Modulation of Ghrelin Release by Exercise Intensity: The Role of Obesity and Prediabetes Status

项目摘要 这项建议的目的是描述两种运动强度剂量对总生长激素释放肽、酰基 生长素释放肽和去酰基生长素释放肽在有和没有前驱糖尿病的瘦和肥胖成人中的作用。Ghrelin（TG）参与 调节食欲、能量平衡、葡萄糖代谢和胰岛素敏感性。胃饥饿素存在于血液中 脱酰基形式（DAG ~ TG的78%）和酰化形式（AG ~ TG的22%）。尽管数量较少， AG具有多种促进能量储存的作用，包括刺激食欲，抑制胰岛素分泌， 从胰腺释放，并通过广泛表征的生长激素促分泌素增加肥胖 受体的相反，DAG通常反对AG促进负能量平衡（食欲抑制和食欲抑制）。 减少脂肪量（FM））和改善胰岛素敏感性，通过尚未鉴定的受体起作用。最优 TG、DAG和AG的比例尚不清楚。同样，需要有针对性的方法， 操纵这些肽以帮助预防和/或治疗肥胖、代谢综合征、前驱糖尿病 和2型糖尿病。运动提供了一种独特的治疗方法，在治疗失调的生长激素释放肽。 有限的动物和人类研究检查运动和ghrelin释放大多是模棱两可的，或只有 文件TG和/或单一（例如AG）形式的生长素释放肽。由于DAG和AG可以协同作用， 拮抗地，或具有独立的作用，这些肽响应于运动的定量是 运动对ghrelin释放的作用以及ghrelin运动诱导的对 整体葡萄糖调节和能量平衡。锻炼强度可能是关键，因为锻炼可以提高 乳酸水平抑制运动后的AG和食欲。在这里，我们建议解决这一知识差距 通过定义急性运动强度的作用，在高于和低于乳酸阈值的剂量下，对TG，AG， 和DAG的释放。具体目标1：检查 运动强度对生长激素释放肽、胰岛素、血糖和自我报告的食欲的影响。假设：更高 运动强度将导致对TG、AG、DAG、AG/DAG、胰岛素和葡萄糖AUC的不同影响， 食欲;受性别、肥胖、腹部内脏脂肪（AVF）和糖尿病前期状态影响。具体目标二： 这是一个探索性的目的，使用回归模型来检查运动引起的变化， 生长激素释放肽对血糖、胰岛素和食欲的影响。假设：TG、AG、DAG和AG/DAG改变将 差异预测葡萄糖代谢、胰岛素敏感性和食欲的变化。这些变化各不相同 按性别、肥胖程度、AVF和前驱糖尿病分类。该试点/可行性应用的结果将告知 一份更大的提交文件，定义了TG、AG和DAG的治疗性运动目标，并检查了 使用精确运动处方技术进行个体化运动训练的效果 Ghrelin释放

Project Summary The goal of this proposal is to characterize the effects of two exercise “intensity doses” on total ghrelin, acyl ghrelin, and des-acyl ghrelin in lean and obese adults with and without prediabetes. Ghrelin (TG) is involved in the regulation of appetite, energy balance, glucose metabolism and insulin sensitivity. Ghrelin exists in the blood in a des-acyl form (DAG ~78% of TG), and in an acylated form (AG ~22% of TG). Despite being less abundant, AG is has multiple actions that promote energy storage, including stimulation of appetite, inhibition of insulin release from the pancreas, and increases in adiposity via a widely characterized growth hormone secretagogue receptor. Conversely, DAG often opposes AG promoting negative energy balance (appetite suppression and reduced fat mass (FM)) and improving insulin sensitivity, acting through a receptor not yet identified. The optimal ratios of TG, DAG, and AG are not clear. Likewise, there is a need for targeted approaches that can effectively manipulate these peptides to aid in the prevention and/or treatment of obesity, metabolic syndrome, prediabetes and type 2 diabetes. Exercise provides a unique therapeutic approach in the treatment of dysregulated ghrelin. Limited animal and human studies examining exercise and ghrelin release are mostly equivocal or only document TG and/or a single (e.g. AG) form of ghrelin. As DAG and AG can act synergistically, antagonistically, or have independent effects, the quantification of these peptides in response to exercise is critical to understanding the role of exercise on ghrelin release and ghrelin's exercise induced influence on overall glucose regulation and energy balance. Exercise intensity may be key, as exercise that elevates levels of lactate suppress AG and appetite post exercise. Here we propose to address this gap in knowledge by defining the role of acute exercise intensity, at doses above and below the lactate threshold, on TG, AG, and DAG release in lean and obese individuals with and without prediabetes. Specific Aim 1: Examine effects of exercise intensity on ghrelin, insulin, glucose and self-reported appetite. Hypothesis: Higher exercise intensity will result in differential effects on TG, AG, DAG, AG/DAG, insulin, and glucose AUC's, and appetite; affected by sex, obesity, abdominal visceral fat (AVF), and prediabetes status. Specific Aim 2: This is an exploratory aim using regression modeling to examine exercise-induced changes in ghrelin on glucose, insulin and appetite. Hypothesis: TG, AG, DAG and AG/DAG alterations will differentially predict changes in glucose metabolism, insulin sensitivity, and appetite. These alterations vary by sex, levels of obesity, AVF, and prediabetes. Results from this pilot/feasibility application will inform a larger submission that defines therapeutic exercise targets for TG, AG, and DAG, and examines the effects of individualized exercise training using precision exercise prescription techniques on ghrelin release.