。三个具体目标将受到考验 这一假设是通过确定1)卵巢激素受体的消融，还是2)直接耗尽卵巢激素受体 卵巢激素调节BMDA的丰度。第三个目标将测量身体成分的变化和 MAP和卵巢激素耗竭小鼠的代谢参数。 这些研究的成功完成有可能确定地图对 脂肪组织的异质性和脂肪组织功能的变化与卵巢激素分泌的丧失有关。 对这一现象的更好理解将突出控制细胞组成和 脂肪组织的功能是对抗更年期并发症的一种新策略。

Menopause is a normal occurrence in all women and a gradual process that begins in the 5th decade of life. Menopause is characterized by the loss of ovarian hormones that ultimately leads to a number of comorbidities including weight gain, redistribution of fat from hips, waist and buttocks to the abdomen, and decreased metabolic activity. Female US military veterans are the fastest growing patient population in the Veterans Administration Health Care system, and more than a third of those patients are pre-, post- or currently menopausal. However, the mechanisms by which menopausal changes in ovarian hormone production regulate body fat content and metabolism is an unexplored area in VA research. We have discovered a subpopulation of adipocytes in adipose depots of mice and humans generated from hematopoietic stem cells, termed bone marrow-derived adipocytes (BMDA). These cells are produced in numbers sufficient to influence adipose tissue function, and their production is increased by loss of gonadal sex hormones in mouse models that mimic menopause in women. These observations were noteworthy because BMDAs differ from conventional adipocytes and possess a potentially detrimental phenotype, characterized by elevated production of inflammatory cytokines. Recent preliminary data demonstrates that BMDA are produced from adipose tissue stromal cells that express both myeloid and mesenchymal marker that we have termed “myeloid adipocyte progenitors” or MAPs. Since evidence supporting the proliferation of mature adipocytes remains controversial, the ability of gonadal hormones to regulate BMDA abundance can be attributed to the production and/or proliferation of MAPs. This project will test the hypothesis that estrogen and follicle stimulating hormone differentially regulate the production of MAPs (and BMDAs), altering the cellular composition of adipose and resulting in significant changes in metabolic and inflammatory phenotype. Three Specific Aims will test this hypothesis by determining whether 1) ablation of ovarian hormone receptors, or 2) direct depletion of ovarian hormones regulates BMDA abundance. A third aim will measure changes in body composition and metabolic parameters in mice with depletion of MAPs and ovarian hormones. Successful completion of these studies has the potential to establish the crucial contribution of MAPs to adipose tissue heterogeneity and changes to adipose tissue function with loss of ovarian hormone production. A better understanding of this phenomenon will highlight opportunities to control the cellular composition and function of adipose tissue as a novel strategy to combat menopausal comorbidities.