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，并且是从 5 世纪 50 年代开始的渐进过程。 更年期的特点是卵巢激素的丧失，最终导致许多疾病。 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 代谢活动下降的美国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，其中超过三分之一的患者是在退伍军人管理局医疗保健系统之前、之后或 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 研究中尚未探索的领域。 我们在小鼠和人类的脂肪库中发现了脂肪细胞亚群 来自造血干细胞，称为骨髓源性脂肪细胞（BMDA）。 数量足以影响脂肪组织功能，并且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。 因为 BMDA 与传统脂肪细胞不同，并且具有潜在的不健康表型， 其特征是炎症细胞因子的产生增加。 最近的初步数据表明 BMDA 是由脂肪组织基质细胞产生的， 表达骨髓和间质标记物，我们称之为“骨髓脂肪细胞祖细胞”或 由于支持成熟脂肪细胞增殖的证据仍存在争议，因此 调节 BMDA 丰度的性腺激素可归因于以下物质的产生和/或增殖： 该项目将检验雌激素和卵泡刺激素存在差异的假设。 调节 MAP（和 BMDA）的产生，改变脂肪和脂肪的细胞组成 导致代谢和炎症表型的显着变化将测试三个特定目标。 这一假设通过确定是否 1) 卵巢激素受体的消融，或 2) 直接耗尽 卵巢激素调节 BMDA 丰度的第三个目标是测量身体成分的变化。 MAP 和卵巢激素耗尽的小鼠的代谢参数。 成功完成这些研究有可能确定 MAP 对 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丧失。 更好地理解这种现象将突出控制细胞组成和 脂肪组织的功能作为对抗更年期合并症的新策略。