Establishment and Maintenance of Healthy Adipose Tissue in Obesity

肥胖会增加患上许多慢性疾病的风险，如胰岛素抵抗、2型糖尿病、脂肪肝和心血管疾病。重要的是，至少在一段时间内，许多肥胖者对这些代谢紊乱有相对的抵抗力。这意味着，BMI以外的因素本身推动了这些状况的发展。临床研究表明，储存能量的白色脂肪组织(WAT)在肥胖症患者中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)皮下水库优先扩张，2)脂肪组织通过增加细胞分化或“脂肪生成”而扩张。这种表型与肥胖患者保留的胰岛素敏感性有很好的相关性。病理性WAT扩张的特征是1)皮下水池有限扩张，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异位脂肪堆积有关。因此，在热量过剩的情况下进行新生脂肪生成是一种保护机制，以确保在水中安全地储存能量，并防止代谢性疾病的发展。了解体内解剖不同区域的脂肪生成控制机制仍然是脂肪生物学领域的优先事项。脂肪细胞前体细胞(APC)作为血管周围PDGFRb壁细胞的一个亚群存在于WAT血管系统中。在卡路里过量的情况下，来自PDGFRb细胞的脂肪生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区域特有的方式控制脂肪生成。在下一个资金周期中，我们建议测试这一假说，即抗成脂、促纤维化、HIFA(低氧诱导因子)依赖的信号级联通过丝氨酸112(S112)磷酸化抑制APC中PPARg的活性，以促进肥胖的不健康WAT模型。我们的具体目标是1)确定壁细胞HIFA信号在肥胖脂肪组织重塑中的作用，2)确定HIFA依赖的信号机制导致肥胖时PPARg活性的抑制和脂肪细胞的增殖。这些目标的成功完成将促进我们对储存库特异性脂肪细胞前体细胞的了解，并促进体内脂肪生成的调控。这可能会导致新的治疗策略，将胰岛素抵抗与肥胖分开。

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.