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: 10225535
• 负责人: Dwight J Klemm
• 金额: $ 31.46万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225535
• 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：项目概要 绝经过渡期是女性不可避免的衰老相关现象， 腹部肥胖和脂肪相关合并症的伴随发生率。虽然之前的研究 主要集中在身体脂肪分布，我们已经产生的证据表明，细胞组成的 脂肪组织（AT）定义了每个个体贮库的表型，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，导致身体的变化， 脂肪分布和代谢健康恶化。我们先前在乳腺癌中发现了一种新的脂肪细胞谱系， 小鼠和人的主要白色脂肪贮库由造血干细胞的骨髓衍生细胞产生， 而不是传统的间充质前体。在小鼠中，骨髓源性脂肪细胞（BMDA） 在腹部脂肪库中检测到的数量更多，并显示炎性细胞因子增加， 瘦素和线粒体脂质氧化基因表达降低，表明在影响 代谢健康此外，卵巢切除术（OVX）显著增加BMDA的产生， 雌二醇（E2）替代。除了E2的下降，绝经（或OVX）也是一个特点， 促卵泡激素（FSH）水平升高。最近的研究质疑， 绝经传统上归因于卵巢E2的特定损失，而可能是由于先前的 促卵泡激素未被重视的上升。在这里，我们扩展了我们以前的观察，以测试中心假设， E2和FSH差异调节BMDA的产生，改变脂肪细胞的细胞组成， 组织中，并导致代谢和炎症表型的显着变化。三个具体目标 目的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的相互作用）：测试是否靶向消除雌性小鼠中的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， 3（与项目1的相互作用）：测试改变的循环FSH和E2水平对脂肪细胞前体的影响 妇女皮下脂肪组织中亚群积累。成功完成这些研究 将定义E2和FSH在控制BMDAs产生中的作用，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 作为一种新的治疗靶点，为预防绝经和衰老相关的慢性疾病提供了新的策略。 疾病风险。