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Physiological Role of Dedifferentiating Dermal Adipose Tissue

真皮脂肪组织去分化的生理作用

基本信息

批准号：
10532175
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
项目类别：
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/10532175
关键词：
Address Adipocytes Adipose tissue Agonist Apoptosis Attenuated Bleomycin Cells Characteristics Collagen Communication 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 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 cell type dermal exposure design driving force feeding gain of function 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

项目摘要

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