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抵抗这些代谢紊乱的发生。这意味着体重指数本身以外的因素也推动了这些病症的发展。将“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表明，肥胖时储存能量的白色脂肪组织（WAT）的重塑方式是代谢健康的关键决定因素。健康的 WAT 扩张的特点是 1) 皮下 WAT 库优先扩张，2) 通过增加细胞分化或“脂肪生成”来扩张脂肪组织。这种表型与肥胖症中保留的胰岛素敏感性密切相关。病理性WAT扩张的特征在于1)皮下WAT库的有限扩张，以及2)病理性WAT重塑，其特征在于有限的脂肪生成、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累相关。因此，热量过量情况下的从头脂肪生成是一种保护机制，可确保 WAT 中能量的安全储存并防止代谢疾病的发生。了解体内不同解剖区域控制脂肪生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+ 细胞的脂肪生成可促进小鼠健康的 WAT 重塑和胰岛素敏感性。重要的是，组织微环境内的强抑制信号以区域特异性方式控制脂肪生成。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、HIFa（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，从而促进肥胖中不健康的 WAT 模型。我们的具体目标是 1) 确定壁细胞 HIFa 信号传导在肥胖症脂肪组织重塑中的作用，2) 确定导致肥胖症 PPARg 活性抑制和脂肪细胞增生抑制的 HIFa 依赖性信号传导机制。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体内脂肪生成调节的理解。这可能会导致新的治疗策略将胰岛素抵抗与肥胖分开。