Glucocorticoids & adipocyte function in human obesity

 描述（由申请人提供）：向心性肥胖，特别是内脏肥胖，与代谢性疾病（如2型糖尿病）的高风险相关。糖皮质激素（GC）是脂肪组织功能的强有力调节剂，其调节脂肪储存和释放，调节脂肪因子的产生，并抑制炎症。GC促进内脏（例如网膜（Om））脂肪组织的优先积累，并且还增加腹部皮下（Abdsc）脂肪组织。为了阐明GC调节人体脂肪组织脂肪分布和功能的机制，我们使用器官培养系统测试了其长期作用。结果表明，GC调节所有基因的~30%，并且响应的剂量依赖性和幅度高度依赖于储库。除了调节代谢途径的基因外，GC还引起转化生长因子β（TGF）途径中基因表达的明显变化。TGF超家族包括许多分泌因子，包括已知调节脂肪形成的TGF β 1和3、激活素A（INHBA）。该途径是令人感兴趣的，因为从组织内的脂肪干细胞（ASC）募集新脂肪细胞的能力防止了现有脂肪细胞的过度肥大，从而保持了脂肪组织的正常代谢和内分泌功能，这对于代谢健康是必不可少的。特别是，与Abdsc ASC相比，Om ASC分化较差。新的初步数据显示，包括INHBA在内的抗脂肪形成因子的表达在Om中更高。GC改变了平衡，有利于脂肪形成，但OM对这些影响不太敏感。与该模型一致，在标准条件下，Om ASC中的净TGF途径信号传导（由SMAD 2的活化指示）与分化程度成比例地增加，并且来自Om脂肪组织或ASC的条件培养基抑制Abdsc ASC的分化。该提案的目标是阐明调节贮库依赖性脂肪组织生长和代谢的分子和细胞机制。我们将讨论三个具体目标：1）确定TGF途径在介导脂肪形成中的贮库差异中的重要性，2）检验GC-TGF串扰调节贮库依赖性基因表达、脂肪形成和脂肪细胞功能的假设，以及3）阐明轻度慢性高皮质醇血症在体内调节人类脂肪组织功能的机制。总的来说，这项工作可能会导致识别GR下游的治疗靶点，以治疗或预防腹部肥胖及其代谢后果。

 DESCRIPTION (provided by applicant): Central obesity, especially visceral obesity, is associated with higher risk for metabolic disease such as Type 2 diabetes. Glucocorticoids (GCs) are powerful regulators of adipose tissue function that modulate fat storage and release, regulate the production of adipokines, and suppress inflammation. GCs promote the preferential accumulation of visceral (e.g. Omental (Om)) adipose tissue, and also increase abdominal subcutaneous (Abdsc) adipose tissue. To elucidate mechanisms by which GCs regulate fat distribution and function of human adipose tissues, we tested its long-term effects using an organ culture system. The results indicated that GCs regulate ~30% of all genes, and that the dose-dependent and magnitude of the response was highly depot dependent. In addition to genes that regulate metabolic pathways, GCs caused clear changes in the expression of genes in the transforming growth factor beta (TGF ) pathway. The TGF superfamily includes many secreted factors, including TGFb1 and 3, activin A (INHBA) that are known to regulate adipogenesis. This pathway was of interest because the ability to recruit new adipocytes from adipose stem cells (ASCs) within the tissues prevents excessive hypertrophy of existing adipocytes, and thereby preserves the normal metabolic and endocrine functions of the adipose tissues that are essential for metabolic health. Paradoxically, compared to Abdsc ASCs, Om ASCs differentiate poorly. New preliminary data show that expression of anti-adipogenic factors including INHBA is higher in Om. GCs shifted the balance to favor adipogenesis, but Om was less sensitive to these effects. Consistent with this model, net TGF pathway signaling (indicated by the activation of SMAD2) was increased in Om ASCs, in proportional to differentiation degree under standard conditions, and conditioned media from Om adipose tissue or ASC inhibited differentiation of Abdsc ASCs. The goal of this proposal is elucidate the molecular and cellular mechanisms that regulate depot-dependent adipose tissue growth and metabolism. We will address three Specific Aims: 1) To determine the importance of TGF pathway in mediating depot differences in adipogenesis, 2) To test the hypothesis that GC-TGF crosstalk modulates depot-dependent gene expression, adipogenesis and adipocyte function, and 3) To elucidate mechanisms by which mild, chronic hypercortisolemia modulates human adipose tissue function in vivo. Collectively, this work may lead to the identification of therapeutic targets downstream o GR to treat or prevent abdominal obesity and its metabolic consequences.