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（由申请人提供）：中心性肥胖，尤其是内脏性肥胖，与 2 型糖尿病等代谢性疾病的较高风险相关。糖皮质激素 (GC) 是脂肪组织功能的强大调节剂，可调节脂肪的储存和释放，调节脂肪的产生。脂肪因子，并抑制炎症，促进内脏（例如网膜（Om））脂肪组织的优先积累，并增加腹部皮下脂肪。 (Abdsc) 脂肪组织。为了阐明 GC 调节人类脂肪组织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影响，结果表明 GC 调节约 30% 的基因。除了调节代谢途径的基因外，GC 还引起转化生长因子 β (TGFβ) 途径中基因表达的明显变化。超家族包括许多分泌因子，包括 TGFb1 和 3、激活素 A (INHBA)，这些因子已知可调节脂肪生成。该途径令人感兴趣，因为从组织内的脂肪干细胞 (ASC) 募集新脂肪细胞的能力可防止现有脂肪细胞过度肥大。矛盾的是，与 Abdsc ASC、Om ASC 相比，脂肪细胞保留了脂肪组织的正常代谢和内分泌功能，这对于代谢健康至关重要。新的初步数据表明，Om 中包括 INHBA 在内的抗脂肪生成因子的表达较高，从而改变了平衡，有利于脂肪生成，但 Om 对这些效应不太敏感，与该模型一致，净 TGFβ 通路信号传导（由Om ASC 中 SMAD2 的激活增加，与标准条件下的分化程度成正比，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储库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标：1) 确定 TGFβ 途径在介导脂肪生成中储库差异中的重要性，2) 测试假设 GC-TGFß 串扰调节库依赖性基因表达、脂肪生成和脂肪细胞功能，以及 3) 阐明轻度、慢性高皮质醇血症的机制总的来说，这项工作可能会导致下游治疗靶点的确定，以治疗或预防腹部肥胖及其代谢后果。