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

基本信息

批准号：
9353798
负责人：
Kathleen Marie Gavin
金额：
$ 14.45万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/9353798
关键词：
3-Dimensional Abdomen Adipocytes Adipose tissue Adrenergic Agents Age Alpha Cell 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 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 Pharmacology Phenotype Physiology Play Population Population Heterogeneity Positioning Attribute Protocols documentation Recruitment Activity Research Risk Role Sampling Scientist Sex Characteristics Stem cells Steroid Receptors Testing Tissue Sample Training Visceral Woman adipocyte biology adipocyte differentiation bone 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

项目摘要

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.

项目摘要/摘要该应用程序的总体目标是为加文博士提供启动必要的专业知识和技能脂肪组织生理学领域的独立研究职业，特别着眼于定义角色脂肪细胞发育和表型中的性和性腺激素。独特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略了脂肪细胞源自居民祖细胞。最近的临床前进步揭示了新的脂肪细胞来自常驻和非居民祖细胞的异质种群。研究在小鼠中，这些非居民祖细胞是由骨髓来源的祖细胞引起的髓样谱系（BMP衍生的脂肪细胞）。重要的是，我们和其他人提供了BMP衍生的证据人类的脂肪细胞。 BMP衍生的脂肪细胞似乎具有与白色或棕色脂肪细胞。这种模式的特征是炎症因子增加并减少线粒体酶，将这种脂肪细胞谱系视为不良代谢的潜在因素与过度肥胖有关的轮廓。初步证据表明，BMP衍生的积累与雄性小鼠相比，雌性的脂肪细胞更大，与完整的雌性小鼠相比，卵巢切除术。此外，内脏仓库中这些细胞的积累增加。总的来说，这些研究表明性腺激素状态与脂肪细胞的发展和健康风险有关过度肥胖。因此，该项目的全球假设是性腺激素调节男女新脂肪细胞的发展途径和代谢表型。具体来说，我们假设减少性腺类固醇激素有利于BMP衍生的募集和分化脂肪细胞。为了检验这些假设，我们将从性腺激素抑制前后的男女。基质分数将与脂肪组织，并通过流式细胞术将其分类为髓样细胞和间充质细胞的种群，然后在培养物中生长，不受性腺激素的暴露。具体目的是确定 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的积累和确定它们在体外进行间充质转变的能力和2）性腺激素状态和祖细胞谱系（髓样与常规）调节增殖，分化，代谢原代人脂肪细胞的表型和代谢组学。探索目的是比较使用腹部手术获得的皮下和内脏脂肪细胞使用目标1和2中提出的方法。如果成功，我们的结果将提供证据表明某些脂肪细胞人类可能是由以前未被认可的起源引起的。此外，它将揭示性腺的重要性激素状态确定脂肪细胞谱系和发育。