Mechanisms Underlying Metabolic Syndrome in Obesity

肥胖代谢综合征的潜在机制

• 批准号: 7272721
• 负责人: CHARLOTTE A. PETERSON
• 金额: $ 17.36万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7272721
• 关键词: Adipocytes; Adipose tissue; Blood Vessels; Cells; Clinical Investigator; Coculture Techniques; Complex; Development; Doctor of Philosophy; Fasting; Fatty Acids; Funding; Gene Expression; Glycogen; Human; Hyperglycemia; Insulin; Insulin Resistance; Link; Lipids; Mediating; Metabolic; Metabolic syndrome; Molecular; Muscle; Muscle Cells; Muscle function; Myoblasts; Obesity; Pioglitazone; Population Study; Role; Signal Transduction; Stromal Cells; Testing; Tissues; Week; Work; adipocyte biology; base; cytokine; experience; extracellular; glucose tolerance; impaired glucose tolerance; improved; insight; interest; macrophage; monocyte; obesity risk; oxidation; research study; response; secretory protein; stem

Obesity is the most common and powerful force for creating insulin resistance and metabolic syndrome, however, the molecular basis of this association is not well understood. In this proposal, three independently funded researchers¿Philip Kem, MD a clinical investigator, and Charlotte Peterson, PhD and Robert McGehee, PhD, with significant experience in muscle and adipocyte biology, respectively¿will formalize a collaborative effort as a natural extension of previous work and shared interests in the fields of obesity, insulin resistance, and tissue lipid accumulation. Our overall hypothesis is that insulin resistance in humans stems largely from ectopic accumulation of intramyocellular lipid (IMCL) during the development of obesity. Further, we hypothesize that excess IMCL accumulation is dependent on secretory proteins derived from a complex interplay between adipocytes and macrophages in adipose tissue. To test these hypotheses, we will examine the interactions among adipocytes, macrophages, and muscle cells isolated and cultured from subjects that are moderately obese with insulin resistance and impaired glucose tolerance (IGT), but who do not yet have fasting hyperglycemia. This study population has elevated IMCL and is at high risk for obesity complications, but avoids the pathophysiologic complications of glucotoxicity. These subjects will be compared to moderately obese subjects with normal glucose tolerance (NOT). Aim 1 will explore mechanisms that contribute to IMCLand elucidate its role in the development of IGT. Cultured muscle cells will be used to determine whether obese subjects with IGT versus NGT demonstrate intrinsic differences in muscle gene expression and metabolic activity under differing extracellular fatty acid concentrations. Lipid accumulation and oxidation, and insulin-mediated glycogen synthesis and signaling will be assessed. Aim 2 will determine if the IMCL accumulation is dependent on adipose tissue secretory proteins. We will use co-cultures of adipocytes, myoblasts, and adipose stromal vascular cells to examine IMCL and the development of insulin resistance. Aim 3 will determine whether the stromal fraction from IGT subjects promotes IMCL more effectively than that from NGT subjects in co-cultures with muscle cells. We will compare the stromal vascular fractions with regard to monocyte/macrophage accumulation and cytokine expression. Aim 4 will determine if improved glucose tolerance in response to a 10- week treatment with pioglitazone results in decreased IMCL and identify cellular mechanisms involved. Co- culture studies will also be used with muscle and stromal cells, before and after pioglitazone treatment. These experiments will provide mechanistic insight into the link between obesity and muscle function leading to metabolic syndrome. _^___

肥胖是创造胰岛素抵抗和代谢综合症的最常见和强大的， 但是，这不是很好的理解。 资助的研究人员医学博士Philip Kem临床研究员，夏洛特·彼得森（Charlotte Peterson），博士和罗伯特·麦吉（Robert McGehee）， 博士，在肌肉和脂肪细胞生物学方面具有丰富的经验。将正式合作 先前工作的富裕扩展，并在肥胖和抗蛋白耐药性领域中保存了利益， 组织脂质的积累。我们的总体假设是 在观察过程中的发育过程中，细胞内脂质（IMCL）的异位积累。 假设过量的弥散取决于从复合物中得出的分泌蛋白 在脂肪组织中解释脂肪细胞和巨噬细胞。 脂肪细胞，巨噬细胞和肌肉细胞之间的相互作用分离为从受试者中 中度肥胖具有胰岛素抵抗和葡萄糖耐受性受损（IGT），但没有禁食 高血糖。 葡萄毒性的病理生理并发症将被比较肥胖 具有正常葡萄糖的受试者（不）。 阐明其在IGT发展中的作用。 IGT与NGT的受试者表现出肌肉基因表达和代谢活性的内在差异 在不同的细胞外脂肪酸浓度下。 糖原合成和信号传导将被评估。 在脂肪组织分泌蛋白上。 血管细胞检查IMCL和胰岛素抵抗的发展。 IGT受试者的基质分数更有效地促进了IMCL的共同培养中的NGT受试者 使用肌肉细胞。 累积和细胞因子的表达将确定是否提高了葡萄糖耐受性 吡格列酮的一周治疗导致IMCL降低并确定涉及的细胞机制。 培养基在吡格列酮治疗之前和之后与肌肉和基质细胞一起使用。 实验也将为肥胖和肌肉功能之间的联系提供机械性 代谢综合征。