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

性激素水平降低刺激炎症性骨髓来源脂肪细胞的产生

• 批准号: 10618777
• 负责人: Dwight J Klemm
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618777
• 关键词: Abdomen; Ablation; Adipocytes; Adipose tissue; Age; Aging; Antibody Therapy; Area; Attenuated; Biogenesis; Body Composition; Body fat; Bone Development; Bone Marrow; Buttocks; Cardiovascular Diseases; Cells; Cellularity; Characteristics; Communities; Data; Diabetes Mellitus; Disease; Energy Metabolism; Estradiol; Estrogen Receptor alpha; Estrogen deficiency; Estrogens; Exhibits; Fatty acid glycerol esters; Female; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Gene Expression; Genes; Gonadal Hormones; Gonadal Steroid Hormones; Health; Healthcare Systems; Hematopoietic stem cells; Heterogeneity; Hip region structure; Hormone Receptor; Human; ITGAM gene; Incidence; Individual; Inflammation; Inflammatory; Integrins; Knock-out; Leptin; Life; Link; Lung diseases; Macrophage; Malignant Neoplasms; Measures; Medical; Menopause; Mesenchymal; Metabolic; Metabolism; Mitochondria; Muramidase; Mus; Myelogenous; Obesity; Operative Surgical Procedures; Ovarian Ablation; Ovarian hormone; Ovariectomy; Patients; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Population; Process; Production; Proliferating; Protein Isoforms; Reporting; Research; Role; Scientific Inquiry; Signal Transduction; Stromal Cells; Testing; Tissues; Veterans; Veterans Health Administration; Weight Gain; Woman; abdominal fat; combat; comorbidity; cytokine; energy balance; hormonal signals; hypothalamic pituitary ovarian axis; interest; male; military veteran; mouse model; novel strategies; patient population; prevent; progenitor; receptor; uncoupling protein 1

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.

更年期是所有女性的正常现象，是一个渐进的过程，从15岁开始。 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。美国女性退伍军人是增长最快的患者群体， 退伍军人管理局医疗保健系统，超过三分之一的患者是前，后或 目前处于更年期。然而，绝经期卵巢激素变化的机制 生产调节体脂肪含量和代谢是VA研究中尚未探索的领域。 我们已经发现了小鼠和人类脂肪库中的脂肪细胞亚群， 来源于造血干细胞，称为骨髓来源的脂肪细胞（BMDA）。这些细胞产生于 数量足以影响脂肪组织功能，并且它们的产生会因性腺的丧失而增加 在小鼠模型中模拟女性更年期的性激素。这些意见值得注意 因为BMDA不同于常规的脂肪细胞并且具有潜在的有害表型， 其特征在于炎性细胞因子的产生增加。 最近的初步数据表明，BMDA由脂肪组织基质细胞产生， 表达我们称为“髓样脂肪细胞祖细胞”的髓样和间充质标志物，或 地图由于支持成熟脂肪细胞增殖的证据仍然存在争议， 调节BMDA丰度的性腺激素可归因于BMDA的产生和/或增殖。 地图本项目将检验雌激素和卵泡刺激素差异 调节MAP（和BMDA）的产生，改变脂肪和 导致代谢和炎症表型的显著变化。三个具体目标将测试 这一假说通过确定是否1）消融卵巢激素受体，或2）直接消耗 卵巢激素调节BMDA丰度。第三个目标是测量身体成分的变化， MAP和卵巢激素耗竭的小鼠的代谢参数。 这些研究的成功完成有可能确定地图的关键贡献， 脂肪组织异质性和脂肪组织功能的变化，以及卵巢激素产生的损失。 更好地理解这种现象将突出控制细胞组成的机会， 脂肪组织的功能作为一种新的策略，以打击更年期合并症。