Establishment and Maintenance of Healthy Adipose Tissue in Obesity

肥胖会增加患多种慢性疾病的风险，如胰岛素抵抗、2型糖尿病、脂肪肝和心血管疾病。重要的是，许多肥胖者至少在一段时间内对这些代谢紊乱有相对的抵抗力。这意味着BMI本身之外的因素推动了这些疾病的发展。通过比较“代谢健康肥胖”与代谢综合征肥胖个体的临床研究表明，肥胖症中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。健康的脂肪组织扩张的特点是：1)皮下脂肪储存库优先扩张；2)脂肪组织通过细胞分化或“脂肪生成”的增加而扩张。这种表型与肥胖患者保持的胰岛素敏感性密切相关。病理性WAT扩张的特征是1)皮下WAT储存库的有限扩张，2)病理性WAT重塑，以有限的脂肪生成、脂肪细胞肥大、炎症和纤维化为特征。这些表型与胰岛素抵抗和非脂肪组织中的异位脂质积累相关。因此，在热量过剩的情况下，新生脂肪形成是一种保护机制，可以确保WAT中安全的能量储存，防止代谢性疾病的发生。了解体内不同解剖区域的脂肪形成机制仍然是脂肪生物学领域的当务之急。脂肪前体细胞（APCs）作为血管周围、PDGFRb+、壁细胞的一个亚群存在于WAT血管中。在热量过剩的情况下，源自PDGFRb+细胞的脂肪形成促进了小鼠健康的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特定区域的方式控制脂肪形成。在下一个资助周期中，我们将验证一个假设，即抗脂肪生成、促纤维生成、hfa（缺氧诱导因子）依赖的信号级联通过丝氨酸112 （S112）磷酸化抑制apc中的ppar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)确定肥胖中壁细胞HIFa信号在脂肪组织重塑中的作用；2)确定HIFa依赖的信号机制，从而抑制肥胖中ppar活性和脂肪细胞增生。成功完成这些目标将促进我们对储存特异性脂肪细胞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来解开胰岛素抵抗与肥胖的关系。

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.