Impaired adipogenesis in insulin resistance: pilot clinical and in-vitro studies

胰岛素抵抗中脂肪生成受损：试点临床和体外研究

• 批准号: 7586169
• 负责人: RICHARD E PRATLEY
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2010-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586169
• 关键词: Accounting; Adipocytes; Adipose tissue; Affect; Age; Agonist; American; Biopsy; Blood Vessels; Body Composition; Body Weight decreased; Buffers; CCL2 gene; Caliber; Cells; Choristoma; Clinical; Clinical Research; Complex; DEXA; DNA; Development; Diabetes Mellitus; Differentiation and Growth; Endocannabinoids; Endocrine; Energy Intake; Energy Metabolism; Epidemic; Ethnic group; Euglycemic Clamping; Exercise; Exposure to; Facilities and Administrative Costs; Failure; Fatty Acids; Fatty acid glycerol esters; Feedback; Feeding behaviors; Functional disorder; Gender; Gene Expression; Glucose Clamp; Growth; Human; Hypertrophy; Immunity; Impairment; In Vitro; Individual; Inflammatory; Insulin; Insulin Resistance; Interleukin-6; Label; Lead; Leptin; Link; Lipodystrophy; Liver; Longitudinal Studies; Measurement; Measures; Metabolic; Metabolism; Morbidity - disease rate; Needle biopsy procedure; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional status; Obesity; Organ; Overweight; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Pilot Projects; Play; Population; Prevention; Public Health; Recruitment Activity; Regulation; Relative (related person); Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Secondary to; Signal Transduction; Signaling Molecule; Site; Skeletal Muscle; Staining method; Stains; Stratification; System; Techniques; Testing; Time; Tissue Sample; Tissues; Triglycerides; Visceral; adipocyte differentiation; adipokines; adiponectin; autocrine; base; cytokine; diabetes risk; economic impact; improved; in vivo; insight; insulin sensitivity; lipid biosynthesis; macrophage; mortality; non-diabetic; novel strategies; nutrition; oral glucose tolerance; paracrine; prevent; research study; response; stable isotope; subcutaneous; theories; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Obesity is the strongest acquired risk factor for type 2 diabetes (T2DM), however the precise mechanisms linking these conditions are not known. The central hypothesis of this pilot project is that a failure to differentiate new subcutaneous adipocytes in response to over nutrition leads to the development of hypertrophic adipocytes that manifest alterations in the expression and secretion of adipokines. These changes, including increases in pro-inflammatory cytokines and decreases in adiponectin, provide feedback through both paracrine and endocrine axes to limit further fat accretion, at the expense of worsening metabolic dysfunction. Four specific aims will be tested in obese insulin resistant subjects (OIR, N = 15) and obese insulin sensitive subjects (OIS, N = 15) to determine: 1) whether preadipocyte proliferation or differentiation is impaired in vivo in OIR vs. OIS, 2) whether preadipocyte proliferation or differentiation is impaired in vitro in OIR vs. OIS, 3) whether impairments in preadipocyte proliferation are associated with hypertrophic adipocytes and a pro-inflammatory phenotype and 4) the role of the endocannabinoid system in regulating preadipocyte proliferation and differentiation. Subjects will undergo measurement of body composition (DEXA), oral glucose tolerance, insulin sensitivity (glucose clamp) and percutaneous needle biopsies of subcutaneous fat. Adipogenesis will be measured in vivo by determining turnover rates of adipocytes and stromal-vascular cells using 2H2O to label DNA. Proliferation and differentiation of preadipocytes in vitro will be measured in primary cultures derived from each subject. Adipocyte size, expression of pro-inflammatory cytokines and the expression of genes involved in the endocannabinoid pathway will be compared in OIR and OIS subjects and related to measures of proliferation and differentiation. Understanding the mechanisms whereby obesity leads to T2DM may improve risk stratification and may suggest novel approaches to prevent and treat T2DM and its complications. Project Narrative: Obesity is a potent risk factor for developing type 2 diabetes. This study tests whether differences in the growth rates of fat cells are related to the risk for diabetes in obese individuals. Results from this study could suggest new prevention / treatment strategies.

描述（由申请人提供）：肥胖是2型糖尿病（T2DM）最强的获得的风险因素，但是连接这些疾病的确切机制尚不清楚。该试验项目的中心假设是，由于过度营养而无法区分新的皮下脂肪细胞，这会导致肥厚的脂肪细胞的发展，从而表现出脂肪因子表达和分泌的改变。这些变化，包括促炎性细胞因子的增加和脂联素的降低，通过旁分泌和内分泌轴提供反馈，以限制进一步的脂肪吸收，牺牲代谢功能障碍的恶化。将在肥胖的胰岛素耐药受试者（OIR，n = 15）和肥胖的胰岛素敏感受试者（OIS，n = 15）中测试四个具体目标，以确定：1）在OIR vs. OIS中，在体内是否受到质量增殖或分化的影响。前脂肪细胞增殖与肥厚的脂肪细胞和促炎的表型有关，以及4）内源性大麻素系统在调节前脂肪细胞增殖和分化方面的作用。受试者将经过人体组成（DEXA），口服葡萄糖耐受性，胰岛素敏感性（葡萄糖夹）和皮下脂肪的经皮针射击。通过使用2H2O标记DNA的脂肪细胞和基质 - 血管细胞的周转率，将在体内测量脂肪形成。体外前细胞的增殖和分化将在每个受试者得出的原发性培养物中进行测量。将在OIR和OIS受试者中比较脂肪细胞大小，促炎细胞因子的表达以及与内源性大麻素途径有关的基因的表达，并且与增殖和分化的测量有关。了解肥胖导致T2DM的机制可能改善风险分层，并可能提出预防和治疗T2DM及其并发症的新方法。 项目叙述：肥胖是患有2型糖尿病的有效风险因素。这项研究测试了脂肪细胞生长速率的差异是否与肥胖个体的糖尿病风险有关。这项研究的结果可以表明新的预防 /治疗策略。