Glucocorticoids & Adipocyte Function in Human Obesity

糖皮质激素

• 批准号: 9458713
• 负责人: Susan K Fried
• 金额: $ 38.14万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9458713
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Affect; Cellularity; Central obesity; Chronic; Chronic Disease; Data; Dependence; Dexamethasone; Dose; Endocrine; Equilibrium; Exhibits; Family; Fatty acid glycerol esters; Fibrosis; Gene Expression; Gene Targeting; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; Health; Human; Hydrocortisone; Hypertrophy; Impairment; Individual; Inflammation; Lead; Long-Term Effects; MADH2 gene; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Microarray Analysis; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Omentum; Organ Culture Techniques; Overweight; Pathway interactions; Phenotype; Phosphorylation; Production; Public Health; Regulation; Risk; Role; Signal Pathway; Signal Transduction; Stem cells; System; Testing; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Triglycerides; Variant; Visceral; Work; activin A; adipokines; autocrine; experimental study; gain of function; gene function; high risk; hypercortisolemia; in vivo; interest; lipid biosynthesis; loss of function; member; new therapeutic target; obesity risk; paracrine; prevent; public health relevance; receptor; recruit; response; stem cell differentiation; subcutaneous; therapeutic target; transcriptome; volunteer

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.

描述（由适用提供）：中枢性肥胖，尤其是内脏肥胖症，与代谢疾病（例如2型糖尿病）的风险更高有关。糖皮质激素（GCS）是脂肪组织功能的强大调节剂，可调节脂肪储存和释放，调节脂肪因子的产生并抑制注射。 GC促进了内脏（例如膜（OM））脂肪组织的首选积累，并增加腹部皮下（ABDSC）脂肪组织。为了阐明GC调节人类脂肪时机的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效应。结果表明，GCS调节了所有基因的30％，并且剂量依赖性和响应的幅度高度依赖。除了调节代谢途径的基因外，GC还引起了转化生长因子β（TGFß）途径中基因表达的明显变化。 TGFß超家族包括许多分泌的因素，包括已知可以调节脂肪形成的TGFB1和3，激活素A（INHBA）。该途径引起了人们的关注，因为从组织内募集新的脂肪细胞（ASC）的新脂肪细胞的能力可以防止现有脂肪细胞的肥大过多，从而保留对代谢健康至关重要的脂肪组织的正常代谢和内分泌功能。矛盾的是，与ABDSC ASC相比，OM ASC的区别差。新的初步数据表明，包括INHBA在内的抗辅助因子的表达在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，OM ASC中的NetTGFß途径信号传导（由SMAD2的激活表示）增加了，与差异度理解标准条件成比例，以及OM脂肪组织或ASC抑制ABDSC ASC的条件培养基。该提案的目的是阐明调节depot依赖性脂肪组织生长和代谢的分子和细胞机制。我们将解决三个具体目的：1）确定TGFß途径在介导源中介导的脂肪生成差异中的重要性，2）检验以下假设：GC-TGFß串扰调节调节依赖性基因表达，脂肪生成和脂肪细胞功能和3）通过慢性，慢性化适应性的机制进行了辅助机制。总的来说，这项工作可能导致鉴定下游的治疗靶标，以治疗或预防腹部肥胖及其代谢后果。