Glucocorticoids & Adipocyte Function in Human Obesity

描述(申请人提供)：中心性肥胖，特别是内脏肥胖，与患代谢性疾病如2型糖尿病的风险较高有关。糖皮质激素(GCs)是脂肪组织功能的强大调节剂，可调节脂肪的储存和释放，调节脂肪因子的产生，并抑制炎症。GCS促进内脏(如大麦(Om))脂肪组织的优先积聚，也增加腹部皮下(Abdsc)脂肪组织。为了阐明GCs调节脂肪分布和人类脂肪组织功能的机制，我们使用器官培养系统测试了它的长期影响。结果表明，GCs调控了约30%的基因，并且反应的剂量和大小高度依赖于仓库。除了调节新陈代谢途径的基因外，GCs还导致转化生长因子β途径中基因表达的明显变化。转化生长因子超家族包括许多分泌因子，包括已知调节脂肪生成的TGFb1和3、激活素A(INHBA)。这一途径之所以令人感兴趣，是因为从组织内的脂肪干细胞(ASCs)中招募新的脂肪细胞的能力可以防止现有脂肪细胞过度肥大，从而保护脂肪组织的正常代谢和内分泌功能，这是代谢健康所必需的。矛盾的是，与Abdsc ASCs相比，Om ASCs的分化较差。新的初步数据显示，包括INHBA在内的抗脂肪生成因子在Om中的表达较高。GCS改变了平衡，有利于脂肪生成，但Om对这些影响不那么敏感。与该模型一致的是，在标准条件下，Om ASCs的净转化生长因子(以Smad2的激活表示)信号增加，与分化程度成正比，来自Om脂肪组织或ASC的条件培养液抑制Abdsc ASCs的分化。这项建议的目的是阐明调节依赖于脂肪的脂肪组织生长和代谢的分子和细胞机制。我们将致力于三个具体目标：1)确定转化生长因子？途径在调节脂肪形成中库的差异中的重要性；2)检验GC-转化生长因子？？串扰调节库依赖的基因表达、脂肪生成和脂肪细胞功能的假设；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。总而言之，这项工作可能导致确定GR下游的治疗靶点，以治疗或预防腹型肥胖及其代谢后果。

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 (TGFß) pathway. The TGFß 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 TGFß 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 TGFß pathway in mediating depot differences in adipogenesis, 2) To test the hypothesis that GC-TGFß 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.