Exercise effects on adipose tissue morphology, metabolic function, and metabolic health with weight loss and weight regain in obesity

运动对肥胖患者体重减轻和体重恢复的脂肪组织形态、代谢功能和代谢健康的影响

• 批准号: 10775266
• 负责人: Jeffrey F Horowitz
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10775266
• 关键词: Abdomen; Adipocytes; Adipose tissue; Blood Pressure; Blood capillaries; Body Weight; Body Weight decreased; Body fat; Caloric Restriction; Capillarity; Cell Size; Cells; Circulation; Clinical; Dendritic Cells; Deposition; Diet; Disease; Endothelial Cells; Event; Exercise; Extracellular Matrix; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Gene Expression; Genes; Goals; Health; Health Benefit; Hour; Immune; Infiltration; Inflammatory; Insulin Resistance; Interval training; Link; Lipids; Lipolysis; Liver; Macrophage; Maintenance; Measures; Metabolic; Modification; Morphology; Nuclear RNA; Obesity; Obesity associated disease; Outcome; Pathway interactions; Pericytes; Phase; Post-Translational Protein Processing; Protocols documentation; Randomized; Regulation; Research Design; Signal Pathway; Signal Transduction; Skeletal Muscle; Standardization; Structure; Time; Tissues; Training; Translating; Visceral; Weight; adult obesity; angiogenesis; blood lipid; cardiometabolism; clinically relevant; density; dietary restriction; exercise intensity; exercise training; follow-up; glucose tolerance; improved; insight; lifestyle intervention; lipid biosynthesis; novel; obesity prevention; obesity treatment; precursor cell; programs; protective effect; response; single nucleus RNA-sequencing; stem; subcutaneous; transcriptome sequencing; weight loss intervention; weight loss program

Project Summary/Abstract The combination of caloric restriction and exercise is the most common first-line treatment for obesity-related disorders, yet we know very little about the synergistic effects of these two very different treatments. A deeper understanding about mechanisms underlying the health benefits of adding exercise to a weight loss program is critical for optimizing modifiable components of lifestyle interventions (e.g., exercise intensity). Importantly, although a reduction in adipose tissue mass is the fundamental adaptation to weight loss, we know almost nothing about the effects that adding exercise may have on structural and functional changes within adipose tissue. This is very important because many obesity-related metabolic health complications are tightly linked with abnormalities in abdominal subcutaneous adipose tissue (aSAT). In particular, high rates of fatty acid release from aSAT, which is very common in obesity, leads to ectopic lipid deposition in liver, visceral adipose tissue, and skeletal muscle, and is a major factor underlying insulin resistance. Therefore, increasing the capacity of aSAT to store and sequester fatty acids will protect against these abnormalities. Importantly, increased capacity of aSAT to store fat does not translate to increased body fat mass, this requires an energy surplus. Based on our exciting preliminary findings, we hypothesize exercise triggers key signaling pathways in aSAT to reprogram the regulation of angiogenesis, adipogenesis, and extracellular matrix (ECM) fibrosis to remodel aSAT for more effective energy storage. We contend these exercise-induced modifications in aSAT will impart persistent health benefits even if some weight is regained after weight loss. Finally, although high-intensity interval training (HIIT) is known to induce robust cardio-metabolic improvements in adults with obesity, little known about the metabolic impact of adding HIIT to a weight loss program. Comparing HIIT vs. more “conventional” moderate-intensity continuous training (MICT) will provide important insights to optimize exercise protocols for adults with obesity. General study design: Obese adults will be randomized to: 1) MICT, 2) HIIT or 3) no exercise (NoEX) - while they all undergo a standardized calorie restricted diet until they lose 10% body weight. After losing 10% body weight, all subjects will enter a 6-month follow-up phase (no diet or exercise requirements). Because long-term adaptations to training largely stem from the accrual of responses to each exercise session, in Aim #1, we will assess changes in signaling events involved in regulating aSAT angiogenesis, adipogenesis, ECM remodeling, and inflammatory pathways, during the 24 hours after a session of exercise (HIIT and MICT). In Aim #2, we will determine the effects of adding exercise training (MICT or HIIT) to a calorie-restricted weight-loss program on changes in aSAT morphology (e.g., capillarization, ECM fibrotic content and composition, cell size, macrophage infiltration) and cell-specific changes (via snRNA-seq) after 10% body weight loss. In Aim #3, during the 6-month period after losing 10% body weight, we will compare weight loss maintenance, aSAT morphology, and relevant clinical metabolic health outcomes among subjects originally randomized to MICT, HIIT, or NoEX.

项目摘要/摘要 热量限制和运动的结合是与肥胖有关的最常见的一线治疗 疾病，但我们对这两种截然不同的治疗方法的协同影响知之甚少。更深 了解将锻炼添加到减肥计划中的健康益处的基础机制是 对于优化可修改的生活方式干预组成部分（例如，运动强度）至关重要。重要的是， 尽管减少脂肪组织质量是减肥的基本适应 添加练习对脂肪中的结构和功能变化的影响没有任何影响 组织。这很重要，因为许多与肥胖有关的代谢健康并发症与 腹部皮下脂肪组织（ASAT）的异常。特别是，高脂肪酸释放速率 从肥胖症中非常普遍的ASAT导致肝脏中的生态脂质沉积，内脏脂肪组织， 和骨骼肌，是胰岛素抵抗的主要因素。因此，增加了能力 储存和隔离脂肪酸的ASAT将预防这些异常。重要的是，能力增加 储存脂肪的ASAT不会转化为增加体内脂肪质量，这需要能量盈余。基于 我们令人兴奋的初步发现，我们假设运动触发了ASAT中的关键信号通路以重新编程 血管生成，脂肪生成和细胞外基质（ECM）纤维化的调节以重塑ASAT 有效的能量存储。我们认为在ASAT中进行的这些运动引起的修改将使持续健康 即使体重减轻后仍保留一些重量，也要收益。最后，尽管高强度间隔训练（HIIT） 已知会引起肥胖成年人的鲁棒心代谢改善，对代谢鲜为人知 将HIIT添加到减肥计划中的影响。比较HIIT与更“常规”中等强度 连续培训（MICT）将提供重要的见解，以优化肥胖成年人的运动方案。 一般研究设计：肥胖的成年人将被随机分为：1）MICT，2）HIIT或3）无运动（NOEX） - 而 他们都接受了标准化的卡路里饮食，直到减轻体重10％。失去10％的身体后 体重，所有受试者将进入6个月的随访阶段（无饮食或运动要求）。因为长期 适应培训的改编很大程度上源于每个练习会议的回应，在AIM＃1中，我们将 评估调节ASAT血管生成，脂肪形成，ECM重塑的信号传导事件的变化， 和炎症途径，在运动后的24小时内（HIIT和MICT）。在AIM＃2中，我们将 确定在对限制卡路里的减肥计划中添加运动训练（MICT或HIIT）的影响 ASAT形态的变化（例如，毛细管，ECM纤维化含量和组成，细胞大小，巨噬细胞 体重减轻10％后，浸润）和细胞特异性变化（通过snRNA-seq）。在AIM＃3中，在6个月中 失去10％体重后，我们将比较减肥，ASAT形态和相关性 最初与MICT，HIIT或NOEX随机分配的受试者之间的临床代谢健康结果。