Physiological Role of Dedifferentiating Dermal Adipose Tissue

真皮脂肪组织去分化的生理作用

• 批准号: 10348609
• 负责人: PHILIPP E SCHERER
• 金额: $ 51.82万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348609
• 关键词: Address; Adipocytes; Adipose tissue; Agonist; Apoptosis; Attenuated; Bleomycin; Cells; Characteristics; Collagen; Cre lox recombination system; Deposition; Dermal; Dermis; Ensure; Extracellular Matrix; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Functional disorder; Genetic; Genetic Models; Heterogeneity; High Fat Diet; Immune system; Inflammation; Label; Laboratories; Leptin; Light; Link; Lipids; Lipolysis; Metabolic; Metabolism; Mind; Modeling; Mus; Mutation; Myofibroblast; Nature; PPAR gamma; Pathogenesis; Pathologic; Physiological; Population; Process; Production; Reporting; Role; Skin; System; Thick; Time; Tissues; Topical application; Translating; Up-Regulation; adipocyte differentiation; adipokines; adiponectin; autocrine; base; cell type; dermal exposure; design; driving force; feeding; genetic approach; genetic manipulation; in vivo; insight; loss of function; mouse model; novel; overexpression; paracrine; precursor cell; prevent; promoter; response; rosiglitazone; single cell sequencing; skin fibrosis; skin lesion; transdifferentiation

Abstract Physiological Role of De-differentiating Dermal Adipose Tissue Adipose tissue fibrosis is an integral component of dysfunctional fat tissue. This fibrosis exerts detrimental effects on local metabolic responses within adipose tissue, in addition to initiating maladaptive systemic responses. The exact cause(s) of fibrosis in adipose tissue are still a matter of debate and as such, are not well defined. Here, we aim to focus on “dermal adipose tissue fibrosis”, primarily due to its 1) ease of accessibility, 2) our new genetic mouse models that we generated to specifically examine dermal adipose tissue dysfunction and, 3) our initial observation that identified extensive dermal adipocyte differentiation and de-differentiation. We believe that the latter processes are a key aspect of the pathological road to adipose tissue fibrosis. Dermal adipose tissue is skin-associated fat located directly under the reticular dermis. Compared to other well-defined fat pads, dermal adipose tissue displays a high degree of plasticity. Under a variety of physiological conditions, dermal adipose tissue has the capacity to either rapidly and locally expand, or reduce its volume. Our in vivo preliminary studies showed that dermal adipose tissue is negatively associated with collagen production in skin fibroblasts. Importantly, more recent studies in our laboratory identified that the highly dynamic nature of dermal adipocytes allows them to 1) undergo de-differentiation into pre-adipocytes or, 2) convert into alpha-SMA-positive myofibroblasts (when examined in a bleomycin-induced fibrosis model). Here, we propose to examine the following hypothesis: that the adipocyte itself is the major player in preventing adipose tissue fibrosis in response to a metabolic challenge of high fat diet feeding, or bleomycin induction. We will address our hypothesis in three Specific Aims: I) We will retain fat cells in a fully differentiated state, by either ectopically exposing dermal adipocytes to PPARgamma agonists. In parallel, we aim to genetically overexpress PPARgamma then assess the impact on the fibrotic response. In addition to this, we will examine the impact of a complete elimination of adipocytes upon the local fibrotic response in the skin. II) Through lineage tracing, we aim to genetically label and track mature adipocytes as they de-differentiate into pre-adipocytes. Some of these pre- adipocytes can convert to myofibroblasts. We have developed a genetic approach to selectively eliminate myofibroblasts that originate from mature adipocytes. This will allow us, for the first time, to examine the functional relevance of these adipocyte-derived myofibroblasts towards the fibrotic response in adipose tissue. III) With a newly developed “Split Cre” system, we take advantage of a dual promoter system that ensures expression uniquely in the dermal adipocyte. We will manipulate leptin and adiponectin levels locally, then address the impact of local adipokine action in the microenvironment of the dermal adipose tissue on the fibrotic response. While we focus on dermal adipose tissue, results from the proposed studies will also have a profound impact on the understanding of the fibrotic response in other fat depots.

摘要 真皮脂肪组织去分化的生理作用 脂肪组织纤维化是功能失调的脂肪组织的组成部分。这种纤维化会产生有害的 对脂肪组织内局部代谢反应的影响，除了引发适应不良的全身性 应答脂肪组织纤维化的确切原因仍然是一个有争议的问题，因此， 定义明确。在这里，我们的目标是集中在“真皮脂肪组织纤维化”，主要是由于它的1）容易， 可访问性，2）我们新的遗传小鼠模型，我们产生专门检查皮肤 脂肪组织功能障碍，3）我们的初步观察，确定了广泛的真皮脂肪细胞 分化和去分化。我们认为，后一个进程是实现千年发展目标的一个关键方面。 病理性脂肪组织纤维化。真皮脂肪组织是直接位于皮肤相关脂肪 在网状真皮下与其他轮廓分明的脂肪垫相比，真皮脂肪组织显示出较高的 可塑性的程度。在各种生理条件下，真皮脂肪组织具有以下能力： 要么迅速地局部膨胀，要么减小其体积。我们的体内初步研究表明， 脂肪组织与皮肤成纤维细胞中的胶原蛋白产生负相关。而更为 我们实验室最近的研究表明，真皮脂肪细胞的高度动态特性使它们能够 1）经历去分化为前脂肪细胞，或2）转化为α-SMA阳性肌成纤维细胞 (when在博来霉素诱导的纤维化模型中检查）。在此，我们建议审查以下问题 假设：脂肪细胞本身是防止脂肪组织纤维化的主要参与者， 对高脂肪饮食喂养或博来霉素诱导的代谢挑战的反应。我们将解决我们的 假设在三个具体的目的：I）我们将保留脂肪细胞在完全分化的状态，通过或异位 将真皮脂肪细胞暴露于PPARgamma激动剂。同时，我们的目标是在基因上过表达PPARgamma， 评估对纤维化反应的影响。除此之外，我们还将研究一个完整的 在皮肤中的局部纤维化反应时消除脂肪细胞。II）通过血统追踪，我们的目标是 在成熟脂肪细胞去分化为前脂肪细胞时，对它们进行遗传标记和跟踪。其中一些前- 脂肪细胞可以转化为肌成纤维细胞。我们开发了一种基因方法， 来源于成熟脂肪细胞的肌成纤维细胞。这将使我们能够第一次检查 这些脂肪细胞来源的肌成纤维细胞对脂肪组织中纤维化反应的功能相关性。 III）通过新开发的“Split Cre”系统，我们利用双启动子系统， 在真皮脂肪细胞中唯一表达。我们将局部控制瘦素和脂联素水平， 解决真皮脂肪组织微环境中局部脂肪因子作用对 纤维化反应虽然我们关注真皮脂肪组织，但拟议研究的结果也将 对理解其他脂肪库中的纤维化反应具有深远的影响。