Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/31/2004
Publication Date: 6/1/2004
Citation: O'Connor, P.M., Kimball, S.R., Suryawan, A., Bush, J.A., Nguyen, H.V., Jefferson, L.S., Davis, T.A. 2004. Regulation of neonatal liver protein synthesis by insulin and amino acids in pigs. American Journal of Physiology - Endocrinology and Metabolism. 286(6):E994-E1003. Interpretive Summary: Growth is very rapid in the newborn because feeding stimulates the synthesis of proteins in all tissues of the body. In the liver, this response to feeding is mediated by the post-feeding increase in amino acid levels. In skeletal muscle, the response to feeding is mediated by the post-feeding increase in amino acids and the hormone, insulin. In this study in which we used newborn pigs as a model of the human, we wished to determine whether insulin affects the stimulation of protein synthesis by amino acids in the liver. We further wished to identify the intracellular signaling pathways that regulate the response. Our work shows that amino acids increase protein synthesis in liver and that this occurs irregardless of the insulin concentration present. Our work further identified the intracellular signaling proteins that respond to amino acids in the liver and showed that these signaling proteins do not respond to insulin in the liver. This information furthers the scientific understanding of the mechanisms underlying the response of different parts of the body to nourishment, and will help us find optimal ways of supporting the proper growth and development of babies.
Technical Abstract: The high efficiency of protein deposition during the neonatal period is driven by high rates of protein synthesis, which are maximally stimulated after feeding. Infusion of amino acids, but not insulin, reproduces the feeding-induced stimulation of liver protein synthesis. To determine whether amino acid-stimulated liver protein synthesis is independent of insulin in neonates, and to examine the role of amino acids and insulin in the regulation of translation initiation in neonatal liver, we performed pancreatic glucose-amino acid clamps in overnight-fasted 7-day-old pigs. Pigs (n = 9-12/group) were infused with insulin at 0, 10, 22, and 110 ng.kg(-0.66).min(-1) to achieve 0, 2, 6, and 30 microU/ml insulin, respectively. At each insulin dose, amino acids were maintained at fasting or fed levels or, in conjunction with the highest insulin dose, allowed to fall to below fasting levels. Insulin had no effect on the fractional rate of protein synthesis in liver. Amino acids increased fractional protein synthesis rates in liver at each dose of insulin, including the 0 microU/ml dose. There was a dose-response effect of amino acids on liver protein synthesis. Amino acids and insulin increased protein S6 kinase and 4E-binding protein 1 (4E-BP1) phosphorylation; however, only amino acids decreased formation of the inactive 4E-BPI.eukaryotic initiation factor-4E (eIF4E) complex. The results suggest that amino acids regulate liver protein synthesis in the neonate by modulating the availability of eIF4E for 48S ribosomal complex formation and that this response does not require insulin.