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Dorothy W. Gietzen - One of the best experts on this subject based on the ideXlab platform.
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measuring the ability of mice to sense dietary essential Amino Acid Deficiency the importance of Amino Acid status and timing
Cell Reports, 2016Co-Authors: Dorothy W. Gietzen, Thomas J. Koehnle, Anne-catherine Maurin, Pierre Fafournoux, Tracy G Anthony, Susan HaoAbstract:The ability to sense and choose appropriate nutrients for survival is a topic of longstanding interest in fields ranging from molecular biology to ecology. Many have contributed to this field, particularly with regard to essential Amino Acids (EAAs), the precursors for protein synthesis, dating back some 100 years (reviewed in Anthony and Gietzen, 2013). A recent report (Leib and Knight, 2015) challenges previous independent but common findings on the sensing of EAA-deficient diets by rodents, including food intake and neurochemical reports over 30 years (see Koehnle et al., 2004).
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effects of essential Amino Acid Deficiency down regulation of kcc2 and the gabaa receptor disinhibition in the anterior piriform cortex
Journal of Neurochemistry, 2013Co-Authors: James W Sharp, Catherine Rossinta, Irene Baccelli, John A Payne, John B Rudell, Dorothy W. GietzenAbstract: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.
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the sensing of essential Amino Acid Deficiency in the anterior piriform cortex that requires the uncharged trna gcn2 pathway is sensitive to wortmannin but not rapamycin
Pharmacology Biochemistry and Behavior, 2010Co-Authors: Shuzhen Hao, Catherine Rossinta, Dorothy W. GietzenAbstract:Animals detect and reject their first essential/indispensable Amino Acid (IAA) deficient meal within 20 min; this IAA sensing requires an intact anterior piriform cortex (APC). In the biochemical responses to IAA Deficiency in the APC we have shown that: uncharged tRNA is the primary sensor; IAA transport is increased; and signaling, including the extracellular-regulated kinase (ERK1/2), is activated. The mammalian target of rapamycin (mTOR) is a potential AA sensor and is regulated by AA transport. Previously, the inhibitors, rapamycin for mTOR, wortmannin for phosphoinositide 3 kinase (PI3K) and PD98059 for ERK, each blocked the upregulation of the System A transporter in IAA depleted APC neurons. Here we injected these same inhibitors into the APC and measured intake of an IAA deficient diet. Rapamycin had no effect on the rejection of the IAA deficient diet, but wortmannin increased ERK activation and intake of the deficient diet before 40 min and PD98059 acted after 40 min to increase the second meal. While the specific wortmannin target involved in blocking the behavioral response remains unclear, we conclude that mTOR is dispensable for sensing IAA Deficiency in the APC, and that ERK is associated with the secondary learned responses to IAA deficient diets.
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mechanisms of food intake repression in indispensable Amino Acid Deficiency
Annual Review of Nutrition, 2007Co-Authors: Dorothy W. Gietzen, Shuzhen Hao, Tracy G AnthonyAbstract: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.
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co localization of phosphorylated extracellular signal regulated protein kinases 1 2 erk1 2 and phosphorylated eukaryotic initiation factor 2α eif2α in response to a threonine devoid diet
The Journal of Comparative Neurology, 2006Co-Authors: James W Sharp, Catherine Rossinta, John B Rudell, Dorothy W. GietzenAbstract: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 α-subunit of the eukaryotic initiation factor 2α (eIF2α) has been directly linked to Amino Acid Deficiency in yeast. Recently, we have shown increased phosphorylation of eIF2α (p-eIF2α) in the rat APC 20 minutes after ingestion of an IAA-deficient meal. We suggest that if phosphorylation of eIF2α is an important mechanism in detection of IAA Deficiency, then APC neurons that show p-eIF2α should also show molecular evidence of potentiation. The present research demonstrates increased expression and co-localization of p-eIF2α 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-eIF2α 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-eIF2α and p-ERK1/2. These chemosensory neurons probably detect IAA Deficiency and generate neuronal signaling to other portions of the brain, changing feeding behavior. J. Comp. Neurol. 494:485–494, 2006. © 2005 Wiley-Liss, Inc.
Anne-catherine Maurin - One of the best experts on this subject based on the ideXlab platform.
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Liver GCN2 controls hepatic FGF21 secretion and modulates whole-body postprandial oxidation profile under a low-protein diet
AJP - Endocrinology and Metabolism, 2019Co-Authors: Tristan Chalvon Demersay, Anne-catherine Maurin, Joanna Moro, Patrick Even, Catherine Chaumontet, Daniel Tomé, Julien Averous, Julien Piedcoq, Claire Gaudichon, Pierre FafournouxAbstract:OBJECTIVE: GCN2 is a kinase which detects Amino Acid Deficiency and is involved in the control of protein synthesis and energy metabolism. However, the role of hepatic GCN2 in the metabolic adaptations in response to the modulation of dietary protein has been seldom studied. METHODS: Wild-type (WT) and liver GCN2-deficient (KO) mice were fed either a normo-protein diet, a low-protein diet or a high-protein diet for 3 weeks. During this period, body weight, food intake and metabolic parameters were followed. RESULTS: In mice fed normo- and high protein diets, GCN2 pathway in the liver is not activated in WT mice leading to a similar metabolic profile with the one of KO mice. On the contrary, a low protein diet activates GCN2 in WT mice inducing FGF21 secretion. In turn, FGF21 maintains a high level of lipid oxidation leading to a different postprandial oxidation profile compared with KO mice. CONCLUSIONS: Hepatic GCN2 controls FGF21 secretion under a low protein diet, and modulates a whole-body postprandial oxidation profile.
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measuring the ability of mice to sense dietary essential Amino Acid Deficiency the importance of Amino Acid status and timing
Cell Reports, 2016Co-Authors: Dorothy W. Gietzen, Thomas J. Koehnle, Anne-catherine Maurin, Pierre Fafournoux, Tracy G Anthony, Susan HaoAbstract:The ability to sense and choose appropriate nutrients for survival is a topic of longstanding interest in fields ranging from molecular biology to ecology. Many have contributed to this field, particularly with regard to essential Amino Acids (EAAs), the precursors for protein synthesis, dating back some 100 years (reviewed in Anthony and Gietzen, 2013). A recent report (Leib and Knight, 2015) challenges previous independent but common findings on the sensing of EAA-deficient diets by rodents, including food intake and neurochemical reports over 30 years (see Koehnle et al., 2004).
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In vivo imaging of the spatiotemporal activity of the eIF2 -ATF4 signaling pathway: Insights into stress and related disorders
Science Signaling, 2015Co-Authors: C. Chaveroux, Anne-catherine Maurin, Celine Jousse, Julien Averous, V. Carraro, L. Canaple, Y. Muranishi, L. Parry, F. Mesclon, E. GattiAbstract:The eIF2 alpha-ATF4 pathway is involved in cellular adaptation to stress and is dysregulated in numerous diseases. Activation of this pathway leads to phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2 alpha) and the recruitment of the transcription factor ATF4 (activating transcription factor 4) to specific CCAAT/enhancer binding protein (C/EBP)-ATF response elements (CAREs) located in the promoters of target genes. To monitor the spatiotemporal modulation of this pathway in living animals, we generated a novel CARE-driven luciferase mouse model (CARE-LUC). These transgenic mice enable the investigation of the eIF2 alpha-ATF4 pathway activity in the whole organism and at the tissue and cellular levels by combining imaging, luciferase assays, and immunochemistry. Using this mouse line, we showed the tissue-specific activation pattern of this pathway in response to Amino Acid Deficiency or endoplasmic reticulum stress and the hepatic induction of this pathway in a stress-related pathology model of liver fibrosis. The CARE-LUC mouse model represents an innovative tool to investigate the eIF2 alpha-ATF4 axis and to develop drugs targeting this important pathway in the remediation of related pathologies.
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Hypothalamic eIF2 alpha signaling regulates food intake
Cell Reports, 2014Co-Authors: Anne-catherine Maurin, Laurent Parry, Valerie Carraro, Celine Jousse, Julien Averous, Alexandre Benani, Anne Lorsignol, Xavier Brenachot, Christophe Guissard, Alain BruhatAbstract:The reversible phosphorylation of the a subunit of eukaryotic initiation factor 2 (eIF2 alpha) is a highly conserved signal implicated in the cellular adaptation to numerous stresses such as the one caused by Amino Acid limitation. In response to dietary Amino Acid Deficiency, the brain-specific activation of the eIF2 alpha kinase GCN2 leads to food intake inhibition. We report here that GCN2 is rapidly activated in the mediobasal hypothalamus (MBH) after consumption of a leucine-deficient diet. Furthermore, knockdown of GCN2 in this particular area shows that MBH GCN2 activity controls the onset of the aversive response. Importantly, pharmacological experiments demonstrate that the sole phosphorylation of eIF2 alpha in the MBH is sufficient to regulate food intake. eIF2 alpha signaling being at the crossroad of stress pathways activated in several pathological states, our study indicates that hypothalamic eIF2 alpha phosphorylation could play a critical role in the onset of anorexia associated with certain diseases.
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Amino-Acid limitation induces the GCN2 signaling pathway in myoblasts but not in myotubes
Biochimie, 2008Co-Authors: Christiane Deval, Jeremie Talvas, Cédric Chaveroux, Anne-catherine Maurin, Sylvie Mordier, Yoan Cherasse, Laurent Parry, Valerie Carraro, Celine Jousse, Alain BruhatAbstract:There is a growing body of evidence that suggests that Amino Acids play an important role in controlling gene expression, but the cell specificity of the Amino-Acid-mediated regulation of gene expression in mammals remains unknown. Using a model of muscle cells (C2C12) at two stages of differentiation, i.e. myoblasts and myotubes, we employed transcriptional profiling to show that Amino-Acid Deficiency does not regulate the same set of gene in differentiated and non-differentiated cells. Furthermore, in myotubes, the GCN2 pathway is not activated by Amino-Acid starvation due to an Amino-Acid supply from intracellular proteolysis associated with a low GCN2 expression.
Martha H Stipanuk - One of the best experts on this subject based on the ideXlab platform.
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effects of single Amino Acid Deficiency on mrna translation are markedly different for methionine versus leucine
Scientific Reports, 2018Co-Authors: Kevin M. Mazor, Leiming Dong, Yuanhui Mao, Robert V Swanda, Shubing Qian, Martha H StipanukAbstract:Although Amino Acids are known regulators of translation, the unique contributions of specific Amino Acids are not well understood. We compared effects of culturing HEK293T cells in medium lacking either leucine, methionine, histidine, or arginine on eIF2 and 4EBP1 phosphorylation and measures of mRNA translation. Methionine starvation caused the most drastic decrease in translation as assessed by polysome formation, ribosome profiling, and a measure of protein synthesis (puromycin-labeled polypeptides) but had no significant effect on eIF2 phosphorylation, 4EBP1 hyperphosphorylation or 4EBP1 binding to eIF4E. Leucine starvation suppressed polysome formation and was the only tested condition that caused a significant decrease in 4EBP1 phosphorylation or increase in 4EBP1 binding to eIF4E, but effects of leucine starvation were not replicated by overexpressing nonphosphorylatable 4EBP1. This suggests the binding of 4EBP1 to eIF4E may not by itself explain the suppression of mRNA translation under conditions of leucine starvation. Ribosome profiling suggested that leucine deprivation may primarily inhibit ribosome loading, whereas methionine deprivation may primarily impair start site recognition. These data underscore our lack of a full understanding of how mRNA translation is regulated and point to a unique regulatory role of methionine status on translation initiation that is not dependent upon eIF2 phosphorylation.
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Upregulation of capacity for glutathione synthesis in response to Amino Acid deprivation: regulation of glutamate-cysteine ligase subunits
Amino Acids, 2014Co-Authors: Angelos K. Sikalidis, Kevin M. Mazor, Lawrence L Hirschberger, Heather B Roman, Martha H StipanukAbstract:Using HepG2/C3A cells and MEFs, we investigated whether induction of GSH synthesis in response to sulfur Amino Acid Deficiency is mediated by the decrease in cysteine levels or whether it requires a decrease in GSH levels per se. Both the glutamate–cysteine ligase catalytic (GCLC) and modifier (GCLM) subunit mRNA levels were upregulated in response to a lack of cysteine or other essential Amino Acids, independent of GSH levels. This upregulation did not occur in MEFs lacking GCN2 (general control non-derepressible 2, also known as eIF2α kinase 4) or in cells expressing mutant eIF2α lacking the eIF2α kinase Ser51 phosphorylation site, indicating that expression of both GCLC and GCLM was mediated by the GCN2/ATF4 stress response pathway. Only the increase in GCLM mRNA level, however, was accompanied by a parallel increase in protein expression, suggesting that the enhanced capacity for GSH synthesis depended largely on increased association of GCLC with its regulatory subunit. Upregulation of both GCLC and GLCM mRNA levels in response to cysteine deprivation was dependent on new protein synthesis, which is consistent with expression of GCLC and GCLM being mediated by proteins whose synthesis depends on activation of the GCN2/ATF4 pathway. Our data suggest that the regulation of GCLC expression may be mediated by changes in the abundance of transcriptional regulators, whereas the regulation of GCLM expression may be mediated by changes in the abundance of mRNA stabilizing or destabilizing proteins. Upregulation of GCLM levels in response to low cysteine levels may serve to protect the cell in the face of a future stress requiring GSH as an antioxidant or conjugating/detoxifying agent.
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growing rats respond to a sulfur Amino Acid deficient diet by phosphorylation of the α subunit of eukaryotic initiation factor 2 heterotrimeric complex and induction of adaptive components of the integrated stress response
Journal of Nutrition, 2010Co-Authors: Angelos K. Sikalidis, Martha H StipanukAbstract:Mammalian cells respond to various kinds of stress, including nutritional stress, via pathways that are initiated by phosphorylation of the α subunit of the eukaryotic initiation factor 2 complex (eIF2α). Because the models used to study eIF2α-kinase–mediated responses to Amino Acid Deficiency have commonly used media or diets devoid of 1 or more essential Amino Acids, we asked whether eIF2α-kinase–mediated responses would be induced in animals fed a more typical diet that was not as imbalanced as one in which 1 essential Amino Acid is totally absent. To answer this question, we fed rats soy protein-based diets that were either adequate or limiting in sulfur-containing Amino Acids (SAA). Rats fed a SAA-deficient diet (3.4 g methionine equivalents/kg diet) grew more slowly than rats fed the control diet (5.86 g methionine equivalents/kg diet). Analysis of liver from rats fed these diets for 7 d showed that the SAA-deficient rats had higher levels of eIF2α phosphorylation and higher levels of activating transcription factor (ATF) 4, ATF3, asparagine synthetase, solute carrier 7A11, cysteinyl-tRNA synthetase, and cystathionine γ-lyase. On the other hand, components of the integrated stress response (ISR) known to promote apoptosis or translational recovery were not induced. Taken together, our results indicate that rats fed the SAA-deficient diet had a prolonged activation of an eIF2α kinase that leads to upregulation of adaptive components of the ISR.
Alain Bruhat - One of the best experts on this subject based on the ideXlab platform.
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Hypothalamic eIF2 alpha signaling regulates food intake
Cell Reports, 2014Co-Authors: Anne-catherine Maurin, Laurent Parry, Valerie Carraro, Celine Jousse, Julien Averous, Alexandre Benani, Anne Lorsignol, Xavier Brenachot, Christophe Guissard, Alain BruhatAbstract:The reversible phosphorylation of the a subunit of eukaryotic initiation factor 2 (eIF2 alpha) is a highly conserved signal implicated in the cellular adaptation to numerous stresses such as the one caused by Amino Acid limitation. In response to dietary Amino Acid Deficiency, the brain-specific activation of the eIF2 alpha kinase GCN2 leads to food intake inhibition. We report here that GCN2 is rapidly activated in the mediobasal hypothalamus (MBH) after consumption of a leucine-deficient diet. Furthermore, knockdown of GCN2 in this particular area shows that MBH GCN2 activity controls the onset of the aversive response. Importantly, pharmacological experiments demonstrate that the sole phosphorylation of eIF2 alpha in the MBH is sufficient to regulate food intake. eIF2 alpha signaling being at the crossroad of stress pathways activated in several pathological states, our study indicates that hypothalamic eIF2 alpha phosphorylation could play a critical role in the onset of anorexia associated with certain diseases.
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Amino-Acid limitation induces the GCN2 signaling pathway in myoblasts but not in myotubes
Biochimie, 2008Co-Authors: Christiane Deval, Jeremie Talvas, Cédric Chaveroux, Anne-catherine Maurin, Sylvie Mordier, Yoan Cherasse, Laurent Parry, Valerie Carraro, Celine Jousse, Alain BruhatAbstract:There is a growing body of evidence that suggests that Amino Acids play an important role in controlling gene expression, but the cell specificity of the Amino-Acid-mediated regulation of gene expression in mammals remains unknown. Using a model of muscle cells (C2C12) at two stages of differentiation, i.e. myoblasts and myotubes, we employed transcriptional profiling to show that Amino-Acid Deficiency does not regulate the same set of gene in differentiated and non-differentiated cells. Furthermore, in myotubes, the GCN2 pathway is not activated by Amino-Acid starvation due to an Amino-Acid supply from intracellular proteolysis associated with a low GCN2 expression.
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The GCN2 kinase biases feeding behavior to maintain Amino Acid homeostasis in omnivores
Cell Metabolism, 2005Co-Authors: Anne-catherine Maurin, Yoan Cherasse, Laurent Parry, Celine Jousse, Alain Bruhat, Julien Averous, Huiqing Zeng, Yuhong Zhang, Heather Harding, David RonAbstract:To insure an adequate supply of nutrients, omnivores choose among available food sources. This process is exemplified by the well-characterized innate aversion of omnivores to otherwise nutritious foods of imbalanced Amino Acid content. We report that brain-specific inactivation of GCN2, a ubiquitously expressed protein kinase that phosphorylates translation initiation factor 2 alpha (eIF2alpha) in response to intracellular Amino Acid Deficiency, impairs this aversive response. GCN2 inactivation also diminishes phosphorylated eIF2alpha levels in the mouse anterior piriform cortex following consumption of an imbalanced meal. An ancient intracellular signal transduction pathway responsive to Amino Acid Deficiency thus affects feeding behavior by activating a neuronal circuit that biases consumption against imbalanced food sources.
Celine Jousse - One of the best experts on this subject based on the ideXlab platform.
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In vivo imaging of the spatiotemporal activity of the eIF2 -ATF4 signaling pathway: Insights into stress and related disorders
Science Signaling, 2015Co-Authors: C. Chaveroux, Anne-catherine Maurin, Celine Jousse, Julien Averous, V. Carraro, L. Canaple, Y. Muranishi, L. Parry, F. Mesclon, E. GattiAbstract:The eIF2 alpha-ATF4 pathway is involved in cellular adaptation to stress and is dysregulated in numerous diseases. Activation of this pathway leads to phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2 alpha) and the recruitment of the transcription factor ATF4 (activating transcription factor 4) to specific CCAAT/enhancer binding protein (C/EBP)-ATF response elements (CAREs) located in the promoters of target genes. To monitor the spatiotemporal modulation of this pathway in living animals, we generated a novel CARE-driven luciferase mouse model (CARE-LUC). These transgenic mice enable the investigation of the eIF2 alpha-ATF4 pathway activity in the whole organism and at the tissue and cellular levels by combining imaging, luciferase assays, and immunochemistry. Using this mouse line, we showed the tissue-specific activation pattern of this pathway in response to Amino Acid Deficiency or endoplasmic reticulum stress and the hepatic induction of this pathway in a stress-related pathology model of liver fibrosis. The CARE-LUC mouse model represents an innovative tool to investigate the eIF2 alpha-ATF4 axis and to develop drugs targeting this important pathway in the remediation of related pathologies.
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Hypothalamic eIF2 alpha signaling regulates food intake
Cell Reports, 2014Co-Authors: Anne-catherine Maurin, Laurent Parry, Valerie Carraro, Celine Jousse, Julien Averous, Alexandre Benani, Anne Lorsignol, Xavier Brenachot, Christophe Guissard, Alain BruhatAbstract:The reversible phosphorylation of the a subunit of eukaryotic initiation factor 2 (eIF2 alpha) is a highly conserved signal implicated in the cellular adaptation to numerous stresses such as the one caused by Amino Acid limitation. In response to dietary Amino Acid Deficiency, the brain-specific activation of the eIF2 alpha kinase GCN2 leads to food intake inhibition. We report here that GCN2 is rapidly activated in the mediobasal hypothalamus (MBH) after consumption of a leucine-deficient diet. Furthermore, knockdown of GCN2 in this particular area shows that MBH GCN2 activity controls the onset of the aversive response. Importantly, pharmacological experiments demonstrate that the sole phosphorylation of eIF2 alpha in the MBH is sufficient to regulate food intake. eIF2 alpha signaling being at the crossroad of stress pathways activated in several pathological states, our study indicates that hypothalamic eIF2 alpha phosphorylation could play a critical role in the onset of anorexia associated with certain diseases.
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Amino-Acid limitation induces the GCN2 signaling pathway in myoblasts but not in myotubes
Biochimie, 2008Co-Authors: Christiane Deval, Jeremie Talvas, Cédric Chaveroux, Anne-catherine Maurin, Sylvie Mordier, Yoan Cherasse, Laurent Parry, Valerie Carraro, Celine Jousse, Alain BruhatAbstract:There is a growing body of evidence that suggests that Amino Acids play an important role in controlling gene expression, but the cell specificity of the Amino-Acid-mediated regulation of gene expression in mammals remains unknown. Using a model of muscle cells (C2C12) at two stages of differentiation, i.e. myoblasts and myotubes, we employed transcriptional profiling to show that Amino-Acid Deficiency does not regulate the same set of gene in differentiated and non-differentiated cells. Furthermore, in myotubes, the GCN2 pathway is not activated by Amino-Acid starvation due to an Amino-Acid supply from intracellular proteolysis associated with a low GCN2 expression.
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The GCN2 kinase biases feeding behavior to maintain Amino Acid homeostasis in omnivores
Cell Metabolism, 2005Co-Authors: Anne-catherine Maurin, Yoan Cherasse, Laurent Parry, Celine Jousse, Alain Bruhat, Julien Averous, Huiqing Zeng, Yuhong Zhang, Heather Harding, David RonAbstract:To insure an adequate supply of nutrients, omnivores choose among available food sources. This process is exemplified by the well-characterized innate aversion of omnivores to otherwise nutritious foods of imbalanced Amino Acid content. We report that brain-specific inactivation of GCN2, a ubiquitously expressed protein kinase that phosphorylates translation initiation factor 2 alpha (eIF2alpha) in response to intracellular Amino Acid Deficiency, impairs this aversive response. GCN2 inactivation also diminishes phosphorylated eIF2alpha levels in the mouse anterior piriform cortex following consumption of an imbalanced meal. An ancient intracellular signal transduction pathway responsive to Amino Acid Deficiency thus affects feeding behavior by activating a neuronal circuit that biases consumption against imbalanced food sources.