Glucocorticoids & adipocyte function in human obesity

糖皮质激素

• 批准号: 7590947
• 负责人: Susan K Fried
• 金额: $ 40.4万
• 依托单位: BOSTON MEDICAL CENTER
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590947
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Affect; American; Apoptosis; Bioinformatics; Candidate Disease Gene; Cardiovascular Diseases; Central obesity; Chronic; Cluster Analysis; Complex; Cortisone; Cushing Syndrome; Data; Deposition; Diabetes Mellitus; Endocrine; Epidemic; Experimental Designs; Fasting; Fatty acid glycerol esters; Gene Expression; Gene Targeting; Generations; Genes; Glucocorticoids; Goals; Hormones; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Immune; In Vitro; Inflammation; Ingestion; Insulin; Leptin; Leucine Zippers; Lipolysis; Literature; Mediating; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Omentum; Operative Surgical Procedures; Organ Culture Techniques; Overweight; Pathway interactions; Peripheral; Phenotype; Physiologic pulse; Physiology; Production; Quality of life; Regulation; Research; Risk; Role; Sampling; Serum; Small Interfering RNA; Stress; Testing; Therapeutic Intervention; Time; Variant; Visceral; Work; adipokines; base; cell type; feeding; high risk; immune function; in vivo; insight; novel; obesity risk; overexpression; prevent; public health relevance; research study; response; subcutaneous

DESCRIPTION (provided by applicant): Obesity, particularly visceral and upper body subcutaneous obesity, is associated with higher risk for obesity-related co-morbidities, including type 2 diabetes and cardiovascular disease. Glucocorticoids (GC) are powerful regulators of fat deposition and fat distribution. Obesity is associated with an increase in local cortisol production within both subcutaneous and visceral adipose tissues. In addition, visceral (omental) adipose tissue is more responsive to GC in vitro, suggesting depot differences in GC action contribute to depot differences in fat cell metabolism and endocrine function. Our preliminary gene array studies show that chronic treatment of human adipose tissue with GCs regulates numerous genes related to metabolism and inflammation in vitro, and identified several potentially important GC targets that could contribute to the depot-specific activation of different gene networks. The relevance of these changes to in vivo physiology and the underlying mechanisms by which GC coordinate the activity of different gene networks that regulate the metabolic and endocrine functions of the adipocyte remain unclear. Thus, Specific Aim 1 of the current proposal will focus on identifying the genes in abdominal subcutaneous adipose tissue that are regulated by glucocorticoids in vivo. Because GC effects depend on nutritional state/insulin, we will compare the effects of hydrocortisone administered in the fasted state or in combination with meals, on global gene expression (Affymatrix gene arrays). Adipose tissue will be sampled 3.5h after hydrocortisone administration (with or without a meal) to determine primary GC target genes. To elucidate the mechanisms underlying the differential effects of GC in visceral fat, Specific Aim 2 will compare GC-regulated gene expression in organ cultures of Abd sc and omental adipose tissue and primary adipocytes in vitro using a candidate gene approach. Specific Aim 3 will test the functional importance of apparent primary GC targets at the level of the adipocyte with analysis of alterations in the expression of downstream targets using analysis of candidate genes and gene arrays, and functional changes in adipocyte metabolism and adipokine secretion. Collectively, these data will enhance understanding of the mechanisms by which GC promote obesity, particularly visceral fat deposition, by pointing to novel targets for therapeutic intervention for visceral obesity and its metabolic complications. PUBLIC HEALTH RELEVANCE: The `diabesity' epidemic and its metabolic complications detract from the quality of life of the majority of Americans. Our proposed work addresses the mechanisms by which glucocorticoids, hormones secreted during stress, regulate the amount of fat deposited in human adipose tissues, and whether the fat is mainly deposited in central (abdominal) or peripheral depots and hence contribute to risk for developing diabetes and cardiovascular disease. These data will provide a critical first step to unraveling the complex, pleiotropic effects of GC in human adipose tissues. Furthermore, identifying the key targets of GC action in fat may provide novel insights into the effects of GC in orchestrating the integration of the endocrine, immune and metabolic functions of the adipocyte.

描述（由申请人提供）：肥胖，尤其是内脏和上身皮下肥胖，与肥胖相关的合并症的风险较高，包括2型糖尿病和心血管疾病。糖皮质激素（GC）是脂肪沉积和脂肪分布的强大调节剂。肥胖与皮质和内脏脂肪组织中局部皮质醇产生的增加有关。此外，内脏（肿瘤）脂肪组织在体外对GC的反应更大，这表明GC作用的仓库差异有助于脂肪细胞代谢和内分泌功能的销售差异。我们的初步基因阵列研究表明，用GCS对人脂肪组织进行长期处理可调节与代谢和体外炎症有关的许多基因，并确定了几种可能有助于不同基因网络库特异性激活的潜在重要的GC靶标。这些变化与体内生理学的相关性以及GC协调调节脂肪细胞代谢和内分泌功能的不同基因网络的活性的潜在机制尚不清楚。因此，当前建议的具体目的1将集中于鉴定体内受糖皮质激素调节的腹部皮下脂肪组织中的基因。由于GC效应取决于营养状态/胰岛素，因此我们将比较禁食状态或与餐食结合使用的氢化可的松对全球基因表达（Affymatrix基因阵列）的影响。氢化可的松给药后（或不用餐）后，将对脂肪组织进行3.5h，以确定一级GC靶基因。为了阐明GC在内脏脂肪中的差异作用的基础机制，特定的AIM 2将比较ABD SC的器官培养物中GC调节的基因表达，使用候选基因方法在体外的膜脂肪组织和原发性脂肪细胞中进行比较。特定目标3将使用候选基因和基因阵列的分析以及脂肪细胞代谢和脂肪因子分泌的功能变化，测试明显主要GC靶标在脂肪细胞水平上的表观主要GC靶标的功能重要性。总的来说，这些数据将通过指出针对内脏肥胖症及其代谢并发症的治疗干预措施的新靶标，从而增强对GC促进肥胖症（尤其是内脏脂肪沉积）的机制的理解。 公共卫生相关性：“糖尿病”的流行及其代谢并发症损害了大多数美国人的生活质量。我们提出的工作解决了糖皮质激素（在压力期间分泌的激素）调节沉积在人脂肪组织中的脂肪量的机制，以及脂肪是否主要沉积在中央（腹部）还是外围仓库中，因此有助于产生糖尿病和心血管疾病的风险。这些数据将提供关键的第一步，以揭示GC在人脂肪组织中的复合物，多效性的影响。此外，识别脂肪中GC作用的关键靶标可以为GC在策划脂肪细胞的内分泌，免疫和代谢功能的整合中的影响提供新的见解。