Glucocorticoids & adipocyte function in human obesity

糖皮质激素

• 批准号: 8446432
• 负责人: Susan K Fried
• 金额: $ 34.69万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446432
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Affect; American; Apoptosis; Bioinformatics; Candidate Disease Gene; Cardiovascular Diseases; Central obesity; Chronic; Cluster Analysis; Comorbidity; 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; Health; Hormones; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Immune; In Vitro; Inflammation; Ingestion; Insulin; Leptin; Leucine Zippers; Lipolysis; Literature; Mediating; Metabolic; Metabolism; Molecular; 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; 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.

说明(申请人提供)：肥胖，特别是内脏和上半身皮下肥胖，与肥胖相关的共病风险较高，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。肥胖与皮下和内脏脂肪组织中局部皮质醇产生的增加有关。此外，内脏(大网膜)脂肪组织在体外对GC更敏感，这表明GC作用的不同导致了脂肪细胞代谢和内分泌功能的不同。我们的初步基因芯片研究表明，GCs对人类脂肪组织的慢性处理在体外调节了许多与新陈代谢和炎症相关的基因，并发现了几个潜在的重要GC靶点，这些靶点可能有助于不同基因网络的仓库特异性激活。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动的潜在机制尚不清楚。因此，当前提案的具体目标1将集中在确定腹部皮下脂肪组织中受体内糖皮质激素调节的基因。由于GC效应取决于营养状态/胰岛素，我们将比较在禁食状态下或与膳食联合使用氢化可的松对全球基因表达的影响(AffyMatrix基因阵列)。脂肪组织将在服用氢化可的松3.5h后(有或没有进餐)进行采样，以确定主要的GC靶基因。为了阐明GC在内脏脂肪中的不同作用机制，Special Aim 2将使用候选基因方法比较体外培养的ABD sc和大网膜脂肪组织以及原代脂肪细胞中GC调控的基因表达。具体目标3将通过分析候选基因和基因阵列分析下游靶标的表达变化，以及脂肪细胞代谢和脂肪因子分泌的功能变化，在脂肪细胞水平上测试表观主要GC靶标的功能重要性。总而言之，这些数据将通过指出内脏肥胖及其代谢并发症的治疗干预的新靶点，加强对GC促进肥胖，特别是内脏脂肪沉积的机制的理解。