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

项目摘要/摘要 该应用程序的总体目标是为Gavin博士提供必要的专业知识和技能 在脂肪组织生理学领域的独立研究生涯，特别关注定义角色 性激素和性腺激素在脂肪细胞发育和表型中的作用。独一无二的重要性 脂肪细胞生物学中的发育途径在很大程度上被忽视了，因为教条持有这种新的 脂肪细胞来源于常驻祖细胞。最近的临床前进展表明，新的 脂肪细胞来源于居住的和非居住的祖细胞的异质性群体。研究 在小鼠体内的研究表明，这些非驻留的祖细胞来自于 髓系(BMP来源的脂肪细胞)。重要的是，我们和其他人提供了BMP来源的证据 人类的脂肪细胞。BMP来源的脂肪细胞似乎有一种不同于 白色或棕色脂肪细胞。这种模式的特点是炎性因子增加和减少 线粒体酶，暗示这种脂肪细胞谱系是不利代谢的潜在贡献者 与过度肥胖有关的个人资料。初步证据表明，BMP来源的积聚 雌鼠的脂肪细胞比雄鼠多，去卵巢的雌鼠的脂肪细胞比完整的雌鼠多。 此外，这些细胞在内脏储存库中的积累增加。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 过度肥胖的症状。因此，该项目的全球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。具体来说，我们 假设性腺类固醇激素减少有利于骨形态发生蛋白来源的募集和分化 脂肪细胞。为了验证这些假设，我们将从以下来源获得腹部皮下脂肪组织活检 女性和男性在性腺激素抑制前后。间质部分将从 脂肪组织，并通过流式细胞术将其分选为髓系细胞和间充质细胞群，然后 在含有和不含有性腺激素的培养中生长。具体目标是确定 1)女性和男性的性腺激素状况是否会改变脂肪组织中髓细胞的聚集和 确定它们在体外经历间充质转化的能力和2)性腺激素状态和 祖细胞谱系(髓系与常规系)调节增殖、分化、代谢 原代人类脂肪细胞的表型和代谢组学特征。探索性的目标将是比较 从接受腹部手术的同一人身上获得皮下和内脏脂肪细胞 如果成功，我们的结果将提供证据，证明一些脂肪细胞在 人类可能起源于以前未被认识到的起源。此外，它还将揭示性腺的重要性 激素状态在决定脂肪细胞谱系和发育中的作用。

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.