Establishment and Maintenance of Healthy Adipose Tissue in Obesity

肥胖症健康脂肪组织的建立和维持

基本信息

批准号：
10705849
负责人：
Rana K Gupta
金额：
$ 45.89万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705849
关键词：
Adipocytes Adipose tissue Adult Anatomy Biology Blood Vessels Body mass index Cardiovascular Diseases Cell Differentiation process Cell Hypoxia Cells Chronic Disease Clinical Research Data Development Dominant-Negative Mutation Doxycycline Ensure Fatty acid glycerol esters Fibrosis Funding Genetic Models HIF1A gene Health High Fat Diet Homeostasis Hyperplasia Hypertrophy Hypoxia Inducible Factor Imatinib Incidence Inflammation Insulin Resistance Intra-abdominal Knowledge Lipids Maintenance Metabolic Metabolic Diseases Metabolic syndrome Modeling Molecular Mouse Strains Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obese Mice Obesity PDGFRB gene Pathologic Phenotype Phosphorylation Production Regulation Resistance Risk Role Serine Signal Transduction Testing Time Tissue Expansion Tissue Model Tissues Transgenic Model adipocyte differentiation adipokines autocrine cell type diet-induced obesity experimental study fatty liver disease feeding in vivo inhibitor insulin sensitivity lipid biosynthesis male mutant novel novel therapeutic intervention obese person obesity treatment overexpression paracrine pharmacologic precursor cell preservation prevent progenitor response subcutaneous transgene expression

项目摘要

Obesity confers significant risk for developing numerous chronic disorders, such as insulin resistance, type 2 diabetes, fatty liver disease, and cardiovascular disease. Importantly, many obese individuals are relatively resistant to developing these metabolic disorders, at least for a period of time. This implies that factors beyond BMI, per se, drive the development of these conditions. Clinical studies comparing the “metabolically healthy obese” to obese individuals with metabolic syndrome have revealed that the manner by which energy-storing white adipose tissue (WAT) remodels in obesity is a critical determinant of metabolic health. Healthy WAT expansion is characterized by 1) preferential expansion of subcutaneous WAT depots, and 2) adipose tissue expansion through an increase in cell differentiation, or “adipogenesis.” This phenotype correlates well with preserved insulin sensitivity in obesity. Pathologic WAT expansion is characterized by 1) limited expansion of subcutaneous WAT depots, and 2) pathologic WAT remodeling, characterized by limited adipogenesis, adipocyte hypertrophy, inflammation, and fibrosis. These phenotypes correlate with insulin resistance and ectopic lipid accumulation in non-adipose tissues. As such, de novo adipogenesis in the setting of caloric excess is a protective mechanism to ensure safe energy storage in WAT and prevent against the development of metabolic disease. Understanding the mechanisms controlling adipogenesis in anatomically distinct regions in vivo remains a high priority in the field of adipose biology. Adipocyte precursor cells (APCs) reside within the WAT vasculature as a subset of perivascular, PDGFRb+, mural cells. Adipogenesis originating from PDGFRb+ cells in the setting of caloric excess promotes healthy WAT remodeling and insulin sensitivity in mice. Importantly, strong inhibitory signals within the tissue microenvironment control adipogenesis in a region-specific manner. During the next funding cycle, we propose to test the hypothesis that an anti-adipogenic, pro-fibrogenic, HIFa (hypoxia-inducible factor)-dependent signaling cascade suppresses PPARg activity in APCs through serine 112 (S112) phosphorylation to promote unhealthy WAT modeling in obesity. Our specific aims are to 1) determine the role of mural cell HIFa signaling in adipose tissue remodeling in obesity, and 2) identify HIFa-dependent signaling mechanisms leading to the inhibition of PPARg activity and suppression of adipocyte hyperplasia in obesity. Successful completion these aims will advance our understanding of depot-specific adipocyte progenitors and the regulation of adipogenesis in vivo. This may lead to novel therapeutics strategies to uncouple insulin resistance from obesity.

肥胖症承认出现出现多种慢性疾病的重大风险，例如胰岛素抵抗，2型糖尿病，脂肪肝病和心血管疾病。重要的是，许多肥胖个体至少在一段时间内相对抵抗发展这些代谢性疾病。这意味着超出BMI的因素本身，推动了这些条件的发展。将“代谢健康肥胖”与代谢综合征肥胖个体进行比较的临床研究表明，肥胖症中能量储能的白脂肪组织（WAT）重塑的方式是代谢健康的关键决定因素。健康的WAT膨胀的特征是1）皮下WAT沉积物的优先扩张，以及2）通过增加细胞分化或“脂肪形成”，脂肪组织扩张。该表型与肥胖症中保留的胰岛素敏感性很好地相关。病理性的WAT膨胀的特征是1）皮下WAT沉积物的膨胀有限，以及2）病理WAT重塑，其特征在于脂肪生成有限，脂肪细胞肥大，炎症和纤维化。这些表型与非脂肪组织中的胰岛素抵抗和生态脂质积累相关。因此，在过量过量的情况下，从头脂肪形成是一种受保护的机制，可确保在WAT中安全储存并防止代谢疾病的发展。了解控制体内解剖区域中脂肪形成的机制仍然是脂肪生物学领域的高度优先级。脂肪细胞前体细胞（APC）位于WAT脉管系统中，作为血管周，PDGFRB+，壁细胞的子集。源自源自PDGFRB+细胞的脂肪形成在热量过量的情况下促进了健康的WAT重塑和胰岛素敏感性。重要的是，组织微环境控制掺杂的强烈抑制信号以特定区域的方式。在下一个融资周期中，我们建议检验以下假设：抗抑制，促纤维化，HIFA（缺氧诱导因子）依赖性信号cascad cascade抑制APC通过丝氨酸112（S112）磷酸化抑制PPARG活性，以促进Obesity的不健康WAT模型。我们的具体目的是1）确定壁画细胞HIFA信号在肥胖症中重塑脂肪组织重塑的作用，2）确定依赖HIFA的信号传导机制，导致PPARG活性抑制和抑制肥胖症中脂肪细胞增生。成功完成这些目标将提高我们对仓库特异性脂肪细胞祖细胞和体内脂肪形成的调节的理解。这可能会导致新的治疗策略，以使胰岛素抵抗肥胖。