RESUMEN
Our health requires continual protein synthesis for maintaining and repairing tissues. For protein synthesis to function, all the essential (indispensable) amino acids (IAAs) must be available in the diet, along with those AAs that the cells can synthesize (the dispensable amino acids). Here we review studies that have shown the location of the detector for IAA deficiency in the brain, specifically for recognition of IAA deficient diets (IAAD diets) in the anterior piriform cortex (APC), with subsequent responses in downstream brain areas. The APC is highly excitable, which makes is uniquely suited to serve as an alarm for reductions in IAAs. With a balanced diet, these neurons are kept from over-excitation by GABAergic inhibitory neurons. Because several transporters and receptors on the GABAergic neurons have rapid turnover times, they rely on intact protein synthesis to function. When an IAA is missing, its unique tRNA cannot be charged. This activates the enzyme General Control Nonderepressible 2 (GCN2) that is important in the initiation phase of protein synthesis. Without the inhibitory control supplied by GABAergic neurons, excitation in the circuitry is free to signal an urgent alarm. Studies in rodents have shown rapid recognition of IAA deficiency by quick rejection of the IAAD diet.
RESUMEN
Background: Low protein amounts are used in ketogenic diets (KDs), where an essential (indispensable) amino acid (IAA) can become limiting. Because the chemically sensitive, seizurogenic, anterior piriform cortex (APC) is excited by IAA limitation, an imbalanced KD could exacerbate seizure activity. Objective: We questioned whether dietary IAA depletion worsens seizure activity in rodents fed KDs. Methods: In a series of 6 trials, male rats or gerbils of both sexes (6-8/group) were given either control diets (CDs) appropriate for each trial, a KD, or a threonine-devoid (ThrDev) diet for ≥7 d, and tested for seizures using various stimuli. Microchip analysis of rat APCs was also used to determine if changes in transcripts for structures relevant to seizurogenesis are affected by a ThrDev diet. Glutamate release was measured in microdialysis samples from APCs during the first meal after 7 d on a CD or a ThrDev diet. Results: Adult rats showed increased susceptibility to seizures in both chemical (58%) and electroshock (doubled) testing after 7 d on a ThrDev diet compared with CD (each trial, P ≤ 0.05). Seizure-prone Mongolian gerbils had fewer seizures after receiving a KD, but exacerbated seizures (68%) after 1 meal of KD minus Thr (KD-T compared with CD, P < 0.05). In kindled rats fed KD-T, both counts (19%) and severities (77%) of seizures were significantly elevated (KD-T compared with CD, P < 0.05). Gene transcript changes were consistent with enhanced seizure susceptibility (7-21 net-fold increases, P = 0.045-0.001) and glutamate release into the APC was increased acutely (4-fold at 20 min, 2.6-fold at 60 min, P < 0.05) after 7 d on a ThrDev diet. Conclusion: Seizure severity in rats and gerbils was reduced after KDs and exacerbated by ThrDev, both in KD- and CD-fed animals, consistent with the mechanistic studies. We suggest that a complete protein profile in KDs may improve IAA balance in the APC, thereby lowering the risk of seizures.
Asunto(s)
Aminoácidos Esenciales/deficiencia , Encéfalo/metabolismo , Dieta Cetogénica , Proteínas en la Dieta , Epilepsia/dietoterapia , Convulsiones/etiología , Animales , Enfermedades Carenciales/etiología , Proteínas en la Dieta/administración & dosificación , Proteínas en la Dieta/química , Epilepsia/complicaciones , Epilepsia/metabolismo , Conducta Alimentaria , Femenino , Gerbillinae , Ácido Glutámico/metabolismo , Masculino , Necesidades Nutricionales , Ratas Sprague-Dawley , Convulsiones/metabolismo , Treonina/deficienciaAsunto(s)
Aminoácidos Esenciales/sangre , Aminoácidos Esenciales/deficiencia , Dieta , Aminoácidos Esenciales/metabolismo , Animales , Ratones , Ratones Noqueados , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN de Transferencia/metabolismo , Factores de TiempoRESUMEN
The anterior piriform cortex (APC) is activated by, and is the brain area most sensitive to, essential (indispensable) amino acid (IAA) deficiency. The APC is required for the rapid (20 min) behavioral rejection of IAA deficient diets and increased foraging, both crucial adaptive functions supporting IAA homeostasis in omnivores. The biochemical mechanisms signaling IAA deficiency in the APC block initiation of translation in protein synthesis via uncharged tRNA and the general amino acid control kinase, general control nonderepressing kinase 2. Yet, how inhibition of protein synthesis activates the APC is unknown. The neuronal K(+) Cl(-) cotransporter, neural potassium chloride co-transporter (KCC2), and GABAA receptors are essential inhibitory elements in the APC with short plasmalemmal half-lives that maintain control in this highly excitable circuitry. After a single IAA deficient meal both proteins were reduced (vs. basal diet controls) in western blots of APC (but not neocortex or cerebellum) and in immunohistochemistry of APC. Furthermore, electrophysiological analyses support loss of inhibitory elements such as the GABAA receptor in this model. As the crucial inhibitory function of the GABAA receptor depends on KCC2 and the Cl(-) transmembrane gradient it establishes, these results suggest that loss of such inhibitory elements contributes to disinhibition of the APC in IAA deficiency. The circuitry of the anterior piriform cortex (APC) is finely balanced between excitatory (glutamate, +) and inhibitory (GABA, -) transmission. GABAA receptors use Cl(-), requiring the neural potassium chloride co-transporter (KCC2). Both are rapidly turning-over proteins, dependent on protein synthesis for repletion. In IAA (indispensable amino acid) deficiency, within 20 min, blockade of protein synthesis prevents restoration of these inhibitors; they are diminished; disinhibition ensues. GCN2 = general control non-derepressing kinase 2, eIF2α = α-subunit of the eukaryotic initiation factor 2.
Asunto(s)
Aminoácidos Esenciales/deficiencia , Vías Olfatorias/metabolismo , Receptores de GABA-A/biosíntesis , Simportadores/biosíntesis , Animales , Regulación hacia Abajo , Potenciales Postsinápticos Excitadores , Masculino , Ratas , Cotransportadores de K ClRESUMEN
PURPOSE OF REVIEW: To understand the principles of amino acid deprivation sensing in the brain and its behavioral and metabolic outcomes with an emphasis on the current literature. RECENT FINDINGS: Sensing essential amino acid (EAA) depletion occurs in the anterior piriform cortex (APC) via general control nonderepressible 2 (GCN2) binding to deacylated tRNA and subsequent glutamatergic signaling to influence behavior. Mapping of the APC output during EAA insufficiency shows axons projecting to the hypothalamus as well as other regions that are involved in feeding and locomotion. Whereas these neurocircuits are clearly important in regulating anorectic responses to an EAA-devoid diet, the propagating events and regulatory factors are still unclear. Recently, several groups examined signaling and gene expression in the arcuate nucleus and lateral hypothalamus during EAA deficiency. In these efforts, several gene products, including somatostatin, corticotrophin-releasing hormone, neuropeptide Y, agouti-related protein, and several novel targets were identified as factors involved in regulating the aversion to EAA-deficient diets. On a different note, marginal EAA deficiency in the form of methionine restriction promotes hyperphagia similar to low-protein diets, yet animals are leaner and live longer. The central mechanisms are unclear but involve sympathetic nervous signaling. How and why different degrees of EAA deficiency cause opposite changes in behavior and body composition require further study. SUMMARY: Scientific inquiry into the central mechanism by which EAA insufficiency is sensed has identified the APC as the brain's initial EAA chemosensor. Beyond this, much remains uncertain. Future investigation into the signaling and gene expression events occurring in the hypothalamus and other brain regions is warranted.
Asunto(s)
Aminoácidos Esenciales/deficiencia , Aminoácidos Esenciales/metabolismo , Hipotálamo/metabolismo , Hipotálamo/fisiopatología , Proteína Relacionada con Agouti/metabolismo , Animales , Dieta con Restricción de Proteínas/efectos adversos , Humanos , Hiperfagia/fisiopatología , Modelos Animales , Neuropéptido Y/metabolismo , Transducción de SeñalRESUMEN
The essential (indispensable) amino acids (IAA) are neither synthesized nor stored in metazoans, yet they are the building blocks of protein. Survival depends on availability of these protein precursors, which must be obtained in the diet; it follows that food selection is critical for IAA homeostasis. If even one of the IAA is depleted, its tRNA becomes quickly deacylated and the levels of charged tRNA fall, leading to disruption of global protein synthesis. As they have priority in the diet, second only to energy, the missing IAA must be restored promptly or protein catabolism ensues. Animals detect and reject an IAA-deficient meal in 20 min, but how? Here, we review the molecular basis for sensing IAA depletion and repletion in the brain's IAA chemosensor, the anterior piriform cortex (APC). As animals stop eating an IAA-deficient meal, they display foraging and altered choice behaviors, to improve their chances of encountering a better food. Within 2 h, sensory cues are associated with IAA depletion or repletion, leading to learned aversions and preferences that support better food selection. We show neural projections from the APC to appetitive and consummatory motor control centers, and to hedonic, motivational brain areas that reinforce these adaptive behaviors.
Asunto(s)
Aminoácidos Esenciales/deficiencia , Encéfalo/fisiología , Dieta , Comidas , Aminoácidos Esenciales/metabolismo , Animales , Preferencias Alimentarias , Humanos , Deficiencia de Proteína/metabolismoRESUMEN
Protein synthesis requires a continuous supply of all of the indispensable (essential) amino acids (IAAs). If any IAA is deficient, animals must obtain the limiting amino acid by diet selection. Sensing of IAA deficiency requires an intact anterior piriform cortex (APC), but does it act alone? Shortly after rats begin eating an IAA-deficient diet, the meal ends and EPSPs are activated in the APC; from there, neurons project to feeding circuits; the meal ends within 20 min. Within the APC in vivo, uncharged tRNA activates the general amino acid control non-derepressing 2 (GCN2) enzyme system increasing phosphorylation of eukaryotic initiation factor (P-eIF2α), which blocks general protein synthesis. If this paleocortex is sufficient for sensing IAA depletion, both neuronal activation and P-eIF2α should occur in an isolated APC slice. We used standard techniques for electrophysiology and immunohistochemistry. After rats ate IAA-devoid or -imbalanced diets, their depleted slices responded to different stimuli with increased EPSP amplitudes. Slices from rats fed a control diet were bathed in artificial CSF replete with all amino acids with or without the IAA, threonine, or a tRNA synthetase blocker, l-threoninol, or its inactive isomer, d-threoninol. Thr depletion in vitro increased both EPSP amplitudes and P-eIF2α. l (but not d)-threoninol also increased EPSP amplitudes relative to control. Thus, we show independent excitation of the APC with responses parallel to those known in vivo. These data suggest a novel idea: in addition to classical processing of peripheral sensory input, direct primary sensing may occur in mammalian cortex.
Asunto(s)
Aminoácidos Esenciales/deficiencia , Corteza Cerebral/metabolismo , Factor 2 Eucariótico de Iniciación/metabolismo , Potenciales Postsinápticos Excitadores/fisiología , Neuronas/metabolismo , Biosíntesis de Proteínas , Proteínas Quinasas/metabolismo , Aminoácidos Esenciales/biosíntesis , Aminoácidos Esenciales/metabolismo , Animales , Corteza Cerebral/fisiología , Dieta , Electrofisiología , Inmunohistoquímica , Masculino , Neuronas/fisiología , Técnicas de Cultivo de Órganos , Fosforilación , Ratas , Ratas Sprague-Dawley , Treonina/deficienciaRESUMEN
Animals reject diets that lead to indispensable amino acid (IAA) depletion or deficiency. This behavior is adaptive, as continued IAA depletion is incompatible with maintenance of protein synthesis and survival. Following rejection of the diet, animals begin foraging for a better IAA source and develop conditioned aversions to cues associated with the deficient diet. These responses require a sensory system to detect the IAA depletion and alert the appropriate neural circuitry for the behavior. The chemosensor for IAA deprivation is in the highly excitable anterior piriform cortex (APC) of the brain. Recently, the well-conserved general AA control non-derepressing system of yeast was discovered to be activated by IAA deprivation via uncharged tRNA in mammalian APC. This system provides the sensory limb of the mechanism for recognition of IAA depletion that leads to activation of the APC, diet rejection, and subsequent adaptive strategies.
Asunto(s)
Aminoácidos Esenciales/administración & dosificación , Aminoácidos Esenciales/deficiencia , Corteza Cerebral/metabolismo , Ingestión de Energía/fisiología , Preferencias Alimentarias , ARN de Transferencia/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Conducta de Elección , Humanos , Ratones , Ratas , Transducción de SeñalRESUMEN
Indispensable amino acids are neither synthesized nor stored in animals and are rapidly depleted when not provided by the diet. To maintain homeostasis, organisms must sense deficiency of an indispensable amino acid and implement a repletion strategy. In rats and birds, the anterior piriform cortex houses the detector, but its mechanism has evaded description for >50 years. Recently, rapid detection of amino acid depletion was shown behaviorally when naïve animals, pre-fed a low nitrogen diet, terminated their first deficient meal within 20 min. The general amino acid control system of yeast, which is activated by amino acid deprivation via deacylated tRNA, was found to be active in rodent brain, showing conservation of amino acid sensory mechanisms across eukaryotic species.
Asunto(s)
Aminoácidos Esenciales/fisiología , Homeostasis/fisiología , Estado Nutricional/fisiología , Animales , Células Quimiorreceptoras/fisiología , HumanosRESUMEN
The anterior piriform cortex (APC) has been shown to be an essential brain structure for the detection of dietary indispensable amino acid (IAA) deficiency, but little has been known about possible molecular detection mechanisms. Increased phosphorylation of the alpha-subunit of the eukaryotic initiation factor 2alpha (eIF2alpha) has been directly linked to amino acid deficiency in yeast. Recently, we have shown increased phosphorylation of eIF2alpha (p-eIF2alpha) in the rat APC 20 minutes after ingestion of an IAA-deficient meal. We suggest that if phosphorylation of eIF2alpha is an important mechanism in detection of IAA deficiency, then APC neurons that show p-eIF2alpha should also show molecular evidence of potentiation. The present research demonstrates increased expression and co-localization of p-eIF2alpha and phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2) in APC neurons, but not in the primary motor or agranular insular cortices in response to an IAA-deficient diet. ERK1/2 is an element of the mitogen-activated protein kinase cascade, an intraneuronal signaling mechanism associated with neuronal activation. The region of the APC that responds to IAA deficiency with increased p-eIF2alpha and p-ERK1/2 labeling ranges from 3.1 to 2.5 mm rostral of bregma. Within this region, only a few neurons respond to IAA deficiency with co-localization of abundant p-eIF2alpha and p-ERK1/2. These chemosensory neurons probably detect IAA deficiency and generate neuronal signaling to other portions of the brain, changing feeding behavior.
Asunto(s)
Factor 2 Eucariótico de Iniciación/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Giro Parahipocampal/enzimología , Treonina/deficiencia , Alimentación Animal , Animales , Células Quimiorreceptoras/enzimología , Inmunohistoquímica , Masculino , Neuronas/enzimología , Giro Parahipocampal/citología , Fosforilación , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiología , Estadísticas no Paramétricas , Treonina/metabolismoRESUMEN
Transition from a normal- (NP) to a high-protein (HP) diet induces a rapid depression in food intake and a progressive but incomplete return to the initial intake during the succeeding days. The aim of this study was to determine which CNS regions are involved in the HP diet-induced satiety in rats. Brains were collected from 3 groups of adult rats after habituation to an NP diet (21 d), during the transition phase to a HP diet (2 d), or after habituation to the HP diet (21 d). Fos expression was measured in several brain areas that are involved in the control of food intake (solitary tract nucleus, anterior piriform cortex, lateral hypothalamus, arcuate nucleus, posterior para ventricular nucleus, medio ventral hypothalamus, dorso medial hypothalamus, amygdala, and accumbens nucleus). Changes occurred in the majority of these regions during the transition period from the NP diet to the HP diet. After habituation to the HP diet, significant changes in Fos expression were restricted to an increase in the nucleus of the solitary tract and a decrease in the ventromedial hypothalamus and the cortex of the amygdala. Considering the functional characteristics of these areas, the present results suggest that the vagus nerve conveys the information relative to the quantity of protein ingested, that hypothalamic sites regulate food intake and may alter sympathetic nervous system activity, and that higher brain functions such as memory processing by the limbic system or food reward system are involved in the HP diet-induced satiety in rats.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Proteínas en la Dieta/administración & dosificación , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Núcleo Solitario/metabolismo , Adaptación Fisiológica , Amígdala del Cerebelo/citología , Animales , Proteínas en la Dieta/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Núcleo Hipotalámico Paraventricular/citología , Ratas , Ratas Wistar , Respuesta de Saciedad/fisiología , Núcleo Solitario/citología , Factores de TiempoRESUMEN
An anorectic response occurs following ingestion of imbalanced amino acid (IMB) diets. There are three phases to this response: 1, recognition of the IMB diet; 2, conditioned development of an aversion to the IMB diet; and 3, adaptation. Blockade of peripheral serotonin-3 (5-HT3) receptors or vagotomy attenuates Phase 2 of the anorectic response. We investigated whether sympathetic efferents interact with the ventral gastric branch (VGB), by cutting it (X), or with the 5-HT3 receptor in these responses. First, VGBX and sham-operated (SHAM) groups were injected with vehicle or phenoxybenzamine (alpha-blocker), or nadolol (beta-blocker) before introducing the IMB diet. At 3 h suppression of the IMB diet ingestion was unchanged, showing no sympathetic efferent effect on Phase 1. Intake of the IMB diet increased 12-24 h later only in the SHAM+phenoxybenzamine group, so the VGB was necessary for alpha-blockade to enhance IMB diet intake during Phase 2 or possibly Phase 3. On days 2-5, intakes by the SHAM+phenoxybenzamine, VGBX+phenoxybenzamine and VGBX+nadolol groups were elevated. Therefore, alpha-blockade enhanced adaptation alone, but VGBX was necessary for beta-receptor blockade to augment Phase 3 adaptation. Both sympathetic efferents and the VGB are involved in Phases 2-3. Second, rats received vehicle or nadolol or scopolamine (nonselective muscarinic blocker) or pirenzepine (muscarinic M-1 receptor blocker),w+/-tropisetron (5-HT3 blocker). Pirenzepine attenuated the tropisetron effect between 6-9 h, but then pirenzepine and nadolol enhanced the tropisetron effect between 9-12 h. Scopolamine attenuated the tropisetron effect between 9-12 h. While neither experiment showed effects during the recognition phase, the autonomic and serotonergic systems interact in the learned and adaptive responses to IMB diets.
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Aminoácidos/administración & dosificación , Vías Autónomas/efectos de los fármacos , Proteínas en la Dieta/administración & dosificación , Aminoácidos/toxicidad , Animales , Anorexia/inducido químicamente , Vías Autónomas/fisiología , Proteínas en la Dieta/toxicidad , Vías Eferentes/efectos de los fármacos , Vías Eferentes/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Recognizing a deficiency of indispensable amino acids (IAAs) for protein synthesis is vital for dietary selection in metazoans, including humans. Cells in the brain's anterior piriform cortex (APC) are sensitive to IAA deficiency, signaling diet rejection and foraging for complementary IAA sources, but the mechanism is unknown. Here we report that the mechanism for recognizing IAA-deficient foods follows the conserved general control (GC) system, wherein uncharged transfer RNA induces phosphorylation of eukaryotic initiation factor 2 (eIF2) via the GC nonderepressing 2 (GCN2) kinase. Thus, a basic mechanism of nutritional stress management functions in mammalian brain to guide food selection for survival.
Asunto(s)
Aminoácidos Esenciales/administración & dosificación , Aminoácidos Esenciales/deficiencia , Factor 2 Eucariótico de Iniciación/metabolismo , Alimentos , Leucina/análogos & derivados , Vías Olfatorias/metabolismo , Proteínas Quinasas/metabolismo , ARN de Transferencia/metabolismo , Acilación , Aminoácidos Esenciales/análisis , Animales , Dieta , Ingestión de Alimentos , Preferencias Alimentarias , Leucina/administración & dosificación , Leucina/farmacología , Ratones , Ratones Endogámicos C57BL , Fosforilación , Proteínas Serina-Treonina Quinasas , Ratas , Estereoisomerismo , Treonina/administración & dosificación , eIF-2 Quinasa/metabolismoRESUMEN
Diets deficient in an indispensable amino acid have long been known to suppress food intake in rats. Detection of dietary deficiency takes place in the anterior piriform cortex (APC). Recent studies showed that the response to amino acid deficiency takes as little as 15 min to develop, but few data exist to correlate the concentration of amino acids in the APC with this rapid response. The purpose of this study was to measure the concentration of amino acids in the APC in a behaviorally relevant time frame. Rats were preconditioned by consumption of a basal diet for 7-10 d, and then given a test diet with either a control or deficient amino acid profile. Both the threonine- and leucine-deficient diets reliably depleted threonine and leucine concentration in the APC within 30 min, respectively. The control diets and a diet lacking the dispensable amino acid glycine did not lead to amino acid depletion. In combination with previous studies, the present results show that the decrease in the concentration of indispensable amino acids in the APC may be the initial sensory signal for recognition of dietary amino acid deficiency.
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Dieta , Leucina/deficiencia , Leucina/metabolismo , Vías Olfatorias/metabolismo , Treonina/deficiencia , Treonina/metabolismo , Animales , Glicina/deficiencia , Glicina/metabolismo , Masculino , Concentración Osmolar , Ratas , Factores de TiempoRESUMEN
Animals decrease intake of an indispensable amino acid (AA)-deficient or devoid diet, due in part to decreased dietary limiting AA (DLAA) concentrations within the anterior piriform cortex (APC), and to a recognition process that occurs as early as 20 min following exposure to AA deficiencies. Glutamate levels within the APC change in response to AA deficiencies. The APC projects to the lateral hypothalamus (LH), where glutamate acts to stimulate food intake. We hypothesize that the APC, through glutamatergic projections to the LH, inhibits the LH, which signals to reject the AA-deficient or devoid diet, and trigger aversions to the AA-deficient or devoid diet via an ascending pathway to the APC. We examined the effects of (1) bilateral APC and LH blockade of glutamate's NMDA receptors with the antagonist, D-AP5, (2) APC blockade of AMPA receptors with the antagonist, NBQX, to block glutamate transmission from the APC, and (3) direct injection of the agonist, NMDA, into the LH on intake of the AA-deficient, devoid, or corrected diet. Administration of D-AP5 into the APC increased intake of AA-deficient diet by 6 h, but D-AP5 in the LH decreased AA-devoid diet preferentially over AA corrected intake sooner. NBQX in the APC increased AA-deficient diet intake, also at 6 h. NMDA injection into the LH-stimulated intake of the AA corrected diet by 3 h, but did not affect AA-devoid diet intake. Thus, the glutamate receptors in the APC and LH are involved in the feeding responses to AA-deficient diet, albeit with regional differences. We suggest that glutamate mediates the anorectic responses to AA-deficient diets through recognition of AA-devoid diet with the glutamatergic output cells of the APC sending glutamate-based signals for changes in food intake within the LH and through learned avoidance of AA-deficient diet within the APC, as indicated through the more immediate and prolonged periods of activation within the LH and APC, respectively.
Asunto(s)
Aminoácidos/deficiencia , Corteza Cerebral/efectos de los fármacos , Área Hipotalámica Lateral/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Aminoácidos/farmacología , Animales , Corteza Cerebral/fisiología , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Área Hipotalámica Lateral/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Diets limiting in an essential amino acid have long been known to suppress food intake. The purpose of this study was to examine the microstructure of feeding behavior of rats within the very first meal of an imbalanced diet. Rats were preconditioned for 12 days on a Baseline diet and were then given a test diet with either a corrected amino acid profile or a diet imbalanced with respect to the essential amino acid threonine. Overall, first-meal intake and first-meal duration were robustly and significantly reduced by the Imbalanced diet but not altered by the Corrected diet. The Corrected diet caused an increase in the number of feeding bouts during the first meal. The Imbalanced diet increased the duration of pauses during the first meal. Most rats in the Imbalanced group stopped eating after just 15 min of exposure to the diet, but those still eating after this time tended to have a lower rate of eating compared to those eating the Corrected diet. On the basis of these results, we conclude that changes in microstructure and meal duration contribute to the reduction in food intake upon exposure to amino-acid-deficient diets.
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Fenómenos Fisiológicos Nutricionales de los Animales , Apetito/fisiología , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , Treonina/deficiencia , Alimentación Animal , Animales , Masculino , RatasRESUMEN
Sensing of indispensable amino acid (IAA) deficiency, an acute challenge to protein homeostasis, is demonstrated by rats as rejection of IAA-deficient diets within 20 min. The anterior piriform cortex (APC) of the brain in rats and birds is essential for this nutrient sensing, and is activated by IAA deficiency. Yet the mechanisms that sense and transduce IAA reduction to signaling in the APC, or indeed in any animal cells, are unknown. Because rejection of a deficient diet within 20 min is too rapid to be explained by transcription-derived signals, brain tissue was taken from rats after 20 min access to either a threonine-basal, -devoid, or -corrected diet and examined for proteins associated with early signaling of IAA deficiency in the yeast model. Western blots and immunohistochemistry showed that the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2alpha[Ser51]) and translation of its downstream product, c-Jun, were increased (47%, P < 0.005, and 55%, P < 0.025, respectively) in APC from rats offered devoid, but not corrected diets, compared with those offered basal diets. This was not seen in other brain areas. In cells intensely labeled for cytoplasmic p-eIF2alpha, there was intense fluorescence for c-Jun in the nucleus. Thus, p-eIF2alpha, which is pivotal in the initiation of global protein translation, and its downstream product, the leucine zipper protein, c-Jun, are increased in the mammalian APC within the time frame necessary for the behavioral response. We suggest that p-eIF2alpha and c-Jun participate in signaling nutrient deficiency in the IAA-sensitive neurons of the APC.
Asunto(s)
Aminoácidos Esenciales/deficiencia , Corteza Cerebral/metabolismo , Factor 2 Eucariótico de Iniciación/metabolismo , Transducción de Señal , Animales , Western Blotting , Dieta , Inmunohistoquímica , Masculino , Fosforilación , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Animals decrease intake of an indispensable amino acid deficient diet, due in part to decreased dietary limiting amino acid concentrations within the anterior piriform cortex (APC). In addition to studies supporting a primary role for the APC in this phenomenon, recent studies have shown that the lateral hypothalamus (LH), which receives projections from the APC, also mediates the anorectic response to amino acid deficiency. The neurochemical changes within the LH that accompany the anorexia to amino acid deficiency are unclear. We hypothesized that norepinephrine (NE), dopamine (DA) and serotonin, whose levels are altered in response to amino acid deficiency within the APC, also act within the LH to mediate amino acid deficiency-induced anorexia. We determined that ingestion of an amino acid devoid diet increased concentrations of NE and the serotonin metabolite, 5-hydroxyindoleacetic acid in the LH. The 5-hydroxytryptamine metabolite was increased overall, according to analysis by area under the curve. Individual points reached significance at 130 min; NE was elevated at 170 min. These results suggest that the sustained anorectic response following ingestion of an amino acid devoid diet may be associated with increased activity of the NE and 5-hydroxytryptamine systems in the LH.
Asunto(s)
Aminoácidos/deficiencia , Monoaminas Biogénicas/metabolismo , Área Hipotalámica Lateral/metabolismo , Animales , Área Bajo la Curva , Dieta , Electroquímica/métodos , Ácido Hidroxiindolacético/metabolismo , Cinética , Masculino , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismoRESUMEN
Omnivores show recognition of essential (indispensable) amino acid deficiency by changing their feeding behavior within 20 min, yet the cellular mechanisms of amino acid sensation in eukaryotes are poorly understood. The anterior piriform cortex (APC) of the brain in rats or its analog in birds likely houses the in vivo amino acid chemosensor. Because amino acid transporters adapt rapidly to essential amino acid deficiency in several cell models, we hypothesized that activation of electrogenic amino acid transport in APC neurons might contribute to the function of the amino acid sensor. We evaluated transport systems in primary cultures of neurons from the APC, hippocampus and cerebellum, or glia, incubated in complete or threonine-devoid (deficient) medium. After 10 min in deficient medium, uptake of threonine or a system A-selective substrate, methyl amino-isobutyric acid, was increased 60% in APC neurons only (P < 0.05). These results demonstrated upregulation of system A, an electrogenic amino acid-sodium symporter. This depletion-induced activation required sodium, intact intracellular trafficking, and phosphorylation of signal transduction-related kinases. Efflux studies showed that other transporter types were functional in the APC; they appeared to be altered dynamically in threonine-deficient cells in response to rapid increases in system A activity. The present data provided support for the chemical sensitivity of the APC and its role as the brain area housing the indispensable amino acid chemosensor. They also showed a region-specific, phosphorylation-dependent activation of the system A transporter in the brain in response to threonine deficiency.
Asunto(s)
Sistema de Transporte de Aminoácidos A/metabolismo , Aminoácidos Esenciales/metabolismo , Corteza Cerebral/metabolismo , Neuronas/metabolismo , Treonina/metabolismo , Animales , Secuencia de Bases , Células Cultivadas , Corteza Cerebral/citología , Medios de Cultivo , Masculino , Datos de Secuencia Molecular , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Omnivores must obtain diets balanced with respect to amino acids to support growth and protein synthesis. The standard paradigm used to study behavioral responses to amino acid deficiency combines deficient diets with dietary novelty. The objective of this study was to examine the effects of amino acid deficiency on the first meal of rats without the confounding effects of novelty. We report on a series of five studies of feeding behavior in rats. Rats were fed low protein diets for 5-7 d and then exposed to diets with and without essential amino acids. Rats consistently demonstrated recognition of essential amino acid deficiency within the first meal by a significant reduction in first meal duration, rejecting the deficient diets after just 12-16 min exposure. This is the first report of a rapid effect of amino acid-deficient diets without the confounding effects of dietary novelty.