Leucine and HMB Supplementation in Early Life to Promote Muscle Growth at the Expense of Adipose Deposition

摘要 婴儿期体重增长的构成和速度对膳食摄入高度敏感。过量脂肪组织 婴儿早期体重增加易患儿童肥胖症，并增加成年肥胖症的风险， 在代谢健康和生产力方面产生短期和长期成本。我们的长期目标是确定 饮食策略，可以转化为人口的风险，人类婴儿和年轻的猪，以促进 以脂肪沉积为代价支持肌肉生长的膳食氨基酸使用。的目的 应用的目的是确定是否用亮氨酸补充完全饮食（喂养以满足需要） 或其代谢产物β-羟基-β-甲基丁酸酯（HMB）通过刺激蛋白质代谢，提高蛋白质利用率。 肌肉的合成代谢过程，从而增强膳食营养素向瘦肉生长的分配， 同时减轻脂肪沉积。核心假设是，在婴儿期，亮氨酸或HMB补充剂 刺激骨骼肌中调节蛋白质合成和卫星细胞复制的途径， 从而促进瘦肉生长。当长期持续时，增加的代谢质量总体上减少 能量平衡和脂肪积累。该假设基于申请人实验室的数据。的 基本原理是，通过了解饮食成分影响肌肉生长的机制， 在婴儿早期，并反过来影响饮食能量利用，我们可以建立适当的饮食指南， 优化瘦体重的增长，同时减轻多余的脂肪沉积。在强有力的初步数据的指导下， 这一假设将通过追求两个具体目标来检验：1）确定是否喂养满足以下条件的完全饮食： 蛋白质和能量的需求，并补充亮氨酸增强肌肉增长，通过上调 蛋白质合成和肌层增生，以及由此产生的代谢质量变化是否减少 可用于脂肪堆积的能量。2)确定完整饮食中的HMB补充是否利用了营养素 类似于亮氨酸的传感途径，以增强肌肉和瘦体重的增加，并减轻脂肪沉积。 使用申请人实验室建立的方法，在生长速率、身体组成、 日粮蛋白质和能量的生长效率，能量消耗，蛋白质合成率，营养素 信号传导，卫星细胞丰度和增殖，激素，底物和代谢产物谱将被 在3周以上的幼猪中测量。这种方法是创新的，因为它将确定细胞如何 肌肉对长期补充亮氨酸和HMB的反应影响全身蛋白质和能量 利用影响生长和体重增加的组成。所提出的研究是有意义的 因为它有望促进我们对亮氨酸及其代谢产物在免疫中作用的基本理解， 调节肌肉生长在生命早期，和骨骼肌的整体能量和 生长中的有机体的蛋白质经济。新的信息将获得的潜力，利用亮氨酸 和HMB补充剂以促进瘦肉生长并减轻婴儿和猪肉生产中的脂肪积累。

ABSTRACT The composition and rate of weight gain in infancy are highly sensitive to dietary intake. Excess adipose tissue gain in early infancy predisposes to childhood obesity and increases the risk for developing adult obesity that incurs short- and long-term costs in terms of metabolic health and productivity. Our long-term goal is to identify dietary strategies that can be translated to populations of at risk human infants and young pigs to promote dietary amino acid use in support of muscle growth at the expense of adipose deposition. The objective of this application is to determine whether supplementation of a complete diet (fed to meet requirements) with leucine or its metabolite β-hydroxy-β-methylbutyrate (HMB) will improve efficiency of protein utilization by stimulating the muscle's anabolic processes and thereby enhance the partitioning of dietary nutrients toward lean growth, while mitigating fat deposition. The central hypothesis is that in infancy, leucine or HMB supplementation stimulates the pathways in skeletal muscle that regulate protein synthesis and satellite cell replication and, thereby, enhance lean growth. When sustained long-term, the increased metabolic mass diminishes overall energy balance and fat accretion. The hypothesis is based on data from the applicants' laboratories. The rationale is that by understanding the mechanisms by which dietary components can influence muscle growth in early infancy and, in turn, impact dietary energy utilization, we can establish appropriate dietary guidelines to optimize the growth of lean mass whilst mitigating excess fat deposition. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine if feeding a complete diet that meets protein and energy requirements and supplemented with leucine enhances muscle accretion by up-regulating protein synthesis and myonuclear accretion, and whether the resulting change in metabolic mass reduces energy available for fat accretion. 2) Determine if HMB supplementation of a complete diet utilizes nutrient sensing pathways similar to leucine to enhance muscle and lean mass accretion, and mitigate fat deposition. Using methods established in the applicants' laboratories, responses in growth rate, body composition, the efficiency of dietary protein and energy use for growth, energy expenditure, protein synthesis rates, nutrient signaling, satellite cell abundance and proliferation, and hormone, substrate, and metabolite profiles will be measured in young pigs over 3 weeks. The approach is innovative because it will identify how the cellular responses of muscle to long-term leucine and HMB supplementation impact whole body protein and energy utilization to influence growth and the composition of weight gain. The proposed research is significant because it is expected to advance our basic understanding of both the role of leucine and its metabolite in the regulation of muscle growth in early life, and the significance of skeletal muscle for the overall energy and protein economy of the growing organism. Novel information will be gained on the potential for using leucine and HMB supplementation to promote lean growth and mitigate fat accretion in infants and for pork production.