Sex Hormones Differentially Regulate Production of a Distinct Adipocyte Population

性激素差异调节不同脂肪细胞群的产生

• 批准号: 10456787
• 负责人: Dwight J Klemm
• 金额: $ 31.1万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456787
• 关键词: Address; Adipocytes; Adipose tissue; Aging; Animals; Antibodies; Antibody Therapy; Area; Attenuated; Award; Bioenergetics; Biogenesis; Biopsy; Body fat; Bone Development; Bone Marrow; Bone Marrow Transplantation; Cells; Cellularity; Characteristics; Chronic Disease; Collaborations; Cortisone; Data; Energy Metabolism; Enrollment; Estradiol; Estrogen Receptor alpha; Fatty acid glycerol esters; Female; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Gene Expression; Genes; Glucocorticoids; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hematopoietic; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Impairment; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Intra-abdominal; Knock-out; Leptin; Lipids; Menopause; Mesenchymal; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Obesity; Ovarian; Ovariectomy; Pathology; Phenotype; Play; Population; Postmenopause; Prevention strategy; Production; Protein Isoforms; Research; Respiration; Role; Scientific Inquiry; Signal Transduction; Testing; Visceral; Woman; abdominal fat; base; blood glucose regulation; comorbidity; cytokine; disorder risk; energy balance; gonad function; hormonal signals; hypothalamic pituitary ovarian axis; interest; metabolic phenotype; new therapeutic target; novel; novel strategies; oxidation; primary outcome; receptor; secondary outcome; subcutaneous; uncoupling protein 1

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.

项目 3：项目摘要 更年期过渡是女性不可避免的衰老相关现象，伴随着更年期的增加 腹部肥胖以及脂肪相关合并症的伴随发生率。虽然之前的研究 主要关注身体脂肪分布，我们已经获得证据表明 脂肪组织 (AT) 定义了每个个体储存库的表型，决定了其对代谢的总体影响 健康。前提是性腺激素的丧失改变了AT的细胞结构，导致身体发生变化 脂肪分布和代谢健康恶化。我们之前发现了一种新的脂肪细胞谱系 小鼠和人类的主要白色脂肪库由骨髓来源的造血细胞产生 谱系而不是传统的间充质前体。在小鼠中，骨髓来源的脂肪细胞（BMDA） 在腹部脂肪库中检测到更多数量，并显示炎症细胞因子增加，但 瘦素和线粒体脂质氧化基因表达减少，表明在影响瘦素和线粒体脂质氧化基因方面发挥着关键作用 代谢健康。此外，卵巢切除术（OVX）显着增加了 BMDA 的产生， 雌二醇（E2）替代品可减弱。除了 E2 下降外，更年期（或 OVX）也具有特征 通过卵泡刺激素 (FSH) 水平升高。最近的研究质疑是否会产生后果 传统上将更年期归因于卵巢 E2 的特定丧失，而这可能是由于先前的 FSH 未被意识到的升高。在这里，我们扩展了之前的观察结果来检验中心假设： E2 和 FSH 差异调节 BMDA 的产生，改变脂肪的细胞组成 组织并导致代谢和炎症表型的显着变化。三个具体目标 将解决这一假设：目标 1：确定 E2 和/或 FSH 信号传导是否调节 BMDA 的产生 雌性小鼠，目标 2（与项目 2 的互动）：测试雌性小鼠中是否有针对性地消耗 BMDA 减少 OVX 引起的能量肥胖、能量平衡、炎症和代谢健康的变化以及目标 3（与项目 1 的交互）：测试循环 FSH 和 E2 水平改变对脂肪细胞前体的影响 女性皮下脂肪组织中亚群的积累。成功完成这些研究 将定义 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。这些数据具有突显 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了新的策略 疾病风险。