Mechanisms Underlying Metabolic Syndrome in Obesity

肥胖代谢综合征的潜在机制

• 批准号: 6935783
• 负责人: CHARLOTTE A. PETERSON
• 金额: $ 17.75万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 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/6935783
• 关键词: adipocytes; biological signal transduction; clinical research; gene expression; glycogen; human subject; insulin sensitivity /resistance; macrophage; metabolic syndrome; muscle cells; muscle function; obesity; oxidation; photon absorptiometry; polymerase chain reaction; secretory protein; tissue /cell culture

DESCRIPTION (provided by applicant): 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 Kern, 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 secretary 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 IMCL and 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 secretary 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. Coculture 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.

描述（由申请人提供）：肥胖是产生胰岛素抵抗和代谢综合征的最常见和强大的力量，但是，这种关联的分子基础尚不清楚。在该提案中，三位独立资助的研究人员 - 菲利普·克恩（Philip Kern），医学博士A临床研究者和夏洛特·彼得森（Charlotte Peterson）博士和罗伯特·麦格希（Robert McGehee）博士，在肌肉和脂肪细胞生物学方面具有丰富的经验，分别将合作努力作为先前的合作努力，以此作为先前的合作努力。在肥胖，胰岛素抵抗和组织脂质积累领域的工作和共同利益。我们的总体假设是，人类的胰岛素抵抗主要源于肥胖发育过程中肌内脂质（IMCL）的异位积累。此外，我们假设过量的IMCL积累取决于脂肪组织中脂肪细胞和巨噬细胞之间复杂相互作用的秘密蛋白质。为了检验这些假设，我们将检查脂肪细胞，巨噬细胞和肌肉细胞之间的相互作用，这些相互作用是从中等肥胖的受试者中分离出来的，具有胰岛素抵抗和葡萄糖耐受性受损（IGT），但尚未忍受禁食性高血糖。这项研究人群的IMCL升高，肥胖并发症的风险很高，但避免了糖毒性的病理生理并发症。这些受试者将与具有正常葡萄糖耐受性的中度肥胖受试者进行比较（非）。 AIM 1将探索有助于IMCL并阐明其在IGT发展中的作用的机制。培养的肌肉细胞将用于确定IGT与NGT的肥胖受试者是否在不同的细胞外脂肪酸浓度下表现出肌肉基因表达和代谢活性的内在差异。将评估脂质积累和氧化，以及胰岛素介导的糖原合成和信号传导。 AIM 2将确定IMCL积累是否取决于脂肪组织秘书蛋白。我们将使用脂肪细胞，成肌细胞和脂肪基质血管细胞的共同培养来检查IMCL和胰岛素抵抗的发展。 AIM 3将确定与肌肉细胞共培养中NGT受试者相比，IGT受试者的基质分数是否更有效地促进IMCL。我们将在单核细胞/巨噬细胞积累和细胞因子表达方面比较基质血管级分。 AIM 4将确定响应于10周的吡格列酮治疗葡萄糖耐受性是否会导致IMCL降低并确定涉及的细胞机制。吡格列酮治疗前后，共培养研究还将与肌肉和基质细胞一起使用。这些实验将提供有关肥胖和肌肉功能之间的联系的机械洞察力，导致代谢综合征。