Sex differences in adipogenic potential of adipose tissue myeloid cells in humans

人类脂肪组织骨髓细胞成脂潜力的性别差异

• 批准号: 9241869
• 负责人: Kathleen Marie Gavin
• 金额: $ 14.6万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241869
• 关键词: 3-Dimensional; Abdomen; Adipocytes; Adipose tissue; Adrenergic Agents; Age; Androgens; Area; Attenuated; Biopsy; Blood; Blood Circulation; Body fat; Bone Marrow; CD14 gene; CD34 gene; CD44 gene; Cell Culture Techniques; Cell Lineage; Cells; Chronic Disease; Coagulation Process; Complement; Data; Development; Environment; Enzymes; Estrogens; Exhibits; Exposure to; Fatty acid glycerol esters; Female; Fibrin; Figs - dietary; Flow Cytometry; Future; Gene Expression Profile; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hematopoietic stem cells; Heterogeneity; Human; Human body; In Vitro; Individual; Inflammatory; Insulin; Investigation; Link; Lipids; Menopause; Mentors; Mesenchymal; Metabolic; Metabolic Diseases; Metabolism; Methods; Mitochondria; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Obesity; Operative Surgical Procedures; Outcome; Ovarian hormone; PTPRC gene; Pathway interactions; Patients; Pattern; Phenotype; Physiology; Play; Population; Population Heterogeneity; Positioning Attribute; Protocols documentation; Research; Risk; Role; Sampling; Scientist; Sex Characteristics; Sorting - Cell Movement; Stem cells; Steroid Receptors; TNFRSF5 gene; Testing; Tissue Sample; Training; Visceral; Woman; adipocyte biology; adipocyte differentiation; career; cell type; disorder risk; glucose uptake; in vivo; insight; lipid biosynthesis; male; men; metabolic phenotype; metabolic profile; metabolomics; older men; older women; pre-clinical; preference; prevent; progenitor; sex; skills; subcutaneous

PROJECT SUMMARY/ABSTRACT The overarching goal of this application is to provide Dr. Gavin the expertise and skills necessary to initiate an independent research career in the field adipose tissue physiology, with a specific focus on defining the role of sex and gonadal hormones in adipocyte development and phenotype. The importance of distinct developmental pathways in adipocyte biology has been largely overlooked because dogma has held that new adipocytes are derived from resident progenitor cells. Recent preclinical advances have revealed that new adipocytes arise from a heterogeneous population of both resident and non-resident progenitor cells. Studies in mice have shown that these non-resident progenitors arise from bone marrow-derived progenitor cells of myeloid lineage (BMP-derived adipocytes). Importantly, we and others have provided evidence of BMP-derived adipocytes in humans. BMP-derived adipocytes appear to have a gene expression pattern that is distinct from white or brown adipocytes. This pattern is characterized by increased inflammatory factors and decreased mitochondrial enzymes, implicating this adipocyte lineage as a potential contributor to the adverse metabolic profile associated with excess adiposity. Preliminary evidence suggests that accumulation of BMP-derived adipocytes is greater in female compared to male mice, and in ovariectomized compared to intact female mice. Furthermore, the accumulation of these cells is increased in visceral depots. Collectively, these studies suggest that gonadal hormone status is mechanistically linked with adipocyte development and the health risks of excess adiposity. Accordingly, the global hypothesis of this project is that gonadal hormones regulate the developmental pathway and metabolic phenotype of new adipocytes in women and men. Specifically, we hypothesize that reduced gonadal steroid hormones favor the recruitment and differentiation of BMP-derived adipocytes. To test these hypotheses, we will obtain subcutaneous abdominal adipose tissue biopsies from women and men before and after gonadal hormone suppression. The stromal fraction will be isolated from adipose tissue and sorted into populations of myeloid and mesenchymal cells by flow cytometry that will then be grown in culture with and without exposure to gonadal hormones. The Specific Aims are to determine whether 1) gonadal hormone status in women and men alters adipose tissue myeloid cell accumulation and determines their ability to undergo mesenchymal transition in vitro and 2) gonadal hormone status and progenitor lineage (myeloid versus conventional) regulate the proliferation, differentiation, metabolic phenotype, and metabolomics profile of primary human adipocytes. An exploratory aim will be to compare subcutaneous and visceral fat cells obtained from the same individuals undergoing abdominal surgery using the methods proposed in Aims 1 and 2. If successful, our results will provide evidence that some adipocytes in humans can arise from a previously unrecognized origin. Furthermore, it will reveal the importance of gonadal hormone status in determining adipocyte lineage and development.

项目总结/摘要 该应用程序的首要目标是为加文博士提供启动所需的专业知识和技能 在脂肪组织生理学领域的独立研究生涯，特别侧重于定义作用 性激素和性腺激素在脂肪细胞发育和表型中的作用。区别的重要性 脂肪细胞生物学中的发育途径在很大程度上被忽视了，因为教条认为， 脂肪细胞来源于固有祖细胞。最近的临床前进展表明， 脂肪细胞来源于固有和非固有祖细胞的异质群体。研究 在小鼠中的研究表明，这些非常驻祖细胞来自于 骨髓谱系（BMP衍生的脂肪细胞）。重要的是，我们和其他人已经提供了BMP衍生的证据， 人体脂肪细胞。BMP-衍生的脂肪细胞似乎具有与BMP-衍生的脂肪细胞不同的基因表达模式。 白色或棕色脂肪细胞。这种模式的特点是增加炎症因子和减少 线粒体酶，暗示这种脂肪细胞谱系是不利的代谢的潜在贡献者。 与过度肥胖相关的特征。初步证据表明，BMP衍生的 雌性小鼠的脂肪细胞比雄性小鼠多，卵巢切除小鼠的脂肪细胞比完整的雌性小鼠多。 此外，这些细胞的积累在内脏库中增加。总的来说，这些研究 提示性腺激素状态与脂肪细胞发育和健康风险有机械联系 肥胖症的症状因此，该项目的总体假设是，性腺激素调节 男女新生脂肪细胞的发育途径和代谢表型。我们特别 假设性腺类固醇激素减少有利于BMP源性细胞的募集和分化， 脂肪细胞为了验证这些假设，我们将从100名患者中获得皮下腹部脂肪组织活检。 女性和男性在性腺激素抑制前后的变化。基质部分将从 脂肪组织，并通过流式细胞术分选成骨髓和间充质细胞群，然后 在有或没有暴露于性腺激素的培养基中生长。具体目标是确定 1）女性和男性的性腺激素状态是否改变脂肪组织髓样细胞积累， 决定它们在体外经历间充质转化的能力和2）性腺激素状态， 祖细胞谱系（骨髓与常规）调节细胞的增殖、分化、代谢、增殖、分化、代谢和分化。 表型和原代人脂肪细胞的代谢组学特征。一个探索性的目标将是比较 皮下和内脏脂肪细胞从接受腹部手术的相同个体获得， 目标1和2中提出的方法。如果成功的话，我们的结果将提供证据表明， 人类可能起源于一个以前未被认识的起源。此外，它将揭示性腺的重要性， 激素状态决定脂肪细胞谱系和发育。