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

项目总结/摘要 热量限制和运动的结合是肥胖相关的最常见的一线治疗方法。 然而，我们对这两种截然不同的治疗方法的协同效应知之甚少。更深 了解在减肥计划中加入运动对健康有益的机制， 对于优化生活方式干预的可改变成分至关重要（例如，运动强度）。重要的是， 虽然脂肪组织质量的减少是减肥的基本适应，但我们几乎知道， 没有任何关于增加运动可能对脂肪组织结构和功能变化的影响， 组织.这一点非常重要，因为许多与肥胖相关的代谢健康并发症与以下因素密切相关： 腹部皮下脂肪组织（aSAT）异常。特别是，脂肪酸的高释放率 从肥胖症中非常常见的aSAT，导致肝脏，内脏脂肪组织， 和骨骼肌，并且是胰岛素抵抗的主要因素。因此，提高 ASAT储存和隔离脂肪酸将防止这些异常。重要的是，提高能力 ASAT储存脂肪并不转化为增加身体脂肪量，这需要能量盈余。基于 根据我们令人兴奋的初步发现，我们假设运动会触发aSAT中的关键信号通路， 调节血管生成、脂肪生成和细胞外基质（ECM）纤维化以重塑aSAT， 有效的能量储存。我们认为，这些运动引起的aSAT变化将带来持久的健康 即使在减肥后恢复一些体重也有好处。高强度间歇训练（HIIT） 已知在肥胖成年人中诱导强大的心脏代谢改善，但对代谢的影响知之甚少。 将HIIT加入减肥计划的影响。比较HIIT与更“传统”的中等强度 持续训练（MICT）将为优化肥胖成年人的运动方案提供重要的见解。 一般研究设计：肥胖成年人将随机分为：1）MICT，2）HIIT或3）无运动（NoEX）， 他们都接受标准化的热量限制饮食，直到他们失去10%的体重。失去10%的身体后 所有受试者将进入6个月随访期（无饮食或运动要求）。因为长期 对训练的适应性很大程度上源于对每次练习的反应，在目标1中，我们将 评估参与调节aSAT血管生成、脂肪生成、ECM重塑的信号传导事件的变化， 和炎症途径，在24小时后的一个会议的运动（HIIT和MICT）。在目标#2中，我们将 确定将运动训练（MICT或HIIT）添加到卡路里限制减肥计划中对 aSAT形态的变化（例如，毛细血管化，ECM纤维含量和组成，细胞大小，巨噬细胞 浸润）和细胞特异性变化（通过snRNA-seq）。在目标3中，在6个月期间， 在失去10%体重后的一段时间内，我们将比较体重减轻的维持、aSAT形态学和相关的 最初随机分配至MICT、HIIT或NoEX组的受试者的临床代谢健康结局。

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.