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: 8001118
• 负责人: RICHARD E PRATLEY
• 金额: $ 3.9万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-21 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001118
• 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（T2 DM）最强的获得性风险因素，但与这些疾病相关的确切机制尚不清楚。该试点项目的中心假设是，未能分化新的皮下脂肪细胞，以响应营养过剩导致肥大脂肪细胞的发展，表现出脂肪因子的表达和分泌的改变。这些变化，包括促炎细胞因子的增加和脂联素的减少，通过旁分泌和内分泌轴提供反馈，以限制进一步的脂肪堆积，代价是代谢功能障碍恶化。将在肥胖胰岛素抵抗受试者中测试四个特定目标（OIR，N = 15）和肥胖胰岛素敏感受试者（OIS，N = 15）以确定：1）前脂肪细胞增殖或分化在OIR与OIS中是否在体内受损，3）前脂肪细胞增殖的损伤是否与肥大脂肪细胞和促炎表型相关，和4）内源性大麻素系统在调节前脂肪细胞增殖和分化中的作用。受试者将接受身体成分（DEXA）、口服葡萄糖耐量、胰岛素敏感性（葡萄糖钳夹）和皮下脂肪经皮穿刺活检的测量。将通过使用2 H2O标记DNA测定脂肪细胞和基质-血管细胞的周转率来体内测量脂肪生成。将在源自每例受试者的原代培养物中测量体外前脂肪细胞的增殖和分化。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和参与内源性大麻素途径的基因的表达，并与增殖和分化的测量相关。了解肥胖导致T2 DM的机制可能会改善风险分层，并可能提出预防和治疗T2 DM及其并发症的新方法。 项目叙述：肥胖是发展2型糖尿病的潜在危险因素。这项研究测试了脂肪细胞生长速度的差异是否与肥胖个体患糖尿病的风险有关。这项研究的结果可以提出新的预防/治疗策略。