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.

肥胖会带来罹患多种慢性疾病的重大风险，例如胰岛素抵抗、2 型糖尿病、脂肪肝疾病和心血管疾病。重要的是，许多肥胖者至少在一段时间内相对不易罹患这些代谢疾病。意味着除了体重指数之外的因素本身也推动了这些疾病的发展，对“代谢健康的肥胖者”与患有代谢综合征的肥胖者进行比较的临床研究揭示了能量储存白色脂肪组织（WAT）的重塑方式。肥胖中的 WAT 扩展是代谢健康的关键决定因素，其特征在于 1）皮下 WAT 库的优先扩展，以及 2）通过细胞分化或“脂肪生成”的增加而实现脂肪组织扩展。肥胖症的病理性 WAT 扩张的特征是 1) 皮下 WAT 库的有限扩张，以及 2) 病理性 WAT 重塑，其特征是脂肪生成有限、脂肪细胞肥大、炎症、这些表型与非脂肪组织中的胰岛素抵抗和异位脂质积累相关，因此，热量过量情况下的从头脂肪生成是确保 WAT 安全能量储存并防止代谢疾病发展的保护机制。了解体内不同解剖区域的脂肪生成机制仍然是脂肪生物学领域的首要任务，脂肪细胞前体细胞 (APC) 作为 WAT 脉管系统的一个子集。热量过量情况下，血管周围的 PDGFRb+ 壁细胞脂肪生成促进健康的 WAT 重塑和胰岛素敏感性。重要的是，组织微环境中的强抑制信号以区域特异性方式控制脂肪生成。循环中，我们建议检验以下假设：抗脂肪形成、促纤维形成、HIFa（缺氧诱导因子）依赖性信号级联抑制APC 中的 PPARg 活性通过丝氨酸 112 (S112) 磷酸化促进肥胖中不健康的 WAT 建模我们的具体目标是 1) 确定壁细胞 HIFa 信号传导在肥胖脂肪重塑组织中的作用，以及 2) 确定 HIFa 依赖性信号传导机制。导致肥胖中 PPARg 活性的抑制和脂肪细胞增生的抑制。成功完成这些目标将增进我们对储库特异性脂肪细胞祖细胞和脂肪细胞的了解。体内脂肪生成的调节这可能会导致新的治疗策略将胰岛素抵抗与肥胖分开。