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Molecular Mechanisms in the Brain Involved in the Anorexia of Branched-Chain Amino Acid Deficiency^{1 ,2}

Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine and Food Intake Laboratory, University of California–Davis, Davis, CA 95616

³To whom correspondence should be addressed. E-mail: dwgietzen{at}ucdavis.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION The IAA chemosensor in... Neural mechanisms for... Molecular mechanisms in the... REFERENCES

 
The anterior piriform cortex (APC) of the rat is thought to be the site of indispensable amino acid (IAA) chemosensation in the brain. The branched-chain amino acids, including leucine, are among the IAA that are recognized in the APC. The behavioral outcome of IAA deficiency is an anorectic response. The specific transduction mechanisms by which IAA deficiency and repletion activate the APC are not fully understood, but clearly phosphorylation of proteins, increases in intracellular calcium, and expression of the immediate early gene c-fos, which are among the earliest events occurring after the initial drop in the concentration of the limiting IAA, cause stimulation in the APC. Subsequently, several neurotransmitter systems, including those for norepinephrine, GABA, serotonin, dopamine and nitric oxide, are activated in the APC of rats that have consumed an IAA-imbalanced diet. These systems appear to modulate the output cells from the APC, glutamatergic pyramidal cells that send neural signals to activate subsequent relays in the brain. Ultimately, the feeding circuits of the brain carry out the anorectic response. Continued consumption of a diet containing an IAA imbalance causes a conditioned taste aversion to the diet in all animals that have been studied. Such learning involves synaptic reorganization, requiring both degradation and synthesis of protein, along with alterations in genomic activity.

KEY WORDS: • rat • anterior piriform cortex • amino acid imbalanced diet • indispensable amino acids • protein synthesis

	INTRODUCTION

TOP ABSTRACT INTRODUCTION The IAA chemosensor in... Neural mechanisms for... Molecular mechanisms in the... REFERENCES

 
Deficiencies of indispensable amino acids (IAA⁴ ), including the branched-chain amino acids (AA), are recognized and then rejected by all of the omnivores and generalist herbivores studied (reviewed in Harper et al. 1970 ). Reports of anorexia with IAA deficiency in animal models date from the early 1900s (Willcock and Hopkins 1906 ). As evidence for such recognition in humans, Rose and colleagues reported decreased appetite with deficiencies of branched-chain AA (Rose 1957 ). Any IAA can be used as the limiting amino acid, including the branched-chain AA (Tews et al. 1990 ).

By definition, IAA are essential in the diet as precursors for protein synthesis. Because free AA are not stored like glycogen or triglycerides, those that are indispensable in the diet must be consumed together nearly simultaneously. For example, the white crowned sparrow cannot use two diets providing complementary mixtures of IAA efficiently if their presentation is separated by as little as 2 h (Murphy and Pearcy 1993 ). It is clear that a system for the rapid detection of deficiencies and repletion of IAA provides an adaptive advantage toward appropriate diet selection. In the absence of an opportunity to choose an adequate diet, the anorectic response serves as a protective mechanism to minimize any deleterious effects from consumption of too much of a diet with an IAA disproportion until the appropriate biochemical and metabolic adaptations can be made (reviewed in Gietzen 1993 , Harper et al. 1970 , Rogers and Leung 1977 ).

The vertebrate system for detection of IAA appears to be in the central nervous system. Here we present evidence for specific sites and neural mechanisms within the brain for recognition of IAA deficiencies and/or repletion of the limiting AA, and for the subsequent learned responses. The nutritional model used for most of the work presented here is focused on the IAA-imbalanced (IMB) diet, which was popularized and reviewed by Harper et al. (1970 ). The protocol includes: first, a prefeeding period using a low-protein basal (BAS) diet that is limiting in the IAA of interest; second, an IMB diet, that contains 100% of the requirement of all the IAA except the growth limiting one, which is present at less than its requirement; and third, a corrected (COR) diet, which contains enough of the limiting IAA to correct the imbalance. The behavioral sequence of the feeding responses reflects: 1) recognition of the metabolic consequences of ingesting a diet that induces either deficiency or repletion of IAA, 2) rejection of an IAA-deficient or IMB diet, or acceptance of the COR diet and 3) development of either a learned aversion to the diet that caused the deficiency or a preference for the COR diet. Both the restoration of feeding after IAA repletion and the learned response (the conditioned taste aversion [CTA]) to the IMB diet require synthesis of protein (Beverly et al. 1991 , Rosenblum et al. 1995 ).

Several lines of evidence suggest that there is a role for the brain in recognition of IAA deficiency (reviewed in Rogers and Leung 1973 , 1977 , Gietzen 1993 , 2000 ). In an elegant series of studies in intact rats and in brain slices, Tews and colleagues demonstrated that the mechanism for the decrease of the limiting AA in the brain depends on competition at the capillary endothelial transport systems for the IAA in the blood–brain barrier (Tackman et al. 1990 , Tews et al. 1978 , 1979 ). IAA imbalances for either valine or leucine (depending on which was limiting in the diet) were created using the branched-chain AA analog, norleucine, which competes with the branched-chain AA at the blood–brain barrier. The addition of norleucine results in the typical IMB-induced anorexia (Tews et al., 1990 ).

Here we discuss evidence for 1) a particular brain area as the primary sensor, 2) the neural mechanisms that transduce and integrate the signals resulting from an IAA deficiency and 3) the molecular mechanisms that support the learned responses, either aversion (CTA) or preference. Many of the ideas presented here are clearly based on extrapolations from the available data. Their inclusion is intended to provide a stimulus for others in the field and a challenge to them to test the validity of our hypotheses.

	The IAA chemosensor in the brain

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Using positron emission tomography, IAA deficiency was seen to activate discrete forebrain areas in humans, including the middle frontal gyrus, orbitofrontal cortex and thalamus. Thus, neural activation by IAA deficiency is seen in humans, but this activation is not seen uniformly throughout the brain (Bremner et al. 1997 ). Similarly in the rat, the concentration of the limiting IAA is decreased in only a few of the 15 brain areas studied, with the largest and most consistent decrease seen in a forebrain structure in the rat, the anterior piriform cortex (APC; reviewed in Gietzen et al. 1998 ). Moreover, the results of lesioning studies done years ago in sites throughout the brain suggested that the APC is the primary IAA chemosensor, because rats with lesions of the APC fail to reject the IMB diet (Leung and Rogers 1971 , 1987 ).

In the paradigm of IAA repletion, for which the most definitive data are available, the animals are made slightly deficient in an IAA using the IMB feeding model, and then the limiting IAA is replaced, either systemically by peripheral injection, by feeding a COR diet (Rogers and Leung 1973 ), or by microinjection into the brain (Beverly et al. 1990a , 1990b ). Increased intake of a COR diet indicates that recognition of dietary repletion of the limiting AA is rapid (30 min or less) in animals switched from an IMB to a COR diet (Gietzen et al. 1986 , Rogers and Leung 1973 , Torii et al. 1987 ).

Persuasive evidence that the APC is the site for recognition of IAA repletion was provided by Beverly and colleagues (1990a ), who showed that 1.0 nmol injections of isoleucine into the APC restores feeding of the isoleucine IMB diet to about 80–85% of the amount of the BAS diet eaten by the rats during the prefeeding (baseline) period, whereas saline or artificial cerebrospinal fluid (CSF)-injected animals eat the IMB diet, at 50–60% of their baseline intake. This finding was replicated with 2.0 nmol threonine in rats fed either a threonine IMB diet (Beverly et al. 1990a ) or a threonine-devoid diet (Monda et al. 1997 ). These injections are specific for the limiting IAA, i.e., isoleucine has no effect in rats fed a threonine-devoid or IMB diet and threonine has no effect when isoleucine is the dietary-limiting IAA. The injections are also anatomically specific, because neither injection 2 mm posterior to the effective site in the APC nor into the amygdala have any effect.

	Neural mechanisms for transduction of the IAA signal

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Protein kinases are ubiquitous mediators of signal transduction in the nervous system, and are important in learning. Because ingestion of an IMB diet leads to a learned aversion (the CTA mentioned above), it seems reasonable to speculate that phosphorylation of protein kinase may play a role in the earliest learned responses to IMB diets. We recently reported that mitogen activated protein kinase (MAPK) is phosphorylated in the APC of rats that have eaten an IMB diet for 1 h (Sharp et al. 2000 ). Also, given the central role of intracellular calcium concentration ([Ca²⁺]_i) as a signaling molecule in the nervous system as well as in learning and memory, we hypothesized that changes in [Ca²⁺]_i in the APC might also play a role in the responses to IMB. We added the limiting IAA to APC slices that had been pretreated with an IAA-deficient or corrected medium and then transferred to a medium containing fura 2 AM, a fluorescent marker for intracellular Ca²⁺. The results of fluorescence ratio measurements show an increase in [Ca²⁺]_i in the slices that were incubated in the deficient medium, but not in those from the control medium (Fig. 1 ). This is true for either threonine or lysine as the limiting IAA (Magrum et al. 1999 ). Thus, an increase in [Ca²⁺]_i may be associated with the initial signal leading to alterations in neurotransmitter activity upon repletion of the limiting IAA.

View larger version (30K): [in this window] [in a new window]   Figure 1. Changes in intracellular calcium (fluorescence ratio) in anterior piriform cortex slices as a percentage of baseline after addition of the amino acid (AA) indicated in the legend. Control slices were incubated in a medium containing all of the essential indispensible amino acids. Amino acid–deficient (AADEF) slices were incubated in threonine-devoid medium (black and white bars) or lysine-devoid medium (gray bars). Significant increases in intracellular calcium were seen in AADEF slices only. Note that the dispensable AA serine uses the same transporter as does threonine. (Data adapted from Magrum et al. 1999 .)

For measurements of the neural changes taking place prior to the anorectic response, we used a mild isoleucine IMB diet, with which the anorectic response is seen at about 6 h after introduction of the diet. Therefore, we took the brain samples at 3.5 h after introduction of this mild IMB diet. The results show that the concentration of isoleucine in the APC is already decreased to 20% of the basal value at 3.5 h, whereas none of the other brain areas measured has a significant change in the limiting IAA at this time. Other changes that are seen before the anorectic response include a decrease in the concentration of norepinephrine (NE) in the APC, and an increase in the concentration of NE in the ventromedial hypothalamus. As suggested by several changes in both serotonin and its metabolite, along with the involvement of the raphe nuclei that house the serotonin cell bodies, the serotonin system is activated as well (Gietzen et al. 1998 ).

To examine the concentrations of AA and neurotransmitters after the anorectic response and to evaluate dose-related responses to increased IAA added to the IMB mixture in the diets, we offered either a BAS or a moderately or severely isoleucine IMB diet and removed the brains just after observing a significant anorectic response, at 2.5 h after introduction of these diets (Gietzen et al. 1998 ). The results indicate again that the limiting amino acid, isoleucine, is decreased in the APC. Also after the anorectic response, the limiting IAA is decreased in the dorsomedial nucleus of the hypothalamus, but not in any of the 13 other areas studied. Additionally, the excitatory AA, aspartate and glutamate, are decreased in the medial hypothalamus; tyrosine and threonine are increased in several areas; and the NE and serotonin systems show activation in several areas. Apparently, many of the same systems are activated both before and after the onset of the anorectic response, with additional systems activated after the behavioral changes, and the changes in these neurochemical levels are proportional to the amounts of the IAA added to the IMB diet to create the IAA imbalance. Thus, it is clear from these findings that several signal transduction and neurotransmitter systems are involved in the responses to IMB diets, secondary to the decreased level of the limiting IAA.

The results from in vivo neuropharmacological studies using microinjections of receptor-selective agonists and antagonists into the APC describe the specific receptor types for several of the neurotransmitter systems in the IMB model, which are implicated in the responses to IAA in the APC (Truong 1999 ). These include the serotonin₃ receptor for serotonin, the ₂ noradrenergic receptor for norepinephrine, the GABA_A receptor for GABA and the dopamine D2 receptor. The data are consistent with the hypothesis that the glutamatergic pyramidal output cells are modulated by each of these transmitter systems. In addition, glutamate itself appears to act via the non-N-methyl D-aspartate (NMDA) receptor, at presynaptic sites within the APC. These relationships are diagramed in Figure 2 .

View larger version (28K): [in this window] [in a new window]   Figure 2. Potential effects of neurotransmitter system receptor activity in modulating the glutamate output cells of the anterior piriform cortex (APC). Each of the receptors indicated can inhibit activity or output of the glutamatergic cells. Abbreviations are: NE, norepinephrine; 2, alpha 2 noradrenergic receptor; 1, alpha 1 noradrenergic receptor; D2, dopamine D2 receptor; 5-HT3, serotonin 3 receptor; IMB, imbalanced diet; GABAA, gamma amino butyric acid receptor (type A); AMPA R’s, -amino-3-hydroxy-5-methyl-4-isoxazole propionate (non-N-methyl-D-aspartate [NMDA]) receptors for glutamate; Glu, glutamate; , stimulation; , inhibition; , leads to; , increases; large down arrow, output via axons of the glutamatergic pyramidal cells of the APC.

Recently, we observed that FOSLI is also dramatically increased in APC slices after in vitro incubation in an IAA-deficient medium for 1 h (Sharp et al. 2000 ). The importance of this observation is the demonstration that the APC does not require input from other brain areas to carry out its role as the IAA chemosensor.

	Molecular mechanisms in the learned responses to IAA

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Using inhibitors injected into the APC in vivo, Beverly et al. (1991 ) showed that the amelioration of the anorexia after replacement of the limiting AA into the APC depends on intact RNA and protein synthesis. Coadministration of puromycin (100 µM) or actinomycin D (10 mM) along with injections of the IAA into the APC blocks the limiting IAA-induced increase in IMB intake and restores choice behavior to control values, but has no effect on intake of the BAS diet. The effect of puromycin is seen, whether the AA is injected with the drug, just before feeding, or 6 h earlier. Thus, when the limiting AA is injected into the APC, both the increased intake of IMB and the reversal of aversion to IMB require de novo RNA and protein synthesis (Beverly et al. 1991 ).

Early in the protein synthetic process the tRNA synthetases become charged with their cognate amino acids prior to interacting with the initiation complex. We expected that a decrease in uncharged tRNA could initiate the signal in our model, as it does in mammalian single-cell systems subjected to IAA limitation (Rabinovitz 1995 ). Contrary to our expectation, the percentage of isoleucyl tRNA charging was increased, rather than decreased in both APC and whole brain taken 2 h after introduction of the IMB diet (Hickman et al. 1998 ). Thus, the percentage of tRNA charging alone does not appear to signal IAA deficiency in the APC. These observations are also consistent with the idea that the decrease in the limiting IAA in the APC evokes a neural signal, and subsequent activation of signal transduction pathways, prior to any alterations in genomic or translational activity.

These findings, when considered with the AA profile in the APC described above and in our earlier reports (Gietzen et al. 1986 ), support the suggestion that a reduction in the concentration of the limiting IAA, specifically in the APC, is followed by signal transduction and neurochemical activity. Further, this activity, ultimately leading to changes in gene expression and protein synthesis, is then involved in the behavioral responses to IMB. We observed increased FOSLI (Wang et al. 1996 ), discussed above, and increased mRNA for neuropeptide (NPY) (Hickman et al. 1996 ) and also decrease in a small acidic protein in APC (Hrupka, 1994 ) after the ingestion of IMB diets. Therefore, the mechanism of the IAA chemosensor is likely to involve both increased and decreased gene expression, as was previously reported for hepatocytes in IAA limitation (Marten et al. 1994 ).

The effects of IAA limitation on the regulation of protein synthesis and gene expression were previously demonstrated in both prokaryotic and eukaryotic systems. In mammalian cells transcription of the gene encoding the System A–amino acid transport protein is regulated by the availability of several IAAs (Kilberg 1986 ). Limitations of any of these IAAs cause increased transcription, whereas increased IAA concentration leads to decreased transcription. As noted above gene expression in liver cells is either increased, decreased or unchanged with IAA limitation (Marten et al. 1994 ). Thus, both specific induction and repression of gene expression may be seen in IAA-limited cells.

Preliminary results of differential gene expression using a microchip-array analysis of APC tissue, which had been taken 2 h after introduction of either an isoleucine IMB diet or a COR diet, indicate that there may be increased expression of a gene associated with the apoptosis pathway in the IMB group and increased expression of ubiquitin-specific protease in APCs from the corrected group (Magrum, L. J. and Gietzen, D. W., unpublished observations). Although these groups of proteins are large and complex (and there is much work to be done to confirm the results and then elucidate the mechanisms of activation in these systems), it is tempting to suggest that these results are consistent with activation of protein degradation after IMB diet feeding, and deactivation of the protein-degrading enzymes of the ubiquitin group after ingestion of the corrected diet.

The available evidence supports the APC as the site of IAA chemosensation in the brain. The specific transduction mechanisms by which IAA deficiency and repletion activate the APC are not known, but clearly phosphorylation of proteins and increases in intracellular calcium are among the early events occurring in the APC after changes in IAA status. Several neurotransmitter systems are activated in the APC after an IMB diet, modulating the glutamatergic output cells, which send neural signals to activate subsequent relays. Ultimately, the feeding circuits of the brain carry out the anorectic response. Diets that induce IAA deficiencies are uniformly rejected, a learned aversion develops, in all animals studied. Such learning involves synaptic reorganization, requiring both degradation and synthesis of protein. The genes involved clearly include c-fos and may also code for members of the ubiquitin and apoptosis systems.

	FOOTNOTES

 
¹ Presented as part of the symposium "Leucine as a Nutritional Signal" given at the Experimental Biology 2000 meeting, held in San Diego, CA on April 18, 2000. This symposium was sponsored by the American Society for Nutritional Sciences and was supported by the National Institutes of Health Division of Nutrition Research Coordination and Division of Digestive Diseases and Nutrition. The proceedings of the symposium are published as a supplement to The Journal of Nutrition. Editors for the symposium publication were Susan M. Hutson, Wake Forest University School of Medicine and Robert A. Harris, Indiana University School of Medicine.

² Supported in part by National Institute of Health grants NS33347, DK50347, DK42274 and DK35747, and U.S. Department of Agriculture NRICGP grant 97-35200-4477.

⁴ Abbreviations used: AA, amino acid(s); IAA, indispensable amino acid; APC, anterior piriform cortex; BAS, basal diet; COR, corrected diet; CSF, cerebrospinal fluid; CTA, conditioned taste aversion; GABA, -aminobutyric acid; FOSLI, Fos-like immunoreactivity; IMB, imbalanced diet; MAPK, mitogen activated protein kinase; NMDA, N-methyl-D-aspartate; NE, norepinephrine.

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