Adequate amino acid (AA) nutrition is essential for the health and well being of humans and animals alike. Because AAs have no storage pool, the development of an indispensable AA (IAA) deficiency can occur rapidly, particularly if a mild state of protein deficiency already exists. IAA deficiencies have been shown to compromise growth and body function that depends on protein synthesis, such as wound healing. However, the growth reduction attributed to IAA imbalance is actually secondary to decreased food intake, an anorectic response to the IAA deficiency. Since AA supplements have become fashionable, and may be used particularly by """"""""health food"""""""" faddists, dieters and athletes, IAA imbalance should be recognized as a potential health hazard. Moreover, individuals with cancer cachexia, disorders of AA metabolism, and other metabolic disorders may also suffer IAA disproportion, which could compromise their recovery. The long-term goal of the work in this laboratory is to determine how the brain recognizes IAA deficiency. Given the importance of AA nutrition, it is imperative that we gain a better understanding of the basic mechanisms by which IAA imbalance affects brain function. We are investigating these mechanisms with a well-described nutritional model using rats fed AA-imbalanced diets (IMB). Our recent work indicates that changes in behavior (rate of eating) in response to IMB occur within the first 12 min of feeding. Within this time period we have found increased glutamine and glutamate in the APC. Rapid changes in vitro include an activation of signal transduction pathways and mobilization of AA transporters. Based on our knowledge of this model, we propose the following specific aims: 1) to identify the initial metabolic signal(s) of IAA deficiency in the APC; 2) to identify the signal transduction pathways activated by the metabolic signals identified in Specific Aim 1; and 3) to identify the mechanisms of activation in the glutamatergic output cells of the APC that signal IAA deficiency. We hypothesize the following: The relative excess of AAs other than the limiting one increase AA metabolism and stimulate the glutamineglutamate cycle, leading to the activation of signaling pathways and the potentiation of APC neurons. When APC neurons are activated, their glutamatergic output first acts at AMPA receptors to signal AA deficiency to other parts of the brain for the anorectic responses.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Nutrition Study Section (NTN)
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Mitler, Merrill
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University of California Davis
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Sharp, James W; Ross-Inta, Catherine M; Baccelli, Irène et al. (2013) Effects of essential amino acid deficiency: down-regulation of KCC2 and the GABAA receptor; disinhibition in the anterior piriform cortex. J Neurochem 127:520-30
Anthony, Tracy G; Gietzen, Dorothy W (2013) Detection of amino acid deprivation in the central nervous system. Curr Opin Clin Nutr Metab Care 16:96-101
Gietzen, Dorothy W; Aja, Susan M (2012) The brain's response to an essential amino acid-deficient diet and the circuitous route to a better meal. Mol Neurobiol 46:332-48
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Gietzen, Dorothy W; Hao, Shuzhen; Anthony, Tracy G (2007) Mechanisms of food intake repression in indispensable amino acid deficiency. Annu Rev Nutr 27:63-78
Gietzen, Dorothy W; Rogers, Quinton R (2006) Nutritional homeostasis and indispensable amino acid sensing: a new solution to an old puzzle. Trends Neurosci 29:91-9
Sharp, James W; Ross-Inta, Catherine M; Hao, Shuzhen et al. (2006) Co-localization of phosphorylated extracellular signal-regulated protein kinases 1/2 (ERK1/2) and phosphorylated eukaryotic initiation factor 2alpha (eIF2alpha) in response to a threonine-devoid diet. J Comp Neurol 494:485-94
Koehnle, Thomas J; Russell, Matthew C; Morin, Andrew S et al. (2004) Diets deficient in indispensable amino acids rapidly decrease the concentration of the limiting amino acid in the anterior piriform cortex of rats. J Nutr 134:2365-71
Sharp, J W; Ross, C M; Koehnle, T J et al. (2004) Phosphorylation of Ca2+/calmodulin-dependent protein kinase type ii and the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (ampa) receptor in response to a threonine-devoid diet. Neuroscience 126:1053-62
Gietzen, Dorothy W; Ross, Catherine M; Hao, Shuzhen et al. (2004) Phosphorylation of eIF2alpha is involved in the signaling of indispensable amino acid deficiency in the anterior piriform cortex of the brain in rats. J Nutr 134:717-23

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