Developmental lineages and functions of macrophages in white adipose tissue

摘要：脂肪组织相关疾病包括肥胖、脂肪营养不良和癌症相关脂肪。 在美国，集体浪费占死亡人数的四分之一(1-3)。尽管这一数字高得惊人 在死亡病例中，治疗选择仍然有限且不能令人满意。自20世纪90年代以来，具有里程碑意义的研究有S 确定了脂肪组织中巨噬细胞的积聚和激活与炎症有关， 胰岛素抵抗和2型糖尿病(4-20)。然而，脂肪组织巨噬细胞在组织外的作用 人们对炎症仍知之甚少。这一点尤其重要，因为研究表明，脂肪组织 巨噬细胞可能参与脂肪发育(21-23)、脂肪储存(24)和防止脂肪浪费。 (25)。我们在《科学》(26)上发表的初步数据表明，胚胎来源的脂肪组织驻留在 巨噬细胞通过产生PDGFcc促进脂肪细胞中的脂肪储存。此过程独立于 骨髓来源的巨噬细胞促进炎症和胰岛素抵抗。 我们在(Aim 1)上的初步数据表明，巨噬细胞是脂肪流失所必需的。因此，在目标1中，我将 描绘负责的巨噬细胞谱系(K99)并确定巨噬细胞依赖机制(R00) 控制脂肪动员/流失的物质。在(目标2)中，我将确定控制脂质储存的转录基础 通过脂肪组织驻留的巨噬细胞使用单核RNA测序(K99)。我希望能推断出 控制脂肪储存的细胞电路和下游信号通路的变化。候选人 这里确定的分子将在这项研究的R00阶段使用人类脂肪有机化合物和在 活体小鼠模型。在(目标3)中，我将使用含有人类常驻样巨噬细胞的人类脂肪有机体 确认PDGFcc在人类脂肪储存中的作用(K99)。我发现人体脂肪类有机化合物含有 与巨噬细胞较少的脂肪器官相比，Pdgfc+驻留的巨噬细胞积累更多的脂质。这就做 (R00)使用这些脂肪类有机物来确定巨噬细胞如何影响脂代谢，并确定 巨噬细胞直接作用于脂肪细胞。此外，人类器官将被用来筛选巨噬细胞- 目标1和目标2中确定的能量储存依赖介体。我将继续接受弗雷德里克博士的指导 巨噬细胞生物学领域的领先者盖斯曼说。 盖斯曼实验室是首批确定 巨噬细胞的发育谱系和功能。我还将受益于我的建议的专业知识 包括安东尼·费兰特、克里斯·格拉斯和奥利维尔·埃莱门托在内的委员会。克里斯·格拉斯博士和奥利维尔博士 Elemento是备受尊敬的科学家，他们在巨噬细胞和白色脂肪组织的分析方面拥有专业知识 通过单细胞方法。鉴于安东尼·费兰特博士是髓系细胞生物学领域的专家， 代谢，脂肪组织功能。我的期望是，这项建议与我在 药物开发不仅将提供脂肪组织巨噬细胞的全面功能图景，还将 帮助开发可控制肥胖、脂肪营养不良或恶病质患者肥胖的治疗方法。

ABSTRACT: Adipose tissue-associated disorders including obesity, lipodystrophy, and cancer-associated fat wasting collectively account for 1 in 4 deaths in the United States (1-3). Despite the devastatingly high number of deaths, therapeutic options remain limited and unsatisfactory. Landmark studies since the 1990’s have established that accumulation and activation of macrophages in adipose tissues are linked to inflammation, insulin resistance, and type 2 diabetes (4-20). However, the roles of adipose tissue macrophages outside tissue inflammation remain poorly understood. This is particularly important, as studies suggest that adipose tissue macrophages may be involved in fat development (21-23), fat storage (24), and protection against fat wasting (25). Our preliminary data published in Science (26) demonstrate that embryo-derived adipose tissue resident macrophages promote lipid storage in adipocytes via production of PDGFcc. This process is independent from inflammation and insulin resistance promoted by bone-marrow-derived macrophages. Our preliminary data in (Aim 1) suggest that macrophages are required for fat loss. Therefore, in Aim 1 I will delineate the responsible macrophage lineages (K99) and identify macrophage-dependent mechanisms (R00) that control fat mobilization/loss. In (Aim 2), I will determine the transcriptional basis for control of lipid storage by adipose tissue resident macrophages using single nucleus RNA-sequencing (K99). I expect to deduce changes in cellular circuitries and downstream signaling pathways that control fat storage. The candidate molecules identified here will be explored in the R00 phase of this research using human fat organoids and in vivo mouse models. In (Aim 3), I will use human fat organoids that contain human resident-like macrophages to confirm the role of PDGFcc in fat storage in humans (K99). I have found that human fat organoids that contain Pdgfc+ resident-like macrophages accumulate more lipids as compared to macrophage-less fat organoids. I will (R00) use these fat organoids to determine how macrophages affect lipid metabolism and identify whether macrophages act directly on adipocytes. Additionally, human organoids will be used to screen for macrophage- dependent mediators of energy storage identified in Aims 1 and 2. I will continue to be mentored by Dr Frederic Geissmann, a leader in the field of macrophage biology. The Geissmann lab is among the first to characterize the developmental lineages and functions of macrophages. I will also benefit from the expertise of my advisory committee that includes Anthony Ferrante, Chris Glass, and Olivier Elemento. Drs. Chris Glass and Olivier Elemento are highly respected scientists with expertise in analysis of macrophages and white adipose tissues by single cell methodologies. Whereas, Drs Anthony Ferrante is an expert in the areas of myeloid cell biology, metabolism, and adipose tissue function. My expectations are that this proposal combined with my expertise in drug development will not only provide a comprehensive functional view of adipose tissue macrophages but also aid in development of therapies that may control adiposity in obese, lipodystrophic, or cachectic patients.