The long-term goals of the studies describes in this application are to fund new therapeutic strategies for the treatment of obesity. Large increases in the size of adipocytes (hypertrophic growth) occur during normal development and aging. Hypertrophic growth involves not only an increase in the size the unilocular lipid droplet, but an increase in the protein content of the adipocytes as well. In obesity, this growth is exaggerated. Nutrients are thought to play an important role in regulating the hypertrophic growth of adipocytes. However, it is not entirely known how overeating translates into changes in the architecture of adipocytes that accommodate the growing lipid droplet. Insulin is involved in this process; it can both regulate protein synthesis in adipocytes and also promote lipid synthesis and storage. Thus the growth promoting actions of nutrients may act on compelling evidence that some nutrients have direct effects that regulate adipose tissue growth in obesity. For example, preliminary data presented herein and previous studies clearly show that amino acids have direct metabolic effects on isolated fat cells. These effects mimic and are additive with those of insulin especially in regard to protein synthesis. The signaling pathways affected by the amino acids in preliminary studies may also be used by insulin to increase lipid synthesis and storage in adipocytes. Therefore the P.I. hypothesizes that amino acids have direct regulatory effects of adipose protein synthesis and lipid accumulation. These effects may be important in regulating hypertrophic growth of adipose tissue. The objectives of this project are to understand how amino acids stimulate protein and lipid metabolism in adipose tissue and delineate the molecular mechanisms involved.
The specific aims of the proposal are: 1) to identify the amino acids capable of stimulating protein synthesis; 2) to determine the mechanisms use to stimulate TOR kinase; 3) to investigate the role of other cell signaling cascades in the stimulation of protein synthesis, 4) to determine the steps in translation that are stimulated by amino acids; and, 5) to examine the effect of amino acids on the synthesis of neutral lipids. These studies will provide further insight into the mechanism through which amino acids regulate adipose protein and lipid metabolism leading to hypertrophic growth. The information gained from these studies may identify new targets for therapeutic intervention in obesity.
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