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: 10684756
• 负责人: Jeffrey F Horowitz
• 金额: $ 64.94万
• 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/10684756
• 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.

项目概要/摘要 热量限制和运动相结合是肥胖相关疾病最常见的一线治疗方法 疾病，但我们对这两种截然不同的治疗方法的协同作用知之甚少。 了解在减肥计划中添加运动对健康有益的潜在机制 对于优化生活方式干预措施的可修改部分（例如运动强度）至关重要。 虽然脂肪组织量的减少是减肥的根本适应，但我们几乎知道 没有提及增加运动可能对脂肪结构和功能变化产生的影响 这非常重要，因为许多与肥胖相关的代谢健康并发症与肥胖密切相关。 腹部皮下脂肪组织（aSAT）异常，特别是脂肪酸释放率高。 来自 aSAT 的脂肪在肥胖中很常见，会导致肝脏、内脏脂肪组织中的异位脂质沉积， 和骨骼肌，并且是胰岛素抵抗的主要因素，因此，增加胰岛素抵抗的能力。 储存和隔离脂肪酸的 aSAT 将防止这些异常，重要的是，增加的能力。 aSAT储存脂肪并不转化为体内脂肪量的增加，这需要能量盈余的基础上。 我们令人兴奋的初步发现，我们勇敢地锻炼会触发 aSAT 中的关键信号通路进行重新编程 调节血管生成、脂肪生成和细胞外基质 (ECM) 纤维化，重塑 aSAT 以获得更多功能 我们认为这些由运动引起的 aSAT 改变将带来持久的健康。 即使减肥后体重反弹，也会有好处。最后，高强度间歇训练（HIIT）。 众所周知，它可以促进肥胖成人的心脏代谢的强劲改善，但人们对代谢知之甚少 比较 HIIT 与更“传统”的中等强度的减肥计划的影响。 持续训练（MICT）将为优化成人肥胖患者的运动方案提供重要见解。 一般研究设计：肥胖成年人将被随机分配至：1) MICT、2) HIIT 或 3) 不运动 (NoEX) - 同时 他们都接受标准化的限制热量饮食，直到体重减轻10%。 体重后，所有受试者都将进入6个月的随访阶段（没有饮食或运动要求），因为是长期的。 对训练的适应很大程度上源于对每次练习的反应的累积，在目标#1中，我们将 评估参与调节 aSAT 血管生成、脂肪生成、ECM 重塑的信号事件的变化， 在运动（HIIT 和 MICT）后的 24 小时内，我们将针对目标 #2 进行研究。 确定在限制热量的减肥计划中添加运动训练（MICT 或 HIIT）的效果 aSAT 形态的变化（例如毛细血管化、ECM 纤维化含量和成分、细胞大小、巨噬细胞 在目标 #3 中，在 6 个月期间，体重减轻 10% 后发生细胞特异性变化（通过 snRNA-seq）。 减掉10%体重后的一段时间，我们会比较减重维持、aSAT形态和相关 最初随机分配至 MICT、HIIT 或 NoEX 组的受试者的临床代谢健康结果。