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Jan Tommassen - One of the best experts on this subject based on the ideXlab platform.
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Variable processing of the IgA protease autotransporter at the cell surface of Neisseria meningitidis
Microbiology, 2014Co-Authors: Virginie Roussel-jazédé, Jesus Arenas, Jan Tommassen, Jeroen D. Langereis, Peter Van UlsenAbstract:As with all classical monomeric autotransporters, IgA protease of Neisseria meningitidis is a modular protein consisting of an N-terminal signal sequence, a passenger domain and a C-terminal translocator domain (TD) that assists in the secretion of the passenger domain across the outer membrane. The passenger of IgA protease consists of three separate domains: the protease domain, the γ-peptide and the α-peptide that contains nuclear localization signals (NLSs). The protease domain is released into the extracellular milieu either via autocatalytic processing or via cleavage by another autotransporter, NALP, expression of which is phase-variable. NALP-mediated cleavage results in the release of a passenger that includes the α- and γ-peptides. Here, we studied the fate of the α-peptide when NALP was not expressed and observed strain-dependent differences. In meningococcal strains where the α-peptide contained a single NLS, the α-peptide remained covalently attached to the TD and was detected at the cell surface. In other strains, the α-peptide contained four NLSs and was separated from the TD by an IgA protease autoproteolytic cleavage site. In many of those cases, the α-peptide was found non-covalently associated with the cells as a separate polypeptide. The cell surface association of the α-peptides may be relevant physiologically. We report a novel function for the α-peptide, i.e. the binding of heparin – an immune-modulatory molecule that in the host is found in the extracellular matrix and connected to cell surfaces.
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involvement of three meningococcal surface exposed proteins the heparin binding protein nhba the α peptide of iga protease and the autotransporter protease NALP in initiation of biofilm formation
Molecular Microbiology, 2013Co-Authors: Jesus Arenas, Tom N. P. Bosma, Reindert Nijland, Francisco J. Rodriguez, Jan TommassenAbstract:Summary Neisseria meningitidis is a common and usually harmless inhabitant of the mucosa of the human nasopharynx, which, in rare cases, can cross the epithelial barrier and cause meningitis and sepsis. Biofilm formation favours the colonization of the host and the subsequent carrier state. Two different strategies of biofilm formation, either dependent or independent on extracellular DNA (eDNA), have been described for meningococcal strains. Here, we demonstrate that the autotransporter protease NALP, the expression of which is phase variable, affects eDNA-dependent biofilm formation in N. meningitidis. The effect of NALP was found in biofilm formation under static and flow conditions and was dependent on its protease activity. Cleavage of the heparin-binding antigen NhbA and the α-peptide of IgA protease, resulting in the release of positively charged polypeptides from the cell surface, was responsible for the reduction in biofilm formation when NALP is expressed. Both NhbA and the α-peptide of IgA protease were shown to bind DNA. We conclude that NhbA and the α-peptide of IgA protease are implicated in biofilm formation by binding eDNA and that NALP is an important regulator of this process through the proteolysis of these surface-exposed proteins.
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Lipidation of the autotransporter NALP of Neisseria meningitidis is required for its function in the release of cell-surface-exposed proteins
Microbiology, 2012Co-Authors: Virginie Roussel-jazédé, Jan Tommassen, Jan Grijpstra, Vincent Van Dam, Peter Van UlsenAbstract:Autotransporters of Gram-negative bacteria consist of an N-terminal signal sequence, a C-terminal translocator domain and the secreted passenger domain in between. The autotransporter NALP of Neisseria meningitidis includes a protease domain that facilitates the release of several immunogenic proteins from the cell surface into the extracellular milieu. Rather exceptionally among autotransporters, NALP is a lipoprotein. We investigated the role of lipidation in the biogenesis and function of the protein. To this end, the N-terminal cysteine, which is lipidated in the wild-type protein, was substituted by alanine. Like the wild-type protein, the mutant protein was secreted into the medium, demonstrating that lipidation is not required for biogenesis of the protein. However, the non-lipidated NALP variant had a drastically reduced capacity to cleave its substrate proteins from the cell surface, suggesting that the lipid moiety is important for function. Kinetic experiments demonstrated that the autocatalytic processing of the non-lipidated protein at the cell surface was much faster than that of the wild-type protein. Thus, the lipid moiety delays the release of NALP from the cell surface, thereby allowing it to release other surface-exposed proteins into the milieu.
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Involvement of three meningococcal surface‐exposed proteins, the heparin‐binding protein NhbA, the α‐peptide of IgA protease and the autotransporter protease NALP, in initiation of biofilm formation
Molecular microbiology, 2012Co-Authors: Jesus Arenas, Tom N. P. Bosma, Reindert Nijland, Francisco J. Rodriguez, Jan TommassenAbstract:Summary Neisseria meningitidis is a common and usually harmless inhabitant of the mucosa of the human nasopharynx, which, in rare cases, can cross the epithelial barrier and cause meningitis and sepsis. Biofilm formation favours the colonization of the host and the subsequent carrier state. Two different strategies of biofilm formation, either dependent or independent on extracellular DNA (eDNA), have been described for meningococcal strains. Here, we demonstrate that the autotransporter protease NALP, the expression of which is phase variable, affects eDNA-dependent biofilm formation in N. meningitidis. The effect of NALP was found in biofilm formation under static and flow conditions and was dependent on its protease activity. Cleavage of the heparin-binding antigen NhbA and the α-peptide of IgA protease, resulting in the release of positively charged polypeptides from the cell surface, was responsible for the reduction in biofilm formation when NALP is expressed. Both NhbA and the α-peptide of IgA protease were shown to bind DNA. We conclude that NhbA and the α-peptide of IgA protease are implicated in biofilm formation by binding eDNA and that NALP is an important regulator of this process through the proteolysis of these surface-exposed proteins.
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A Neisserial autotransporter NALP modulating the processing of other autotransporters.
Molecular microbiology, 2003Co-Authors: Peter Van Ulsen, Loek Van Alphen, Jan Ten Hove, Floris Fransen, Peter Van Der Ley, Jan TommassenAbstract:Autotransporters constitute a relatively simple secretion system in Gram-negative bacteria, depending for their translocation across the outer membrane only on a C-terminal translocator domain. We have studied a novel autotransporter serine protease, designated NALP, from Neisseria meningitidis strain H44/76, featuring a lipoprotein motif at the signal sequence cleavage site. Indeed, lipidation of NALP could be demonstrated, but the secreted 70 kDa domain of NALP lacked the lipid-moiety as a result of additional N-terminal processing. A NALP mutant showed a drastically altered profile of secreted proteins. Mass-spectrometric analysis of tryptic fragments identified the autotransporters IgA protease and App, a homologue of the adhesin Hap of Haemophilus influenzae, as the major secreted proteins. Two forms of both of these proteins were found in the culture supernatant of the wild-type strain, whereas only the lower molecular-weight forms predominated in the culture supernatant of the NALP mutant. The serine-protease active site of NALP was required for the modulation of the processing of these autotransporters. We propose that, apart from the autoproteolytic processing, NALP can process App and IgA protease and hypothesize that this function of NALP could contribute to the virulence of the organism.
Austin L. Hughes - One of the best experts on this subject based on the ideXlab platform.
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Evolutionary relationships of vertebrate NACHT domain-containing proteins
Immunogenetics, 2006Co-Authors: Austin L. HughesAbstract:Phylogenetic analyses of conserved [neuronal apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomerase-associated protein (TP1)] (NACHT) domains were used to reconstruct the evolutionary history of vertebrate NACHT-containing proteins. The results supported the hypothesis that NOD3 is basal to the other NACHT-containing proteins found in tetrapods. The latter formed two strongly supported clusters or subfamilies, here designated NALP and nucleotide-binding oligomerization domain (NOD). The presence of apparent bony fish orthologs of NOD3 and CIITA supported the hypothesis that the origin of these molecules predates the origin of tetrapods, and the presence of avian sequences in both NALP and NOD clusters supported the origin of these subfamilies before the bird–mammal divergence. However, the extensive diversification of the NALP subfamily seen in mammals evidently occurred within the mammalian lineage. Both NALP and NOD subfamilies include members with differential expression in the antigen-presenting cells of the immune system, and the phylogenetic analyses supported the hypothesis that this expression pattern has evolved independently more than once in each of these subfamilies.
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Evolutionary relationships of vertebrate NACHT domain-containing proteins
Immunogenetics, 2006Co-Authors: Austin L. HughesAbstract:Phylogenetic analyses of conserved [neuronal apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomerase-associated protein (TP1)] (NACHT) domains were used to reconstruct the evolutionary history of vertebrate NACHT-containing proteins. The results supported the hypothesis that NOD3 is basal to the other NACHT-containing proteins found in tetrapods. The latter formed two strongly supported clusters or subfamilies, here designated NALP and nucleotide-binding oligomerization domain (NOD). The presence of apparent bony fish orthologs of NOD3 and CIITA supported the hypothesis that the origin of these molecules predates the origin of tetrapods, and the presence of avian sequences in both NALP and NOD clusters supported the origin of these subfamilies before the bird–mammal divergence. However, the extensive diversification of the NALP subfamily seen in mammals evidently occurred within the mammalian lineage. Both NALP and NOD subfamilies include members with differential expression in the antigen-presenting cells of the immune system, and the phylogenetic analyses supported the hypothesis that this expression pattern has evolved independently more than once in each of these subfamilies.
Jesus Arenas - One of the best experts on this subject based on the ideXlab platform.
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Variable processing of the IgA protease autotransporter at the cell surface of Neisseria meningitidis
Microbiology, 2014Co-Authors: Virginie Roussel-jazédé, Jesus Arenas, Jan Tommassen, Jeroen D. Langereis, Peter Van UlsenAbstract:As with all classical monomeric autotransporters, IgA protease of Neisseria meningitidis is a modular protein consisting of an N-terminal signal sequence, a passenger domain and a C-terminal translocator domain (TD) that assists in the secretion of the passenger domain across the outer membrane. The passenger of IgA protease consists of three separate domains: the protease domain, the γ-peptide and the α-peptide that contains nuclear localization signals (NLSs). The protease domain is released into the extracellular milieu either via autocatalytic processing or via cleavage by another autotransporter, NALP, expression of which is phase-variable. NALP-mediated cleavage results in the release of a passenger that includes the α- and γ-peptides. Here, we studied the fate of the α-peptide when NALP was not expressed and observed strain-dependent differences. In meningococcal strains where the α-peptide contained a single NLS, the α-peptide remained covalently attached to the TD and was detected at the cell surface. In other strains, the α-peptide contained four NLSs and was separated from the TD by an IgA protease autoproteolytic cleavage site. In many of those cases, the α-peptide was found non-covalently associated with the cells as a separate polypeptide. The cell surface association of the α-peptides may be relevant physiologically. We report a novel function for the α-peptide, i.e. the binding of heparin – an immune-modulatory molecule that in the host is found in the extracellular matrix and connected to cell surfaces.
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involvement of three meningococcal surface exposed proteins the heparin binding protein nhba the α peptide of iga protease and the autotransporter protease NALP in initiation of biofilm formation
Molecular Microbiology, 2013Co-Authors: Jesus Arenas, Tom N. P. Bosma, Reindert Nijland, Francisco J. Rodriguez, Jan TommassenAbstract:Summary Neisseria meningitidis is a common and usually harmless inhabitant of the mucosa of the human nasopharynx, which, in rare cases, can cross the epithelial barrier and cause meningitis and sepsis. Biofilm formation favours the colonization of the host and the subsequent carrier state. Two different strategies of biofilm formation, either dependent or independent on extracellular DNA (eDNA), have been described for meningococcal strains. Here, we demonstrate that the autotransporter protease NALP, the expression of which is phase variable, affects eDNA-dependent biofilm formation in N. meningitidis. The effect of NALP was found in biofilm formation under static and flow conditions and was dependent on its protease activity. Cleavage of the heparin-binding antigen NhbA and the α-peptide of IgA protease, resulting in the release of positively charged polypeptides from the cell surface, was responsible for the reduction in biofilm formation when NALP is expressed. Both NhbA and the α-peptide of IgA protease were shown to bind DNA. We conclude that NhbA and the α-peptide of IgA protease are implicated in biofilm formation by binding eDNA and that NALP is an important regulator of this process through the proteolysis of these surface-exposed proteins.
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Involvement of three meningococcal surface‐exposed proteins, the heparin‐binding protein NhbA, the α‐peptide of IgA protease and the autotransporter protease NALP, in initiation of biofilm formation
Molecular microbiology, 2012Co-Authors: Jesus Arenas, Tom N. P. Bosma, Reindert Nijland, Francisco J. Rodriguez, Jan TommassenAbstract:Summary Neisseria meningitidis is a common and usually harmless inhabitant of the mucosa of the human nasopharynx, which, in rare cases, can cross the epithelial barrier and cause meningitis and sepsis. Biofilm formation favours the colonization of the host and the subsequent carrier state. Two different strategies of biofilm formation, either dependent or independent on extracellular DNA (eDNA), have been described for meningococcal strains. Here, we demonstrate that the autotransporter protease NALP, the expression of which is phase variable, affects eDNA-dependent biofilm formation in N. meningitidis. The effect of NALP was found in biofilm formation under static and flow conditions and was dependent on its protease activity. Cleavage of the heparin-binding antigen NhbA and the α-peptide of IgA protease, resulting in the release of positively charged polypeptides from the cell surface, was responsible for the reduction in biofilm formation when NALP is expressed. Both NhbA and the α-peptide of IgA protease were shown to bind DNA. We conclude that NhbA and the α-peptide of IgA protease are implicated in biofilm formation by binding eDNA and that NALP is an important regulator of this process through the proteolysis of these surface-exposed proteins.
Robert A. Steiner - One of the best experts on this subject based on the ideXlab platform.
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Altered response to metabolic challenges in mice with genetically targeted deletions of galanin-like peptide
American Journal of Physiology-endocrinology and Metabolism, 2008Co-Authors: Heather M. Dungan Lemko, Donald K. Clifton, Robert A. Steiner, Gregory S FraleyAbstract:Galanin-like peptide (GALP) is expressed in the arcuate nucleus and is implicated in the neuroendocrine regulation of metabolism and reproduction. To investigate the physiological significance of GALP, we generated and characterized a strain of mice with a genetically targeted deletion in the GALP gene [GALP knockout (KO) mice]. We report that GALP KO mice have a subtle, but notable, metabolic phenotype that becomes apparent during adaptation to changes in nutrition. GALP KO mice are indistinguishable from wild-type (WT) controls in virtually all aspects of growth, sexual development, body weight, food and water consumption, and motor behaviors, when they are allowed unlimited access to standard rodent chow. However, GALP KO mice have an altered response to changes in diet. 1) Male GALP KO mice consumed less food during refeeding after a fast than WT controls (P < 0.01). 2) GALP KO mice of both sexes gained less weight on a high-fat diet than WT controls (P < 0.01), despite both genotypes having consumed equal amounts of food. We conclude that although GALP signaling may not be essential for the maintenance of energy homeostasis under steady-state nutritional conditions, GALP may play a role in readjusting energy balance under changing nutritional circumstances.
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Galanin-Like Peptide Rescues Reproductive Function in the Diabetic Rat
Diabetes, 2005Co-Authors: Angela G. Stoyanovitch, Marlie A. Johnson, Donald K. Clifton, Robert A. Steiner, Gregory S FraleyAbstract:Galanin-like peptide (GALP) is expressed in the hypothalamic arcuate nucleus and is regulated by leptin and insulin. Centrally administered GALP stimulates gonadotropin secretion and sexual behavior in the rat. Type 1 diabetes is associated with reduced expression of GALP, as well as an overall decline in reproductive function. We postulated that tonic activity of GALP in the brain is required to sustain normal reproductive activity. To test this hypothesis, we examined whether central (intracerebroventricular) immunoblockade of GALP would reduce sexual behaviors and serum levels of luteinizing hormone (LH) in normal adult male rats. We found that GALP antibody reversibly reduced serum levels of LH and abolished male sexual behaviors ( P < 0.05 and 0.001, respectively). Second, we tested whether intracerebroventricular GALP could restore normal plasma LH levels and sexual behavior in diabetic animals. We compared groups of diabetic rats that received intracerebroventricular GALP or vehicle and found that GALP increased serum levels of LH and sexual behavior. Third, we examined whether intracerebroventricular administration of affinity-purified GALP antibody could block the effect of insulin and leptin in reversing the effects of diabetes on LH and sexual behavior. We found that treatment of diabetic animals with insulin and leptin nearly normalized LH levels and sexual behaviors; however, this effect was attenuated by intracerebroventricular administration of GALP antibody ( P < 0.05). These observations demonstrate that endogenous GALP provides trophic support to the neuroendocrine reproductive axis, including sexual behavior.
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Effects of Diabetes and Insulin on the Expression of Galanin-Like Peptide in the Hypothalamus of the Rat
Diabetes, 2004Co-Authors: Gregory S Fraley, Dawit N. Teklemichael, Issei Shimada, Blake V Acohido, Donald K. Clifton, Jarrad M Scarlett, Robert A. SteinerAbstract:Galanin-like peptide (GALP) is produced in a small population of neurons in the arcuate nucleus of the hypothalamus, and leptin stimulates the hypothalamic expression of GALP mRNA. Because insulin and leptin share common signaling pathways in the brain, we reasoned that GALP neurons might also be responsive to changes in circulating concentrations of insulin. To test this hypothesis, we first studied the effect of insulin deficiency on the expression of GALP by comparing levels of GALP mRNA between normal and diabetic animals. Streptozotocin-induced diabetes was associated with a significant reduction in the expression of GALP mRNA, which was reversed by treatment with either insulin or leptin. Second, we examined the effect of insulin administered directly into the brain on the expression of GALP mRNA in fasted rats. Hypothalamic levels of GALP mRNA were lower in animals after a 48-h fast, and central treatment with insulin reversed this effect. These results suggest that GALP neurons are direct targets for regulation by insulin and implicate these cells for a role in the metabolic and behavioral sequelae of type 1 diabetes.
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Galanin-Like Peptide as a Possible Link between Metabolism and Reproduction in the Macaque
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Matthew J Cunningham, M. Susan Smith, Tony M Plant, Judy L Cameron, Donald K. Clifton, Muhammad Shahab, Kevin L Grove, Jarrad M Scarlett, Robert A. SteinerAbstract:Galanin-like peptide (GALP) is a hypothalamic neuropeptide that has been implicated in the control of feeding, metabolism, and reproduction. The goal of this study was to examine the effects of central infusions of GALP on GnRH and LH secretion and to identify physiological factors that influence the expression of GALP mRNA in the brain of a primate species. Infusions of GALP into the lateral cerebroventricle of the macaque caused a significant increase in LH secretion, which was blocked by administration of the GnRH receptor antagonist acyline. However, the expression of GALP mRNA in the arcuate nucleus, as determined by in situ hybridization, was not regulated by either estradiol or progesterone. Compared with feeding ad libitum, fasting for 48 h produced a significant reduction in the hypothalamic expression of GALP mRNA. GALP neurons were found to express both neuropeptide Y Y1 receptor and serotonin 2C receptor by double-label in situ hybridization. Taken together, these results suggest that GALP neu...
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A role for galanin-like peptide in the integration of feeding, body weight regulation, and reproduction in the mouse.
Endocrinology, 2003Co-Authors: Stephanie M. Krasnow, Sonya M. Schuh, James W. Baumgartner, Gregory S Fraley, Donald K. Clifton, Robert A. SteinerAbstract:Galanin-like peptide (GALP) shares sequence homology with galanin and binds to galanin receptors in vitro. GALP neurons in the arcuate nucleus coexpress leptin receptors, and GALP mRNA expression is up-regulated by leptin. Based on these observations, we postulated that GALP plays a role in mediating leptin’s inhibitory effects on food intake (FI) and body weight (BW), as well as its stimulatory effect on the reproductive axis. To test these hypotheses, we performed several studies in which mice received intracerebroventricular injections of either GALP or vehicle. Acute GALP treatment elicited a dose-dependent suppression of FI and BW. Long-term treatment with GALP caused only transient reductions in FI and BW, demonstrating that the mice became refractory to continued exposure to GALP. GALP inhibited FI as early as 1 h post injection. Central injection of GALP suppressed locomotor activity and elicited the formation of a conditioned taste aversion. In male mice, serum levels of LH and testosterone were ...
Gregory S Fraley - One of the best experts on this subject based on the ideXlab platform.
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Galanin-like peptide: Neural regulator of energy homeostasis and reproduction
Experientia supplementum (2012), 2010Co-Authors: Catherine B. Lawrence, Gregory S FraleyAbstract:Galanin-like peptide (GALP) was discovered in 1999 in the porcine hypothalamus and was found to be a 60 amino-acid neuropeptide. GALP shares sequence homology to galanin (1–13) in position 9–21 and can bind to and activate the three galanin receptor subtypes (GalR1–3). GALP-expressing cells are limited, and are mainly found in the arcuate nucleus of the hypothalamus (ARC) and the posterior pituitary. GALP-positive neurons in the ARC, project to several brain regions where they appear to make contact with several neuromodulators that are involved in the regulation of energy homeostasis and reproduction, anatomical evidence that suggests a role for GALP in these physiological functions. In support of this idea, GALP gene expression is regulated by several factors that reflect metabolic state including the metabolic hormones leptin and insulin, thyroid hormones, and blood glucose. Considerable evidence now exists to support the hypothesis that GALP has a role in the regulation of energy homeostasis and reproduction; and, that that GALP’s role may be independent of the known galanin receptors. In this chapter we (1) provide an overview of the distribution of GALP, and discuss the potential relationship between GALP and other neuromodulators of energy homeostasis and reproduction, (2) discuss the metabolic factors that regulate GALP expression, (3) review the evidence for the role of GALP in energy homeostasis and reproduction, (4) discuss the potential downstream mediators and mechanisms underlying GALP’s effects, and (5) discuss the possibility that GALP may mediate it’s effects via an as yet unidentified GALP-specific receptor.
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Galanin-like Peptide (GALP) is a Hypothalamic Regulator of Energy Homeostasis and Reproduction
Frontiers in Neuroendocrinology, 2010Co-Authors: Catherine B. Lawrence, Gregory S FraleyAbstract:Abstract Galanin-like peptide (GALP) was discovered in 1999 in the porcine hypothalamus and was found to be a 60 amino acid neuropeptide. GALP shares sequence homology to galanin (1–13) in position 9–21 and can bind to, as well as activate, the three galanin receptor subtypes (GalR1–3). GALP-expressing cells are limited, and are mainly found in the arcuate nucleus of the hypothalamus (ARC) and the posterior pituitary. GALP-positive neurons in the ARC project to several brain regions where they appear to make contact with multiple neuromodulators. These neuromodulators are involved in the regulation of energy homeostasis and reproduction, anatomical evidence that suggests a role for GALP in these physiological functions. In support of this idea, GALP gene expression is regulated by several factors that reflect metabolic state including the metabolic hormones leptin and insulin, thyroid hormones, and blood glucose. Considerable evidence now exists to support the hypothesis that GALP has a role in the regulation of energy homeostasis and reproduction; and, that GALP’s role may be independent of the known galanin receptors. In this review, we (1) provide an overview of the distribution of GALP, and discuss the potential relationship between GALP and other neuromodulators of energy homeostasis and reproduction, (2) discuss the metabolic factors that regulate GALP expression, (3) review the evidence for the role of GALP in energy homeostasis and reproduction, (4) discuss the potential downstream mediators and mechanisms underlying GALP’s effects, and (5) discuss the possibility that GALP may mediate its effects via an as yet unidentified GALP-specific receptor.
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Altered response to metabolic challenges in mice with genetically targeted deletions of galanin-like peptide
American Journal of Physiology-endocrinology and Metabolism, 2008Co-Authors: Heather M. Dungan Lemko, Donald K. Clifton, Robert A. Steiner, Gregory S FraleyAbstract:Galanin-like peptide (GALP) is expressed in the arcuate nucleus and is implicated in the neuroendocrine regulation of metabolism and reproduction. To investigate the physiological significance of GALP, we generated and characterized a strain of mice with a genetically targeted deletion in the GALP gene [GALP knockout (KO) mice]. We report that GALP KO mice have a subtle, but notable, metabolic phenotype that becomes apparent during adaptation to changes in nutrition. GALP KO mice are indistinguishable from wild-type (WT) controls in virtually all aspects of growth, sexual development, body weight, food and water consumption, and motor behaviors, when they are allowed unlimited access to standard rodent chow. However, GALP KO mice have an altered response to changes in diet. 1) Male GALP KO mice consumed less food during refeeding after a fast than WT controls (P < 0.01). 2) GALP KO mice of both sexes gained less weight on a high-fat diet than WT controls (P < 0.01), despite both genotypes having consumed equal amounts of food. We conclude that although GALP signaling may not be essential for the maintenance of energy homeostasis under steady-state nutritional conditions, GALP may play a role in readjusting energy balance under changing nutritional circumstances.
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Galanin-Like Peptide Rescues Reproductive Function in the Diabetic Rat
Diabetes, 2005Co-Authors: Angela G. Stoyanovitch, Marlie A. Johnson, Donald K. Clifton, Robert A. Steiner, Gregory S FraleyAbstract:Galanin-like peptide (GALP) is expressed in the hypothalamic arcuate nucleus and is regulated by leptin and insulin. Centrally administered GALP stimulates gonadotropin secretion and sexual behavior in the rat. Type 1 diabetes is associated with reduced expression of GALP, as well as an overall decline in reproductive function. We postulated that tonic activity of GALP in the brain is required to sustain normal reproductive activity. To test this hypothesis, we examined whether central (intracerebroventricular) immunoblockade of GALP would reduce sexual behaviors and serum levels of luteinizing hormone (LH) in normal adult male rats. We found that GALP antibody reversibly reduced serum levels of LH and abolished male sexual behaviors ( P < 0.05 and 0.001, respectively). Second, we tested whether intracerebroventricular GALP could restore normal plasma LH levels and sexual behavior in diabetic animals. We compared groups of diabetic rats that received intracerebroventricular GALP or vehicle and found that GALP increased serum levels of LH and sexual behavior. Third, we examined whether intracerebroventricular administration of affinity-purified GALP antibody could block the effect of insulin and leptin in reversing the effects of diabetes on LH and sexual behavior. We found that treatment of diabetic animals with insulin and leptin nearly normalized LH levels and sexual behaviors; however, this effect was attenuated by intracerebroventricular administration of GALP antibody ( P < 0.05). These observations demonstrate that endogenous GALP provides trophic support to the neuroendocrine reproductive axis, including sexual behavior.
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Effects of galanin-like peptide (GALP) on locomotion, reproduction, and body weight in female and male mice.
Hormones and Behavior, 2005Co-Authors: Alexander S Kauffman, Jennifer Buenzle, Gregory S Fraley, Emilie F. RissmanAbstract:Galanin-like peptide (GALP) has been implicated in the neuroendocrine regulation of both feeding and reproduction. In male rodents and primates, intracerebroventricular (icv) infusions of GALP stimulate luteinizing hormone (LH) release, induce Fos expression in brain areas implicated in feeding and reproduction, and affect food intake and body weight in rodents. In gonad-intact and castrated male rats, icv administration of GALP also stimulates male sexual behavior. While the effects of GALP on male physiology and behavior are well documented, no studies have addressed such a role of GALP in females. We tested the effects of icv GALP infusions on LH release, locomotor activity, motor control, and body weight regulation in adult ovariectomized female mice hormonally primed with estradiol benzoate and progesterone. In addition, sexually-experienced male and female mice were treated with GALP and tested for sexual behavior. In females, GALP reduced open-field locomotor activity, the ability to maintain grip on an accelerating rotarod, and 24-h body weight in a dose-dependent manner. GALP also increased LH secretion in female mice, an effect that was blocked by pre-treatment with Antide, a gonadotropin-releasing hormone (GnRH) type-1 receptor antagonist. GALP infusions slightly decreased the occurrence of lordosis behavior in female mice and significantly increased the latencies with which females displayed receptivity. Unlike previous reports in male rats, GALP inhibited male sexual behavior in mice. Our data indicate that in female mice, GALP stimulates LH release via GnRH, and decreases body weight, motor control, and locomotor activity via GnRH-independent pathways. Furthermore, our sexual behavior and locomotor findings suggest species-specific differences in the mechanism and/or location of GALP action in the brains of rats and mice.
