Establishment and Maintenance of Healthy Adipose Tissue in Obesity

肥胖症健康脂肪组织的建立和维持

• 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
• 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

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.

肥胖会导致许多慢性疾病，如胰岛素抵抗、2型糖尿病、脂肪肝和心血管疾病。重要的是，许多肥胖个体相对抵抗发展这些代谢紊乱，至少在一段时间内。这意味着BMI本身以外的因素推动了这些疾病的发展。比较“代谢健康的肥胖者”与患有代谢综合征的肥胖个体的临床研究已经揭示，肥胖中能量储存白色脂肪组织（WAT）重塑的方式是代谢健康的关键决定因素。健康WAT扩增的特征在于1）皮下WAT储库的优先扩增，和2）通过细胞分化或“脂肪生成”的增加的脂肪组织扩增。这种表型与肥胖症中胰岛素敏感性的保持密切相关。病理性WAT扩张的特征在于1）皮下WAT储库的有限扩张，和2）病理性WAT重塑，其特征在于有限的脂肪形成、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异位脂质积聚相关。因此，在热量过量的情况下从头脂肪形成是一种保护机制，以确保WAT中的安全能量储存并防止代谢疾病的发展。了解控制体内不同解剖学区域脂肪形成的机制仍然是脂肪生物学领域的一个高度优先事项。 脂肪细胞前体细胞（APC）作为血管周围PDGFRb+壁细胞的子集存在于WAT脉管系统内。在热量过量的情况下，源自PDGFRb+细胞的脂肪生成促进小鼠的健康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形成。在下一个资助周期中，我们建议测试以下假设：抗脂肪形成、促纤维形成、HIF a（缺氧诱导因子）依赖性信号级联通过丝氨酸112（S112）磷酸化抑制APC中的PPARg活性，以促进肥胖症中的不健康WAT建模。我们的具体目标是1）确定壁细胞HIF α信号传导在肥胖症中脂肪组织重塑中的作用，和2）鉴定导致肥胖症中PPARg活性抑制和脂肪细胞增生抑制的HIF α依赖性信号传导机制。这些目标的成功实现将促进我们对贮库特异性脂肪祖细胞和体内脂肪形成调控的理解。这可能会导致新的治疗策略，从肥胖症中分离胰岛素抵抗。