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 ?-hydroxy-?-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.
The proposed research is relevant to public health because the discovery of mechanisms by which the diet of the newborn can be manipulated to improve lean growth without incurring excess fat deposition is expected to bring basic research closer to the translational level of improving the nutritional recommendations for infants as well as the efficiency of utilization of dietary nutrients for pork production. Thus, the proposed research using an agriculturally important domestic species is relevant to the missions of the NIH and USDA as it will provide fundamental new knowledge that has dual benefits relevant for the improvement of human health and food animal production.
