Testing the Adipose Expandability Hypothesis In Vivo During Overfeeding

项目摘要/摘要 脂肪膨胀是适应长期过量卡路里摄入所必需的，其特征是 脂肪细胞的大小(肥大)和数量(增殖；脂肪生成)的增加。尽管肥胖症与 在脂质处理和储存能力方面，肥胖和新陈代谢之间联系的潜在机制 人们对甲胎综合征(METS)知之甚少。AT可扩充性假设假设 皮下(亚Q)脂肪扩张是代谢健康的一个重要决定因素，因为受损 脂肪生成(局限性增生)可能导致非脂肪器官中的异位脂肪沉积，导致 肥胖相关疾病的发展。一些体外研究报告说，小脂肪细胞的数量更多 甲硫氨酸转运蛋白(METS)和2型糖尿病患者(即增生症)。来自两项人类过度喂养研究的数据(一项 来自我们小组的)表明，较小的脂肪细胞尺寸会导致更大的胰岛素敏感性损害 随着体重的增加。我们是唯一一个通过掺入SubQ AT来评估体内脂肪生成的小组 进入肥胖女性脂肪细胞中，表明高脂肪细胞的形成与肥胖女性 代谢健康受损的几个方面。我们的发现和其他发现与AT可扩充性假设相反 提供更高(而不是更低)的脂肪生成(即肥胖症)与肥胖相关的证据 精神错乱。使用随机对照试验(RCT)，我们将检查为期9周的干预对 AT的可扩展性机制。超重的男性和女性将被随机分配到30%的过度饮食(OF)或 体重稳定对照组(CTL)。该提案的目标是测试体内脂肪生成，使用一种 经过验证的2H标记方法，以及响应体重增加的SubQ AT扩展的其他机制，以及 评估脂肪膨胀与代谢结果变化的关系。主要的假设是 OF的高脂肪生成将伴随内脏脂肪增加和异位 伴有SubQ AT扩张受损个体的血脂、胰岛素敏感性降低和病理性AT重构。 因此，尽管体重增加者有增生，但有限的脂肪细胞储存能力可能有利于受损的 健康结果。这是第一个检验“At可扩充性假说”有效性的随机对照试验。调查结果将提供 脂肪特性对代谢反应动态变化影响的新认识 人类的体重。

PROJECT SUMMARY/ABSTRACT Adipose expansion is necessary to accommodate chronic excess caloric intake and characterized by an increase in adipocyte size (hypertrophy) and number (hyperplasia; adipogenesis). Though obesity is related to AT lipid handling and storage capacity, the mechanisms underlying the link between obesity and the metabolic syndrome (MetS) are poorly understood. The AT expandability hypothesis postulates that the capacity for subcutaneous (subQ) adipose expansion is a significant determinant of metabolic health, as impaired adipogenesis (limited hyperplasia) may lead to ectopic lipid deposition in non-adipose organs, contributing to the development of obesity-associated diseases. Some in vitro studies report a higher population of small fat cells (i.e. hyperplasia) in individuals with MetS and type 2 diabetes. Data from two human overfeeding studies (one from our group) demonstrate that a smaller adipocyte size resulted in a greater impairment of insulin sensitivity with weight gain. We are the only group to assess in vivo adipogenesis in subQ AT via the incorporation of deuterium (2H) into adipose cells of obese women and show that higher adipocyte formation was associated with facets of impaired metabolic health. Our findings and others are contrary to the AT expandability hypothesis and provide evidence that higher (not lower) adipogenesis (i.e. hyperplasia) is associated with obesity-related disorders. Using a randomized controlled trial (RCT), we will examine the effects of a 9-week intervention on mechanisms of AT expandability. Overweight men and women will be randomized to 30% overfeeding (OF) or a weight stable Control (CTL) group. The objectives of the proposal are to test in vivo adipogenesis, using a validated 2H-labeling approach, and other mechanisms of subQ AT expansion in response to weight gain, and to assess the relationship of adipose expansion with changes in metabolic outcomes. The primary hypothesis is that higher adipogenesis in response to OF will be accompanied by increased visceral adiposity and ectopic lipid, reduced insulin sensitivity, and pathological AT remodeling in individuals with impaired subQ AT expansion. Therefore, despite hyperplasia in weight gainers, a limited storage capacity of adipocytes may facilitate impaired health outcomes. This is the first RCT to test the validity of the `AT expandability hypothesis'. Findings will provide new knowledge on the influence of adipose characteristics on the metabolic responses to dynamic changes in weight in humans.