Mating Behavioral Function of Preoptic Galanin Neurons Is Shared between Fish with Alternative Male Reproductive Tactics and Tetrapods.

Understanding the contribution of neuropeptide-containing neurons to variation in social behavior remains critically important. Galanin has gained increased attention because of the demonstration that galanin neurons in the preoptic area (POA) promote mating and parental care in mammals. How widespread these mechanisms are among vertebrates essentially remains unexplored, especially among teleost fishes, which comprise nearly one-half of living vertebrate species. Teleosts with alternative reproductive tactics exhibit stereotyped patterns of social behavior that diverge widely between individuals within a sex. This includes midshipman that have two male morphs. Type I males mate using either acoustic courtship to attract females to enter a nest they guard or cuckoldry during which they steal fertilizations from a nest-holding male using a sneak or satellite spawning tactic, whereas type II males only cuckold. Using the neural activity marker phospho-S6, we show increased galanin neuron activation in courting type I males during mating that is not explained by their courtship vocalizations, parental care of eggs, or nest defense against cuckolders. This increase is not observed during mating in cuckolders of either morph or females (none of which show parental care). Together with their role in mating in male mammals, the results demonstrate an unexpectedly specific and deep-rooted, phylogenetically shared behavioral function for POA galanin neurons. The results also point to galanin-dependent circuitry as a potential substrate for the evolution of divergent phenotypes within one sex and provide new functional insights into how POA populations in teleosts compare to the POA and anterior hypothalamus of tetrapods.SIGNIFICANCE STATEMENT Studies of neuropeptide regulation of vertebrate social behavior have mainly focused on the vasopressin-oxytocin family. Recently, galanin has received attention as a regulator of social behavior largely because of studies demonstrating that galanin neurons in the preoptic area (POA) promote mating and parental care in mammals. Species with alternative reproductive tactics (ARTs) exhibit robust, consistent differences in behavioral phenotypes between individuals within a sex. Taking advantage of this trait, we show POA galanin neurons are specifically active during mating in one of two male reproductive tactics, but not other mating-related behaviors in a fish with ARTs. The results demonstrate a deep, phylogenetically shared role for POA galanin neurons in reproductive-related social behaviors with implications for the evolution of ARTs.

Galanin peptide family regulation of glucose metabolism.

Recent preclinical and clinical studies have indicated that the galanin peptide family may regulate glucose metabolism and alleviate insulin resistance, which diminishes the probability of type 2 diabetes mellitus. The galanin was discovered in 1983 as a gut-derived peptide hormone. Subsequently, galanin peptide family was found to exert a series of metabolic effects, including the regulation of gut motility, body weight and glucose metabolism. The galanin peptide family in modulating glucose metabolism received recently increasing recognition because pharmacological activiation of galanin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes mellitus. To date, however, few papers have summarized the role of the galanin peptide family in modulating glucose metabolism and insulin resistance. In this review we summarize the metabolic effect of galanin peptide family and highlight its glucoregulatory action and discuss the pharmacological value of galanin pathway activiation for the treatment of glucose intolerance and type 2 diabetes mellitus.

Short-term changes and correlations of plasma spexin, kisspeptin, and galanin levels after laparoscopic sleeve gastrectomy.

PURPOSE: To determine the circulating levels of spexin, kisspeptin, galanin, and the correlations between these peptides after laparoscopic sleeve gastrectomy (LSG). METHODS: The plasma levels of the spexin, kisspeptin, and galanin and metabolic parameters (body mass index, weight loss, % excess weight loss, body fat, fasting glucose, HbA1C, and cholesterol levels) were measured (baseline, 1 month, and 3 months) and correlated in thirty adult individuals with obesity (22 female and 8 male) after LSG. RESULTS: The body mass index (BMI), body fat, fasting glucose, total and low-density lipoprotein cholesterol decreased, while high-density lipoprotein cholesterol and % EWL (excess weight loss) increased at 3 months after surgery. The plasma spexin levels increased at 3 months, kisspeptin levels increased at 1 month and stabilized afterward, and galanin levels decreased at 3 months after LSG. Significant correlations were found between metabolic parameters with spexin, kisspeptin, and galanin. In addition, spexin and kisspeptin were negatively correlated with galanin, while spexin was positively correlated with kisspeptin. CONCLUSIONS: The biochemical data reveal evidence that LSG causes an increase in the levels of spexin, and kisspeptin and a decrease in galanin levels. Our findings, therefore, suggest a possible interaction between these novel peptides, which have potential roles in obesity and glucose metabolism.

Human spinal ejaculation generator.

OBJECTIVE: A spinal ejaculation generator (SEG) has been identified in the rat with lumbar galaninergic interneurons playing a pivotal role (Science 2002;297:1566-1569). The aim was to evidence a SEG in humans. METHODS: Spatial distribution of galaninergic neurons was studied in postmortem spinal cord segments of 6 men and compared with that of 6 women for evidencing sexual dimorphism. Based on the identified segmental distribution of galaninergic neurons, the ability for penile vibratory stimulation (PVS) to elicit ejaculation when the concerned spinal segments were injured was studied in 384 patients with clinically complete spinal cord injury (SCI) and consequent anejaculation. Such patients represent a unique model to investigate the role of defined spinal segments in the control of ejaculation. RESULTS: Galaninergic neurons were mostly located between L2 and L5 segments in medial lamina VII, with a maximal density within L4. Three-dimensional 3D reconstruction showed that these neurons were grouped into single columns bilaterally to the central canal. In addition, galaninergic neuron density was found higher in L3 and L4 segments in men as compared to women supporting sexual dimorphism. In the patients' cohort, injury of L3-L5 segments was the sole independent predictor for failure of PVS to induce ejaculation. Although evidence from clinical observations was indirect, there is close correspondence to neuroanatomical data. INTERPRETATION: Organization and sexual dimorphism of human spinal galaninergic neurons were similar to the rat's SEG. Neurohistological data, together with clinical results, corroborate the existence of an SEG in humans in L3-L5 segments. Such a generator could be targeted to treat neurogenic and non-neurogenic ejaculatory disorders. ANN NEUROL 2017;81:35-45.

Selective Expression of Galanin in Neuronal-Like Cells of the Human Carotid Body.

The carotid body is a neural-crest-derived organ devoted to respiratory homeostasis through sensing changes in blood oxygen levels. The sensory units are the glomeruli composed of clusters of neuronal-like (type I) cells surrounded by glial-like (type II) cells. During chronic hypoxia, the carotid body shows growth, with increasing neuronal-like cell numbers. We are interested in the signals involved in the mechanisms that underlie such response, because they are not well understood and described. Considering that, in literature, galanin is involved in neurotrophic or neuroprotective role in cell proliferation and is expressed in animal carotid body, we investigated its expression in human. Here, we have shown the expression and localisation of galanin in the human carotid body.

Go2 G protein mediates galanin inhibitory effects on insulin release from pancreatic ß cells.

The neuropeptide galanin regulates numerous physiological activities in the body, including feeding and metabolism, learning and memory, nociception and spinal reflexes, and anxiety and related behaviors. Modulation of blood glucose levels by suppressing insulin release was the first reported activity for galanin. This inhibition was mediated by one or more pertussis toxin-sensitive G proteins of the G(i/o) subfamily. However, the molecular identities of the specific G protein(s) and intracellular effectors have not been fully revealed. Recently, we demonstrated that mice lacking G(o)2, but not other members of the G(i/o) protein family, secrete more insulin than controls upon glucose challenge, indicating that G(o)2 is a major transducer for the inhibitory regulation of insulin secretion. In this study, we investigated galanin signaling mechanisms in ß cells using cell biological and electrophysiological approaches. We found that islets lacking G(o)2, but not other G(i/o) proteins, lose the inhibitory effect of galanin on insulin release. Potentiation of ATP-sensitive potassium (K(ATP)) and inhibition of calcium currents by galanin were disrupted by anti-G(o)2α antibodies. Galanin actions on K(ATP) and calcium currents were completely lost in G(o)2(-/-) ß cells. Furthermore, the hyperglycemic effect of galanin is also blunted in G(o)2(-/-) mice. Our results demonstrate that G(o)2 mediates the inhibition of insulin release by galanin by regulating both K(ATP) and Ca(2+) channels in mice. Our findings provide insight into galanin's action in glucose homeostasis. The results may also be relevant to the understanding of galanin signaling in other biological systems, especially the central nervous system.

Paeoniflorin protects cells from GalN/TNF-α-induced apoptosis via ER stress and mitochondria-dependent pathways in human L02 hepatocytes.

Paeoniflorin (PF) is one of the main effective components extracted from the root of Paeonia lactiflora, which has been used clinically to treat hepatitis in traditional Chinese medicine, but the details of the underlying mechanism remain unknown. The present study was designed to investigate the mechanism of protective effect of PF on d-galactosamine (GalN) and tumor necrosis factor-α (TNF-α)-induced cell apoptosis using human L02 hepatocytes. Our results confirmed that PF could attenuate GalN/TNF-α-induced apoptotic cell death in a dose-dependent manner. The disruption of mitochondrial membrane potential and the disturbance of intracellular Ca(2+) concentration were also recovered by PF. Western blot analysis revealed that GalN/TNF-α induced the activation of a number of signature endoplasmic reticulum (ER) stress and mitochondrial markers, while PF pre-treatment had a marked dose-dependent suppression on them. Additionally, the anti-apoptotic effect of PF was further evidenced by the inhibition of caspase-3/9 activities in L02 cells. These findings suggest that PF can effectively inhibit hepatocyte apoptosis and the underlying mechanism is related to the regulating mediators in ER stress and mitochondria-dependent pathways.

The therapeutic potential of galanin in the management of pain - a review article.

Neuropeptides represent the most diverse family of neurotransmitters counting numerous members and even more G protein-coupled receptors, all of which are potential targets for drug development. Here, we focus on galanin and its three receptors by describing their possible involvement in pain and regeneration. Although animal experiments indicate that galanin, together with other molecules, may act as an endogenous system protecting against pain and improving nerve growth, these results have so far not been translated into patient treatments.

Peripheral cardiac sympathetic hyperactivity in cardiovascular disease: role of neuropeptides.

High levels of sympathetic drive in several cardiovascular diseases including postmyocardial infarction, chronic congestive heart failure and hypertension are reinforced through dysregulation of afferent input and central integration of autonomic balance. However, recent evidence suggests that a significant component of sympathetic hyperactivity may also reside peripherally at the level of the postganglionic neuron. This has been studied in depth using the spontaneously hypertensive rat, an animal model of genetic essential hypertension, where larger neuronal calcium transients, increased release and impaired reuptake of norepinephrine in neurons of the stellate ganglia lead to a significant tachycardia even before hypertension has developed. The release of additional sympathetic cotransmitters during high levels of sympathetic drive can also have deleterious consequences for peripheral cardiac parasympathetic neurotransmission even in the presence of ß-adrenergic blockade. Stimulation of the cardiac vagus reduces heart rate, lowers myocardial oxygen demand, improves coronary blood flow, and independently raises ventricular fibrillation threshold. Recent data demonstrates a direct action of the sympathetic cotransmitters neuropeptide Y (NPY) and galanin on the ability of the vagus to release acetylcholine and control heart rate. Moreover, there is as a strong correlation between plasma NPY levels and coronary microvascular function in patients with ST-elevation myocardial infarction being treated with primary percutaneous coronary intervention. Antagonists of the NPY receptors Y1 and Y2 may be therapeutically beneficial both acutely during myocardial infarction and also during chronic heart failure and hypertension. Such medications would be expected to act synergistically with ß-blockers and implantable vagus nerve stimulators to improve patient outcome.

Galanin-like peptide (GALP) is a hypothalamic regulator of energy homeostasis and reproduction.

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.

The neuropeptide galanin is a novel inhibitor of human hair growth.

BACKGROUND: Galanin is a trophic factor of the central and peripheral nervous system that shows widespread distribution in human skin. However, the exact localization and the role of galanin in the hair follicle (HF) remain to be clarified. OBJECTIVES: To characterize galanin expression in human scalp HFs and to examine the effects of galanin on normal human scalp HF growth in organ culture. METHODS: Immunohistochemistry was performed on cryosections of human female scalp skin. Anagen HFs were microdissected and cultured up to 9 days and treated with 100 nmol L(-1) galanin. Staining for Ki-67, TUNEL and Masson-Fontana were used to analyse proliferation, apoptosis and hair cycle staging of the HFs. Functional effects of galanin were tested in serum-free HF organ culture. RESULTS: Galanin-like immunoreactivity was detected in the outer root sheath (ORS) and inner root sheath. Additionally, galanin mRNA was detected in ORS keratinocytes and all HF samples tested. Galanin receptor transcripts (GalR2, GalR3) were also detected in selected samples. Galanin reduced proliferation of hair matrix keratinocytes in situ compared with vehicle-treated controls, shortened the hair growth phase (anagen) in vitro and reduced hair shaft elongation. This was accompanied by the premature development of a catagen-like morphology of galanin-treated HFs. CONCLUSIONS: We present the first evidence that human HFs are both a source and a functionally relevant target of galanin. Due to its hair growth-inhibitory properties in vitro, galanin application deserves further exploration as a potential new treatment strategy for unwanted hair growth (hirsutism, hypertrichosis).

Activation of gastrin-releasing peptide receptors in the lumbosacral spinal cord is required for ejaculation in male rats.

INTRODUCTION: Ejaculation is a complex reflex mediated by a spinal ejaculation generator located in the lumbosacral spinal cord and consisting of a population of lumbar spinothalamic (LSt) neurons. LSt neurons and their intraspinal axonal projections contain several neuropeptides, including gastrin-releasing peptide (GRP). AIM: To test the hypothesis that GRP is critically involved in mediating ejaculation by acting in autonomic and motor areas of the lumbosacral spinal cord, utilizing a physiological paradigm to investigate ejaculatory reflexes in isolation of supraspinal inputs. METHODS: Dual immunohistochemistry for GRP and galanin was performed to investigate co-expression of GRP in LSt cells of control male rats. Next, anesthetized, spinalized male rats received intrathecal infusions of either GRP antagonist RC-3095 (0, 10, or 20 nmol/10 µL) or GRP (0, 0.2, 0.5 nmol/10 µL). Ejaculatory reflexes were induced by electrical stimulation of the dorsal penile nerve (DPN) which reliably triggers rhythmic increases in seminal vesicle pressure (SVP) and contractions of the bulbocavernosus muscle (BCM), indicative of the emission and expulsion phases of ejaculation, respectively. MAIN OUTCOME MEASURES: GRP in LSt cells was expressed as percentages of co-expression. SVP and electromyographic recording (EMG) of BCM activity following drug treatment and DPN stimulation were recorded and analyzed for numbers of SVP increases, BCM events and bursts. RESULTS: GRP was exclusively expressed in LSt cells and axons. Intrathecal infusion of RC-3095, but not saline, blocked SVP increases and BCM bursting induced by DPN stimulation. Intrathecal infusions of GRP, but not saline, triggered SVP increases and BCM bursting in 43-66% of animals and facilitated SVP increases and BCM bursting induced by subthreshold DPN stimulation in all animals. CONCLUSION: These data support a critical role for GRP for control of the emission and expulsion phases of ejaculation in male rats by acting in LSt target areas in the lumbosacral spinal cord.

Galanin peptide family as a modulating target for contribution to metabolic syndrome.

Metabolic syndrome (MetS) is defined as abdominal central obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance and hypertension. The rapid increasing prevalence of MetS and the consequent diseases, such as type 2 diabetes mellitus and cardiovascular disorder, are becoming a global epidemic health problem. Despite considerable research into the etiology of this complex disease, the precise mechanism underlying MetS and the association of this complex disease with the development of type 2 diabetes mellitus and increased cardiovascular disease remains elusive. Therefore, researchers continue to actively search for new MetS treatments. Recent animal studies have indicated that the galanin peptide family of peptides may increase food intake, glucose intolerance, fat preference and the risk for obesity and dyslipidemia while decreasing insulin resistance and blood pressure, which diminishes the probability of type 2 diabetes mellitus and hypertension. To date, however, few papers have summarized the role of the galanin peptide family in modulating MetS. Through a summary of available papers and our recent studies, this study reviews the updated evidences of the effect that the galanin peptide family has on the clustering of MetS components, including obesity, dyslipidemia, insulin resistance and hypertension. This line of research will further deepen our understanding of the relationship between the galanin peptide family and the mechanisms underlying MetS, which will help develop new therapeutic strategies for this complex disease.

Biphasic modulation by galanin of excitatory synaptic transmission in substantia gelatinosa neurons of adult rat spinal cord slices.

Although intrathecally administrated galanin modulates nociceptive transmission in a biphasic manner, this has not been fully examined previously. In the present study, the action of galanin on synaptic transmission in the substantia gelatinosa (SG) neurons of adult rat spinal cord slices was examined, using the whole cell patch-clamp technique. Galanin concentration-dependently increased the frequency of spontaneous excitatory postsynaptic current (EPSC; EC(50) = 2.0 nM) without changing the amplitude, indicating a presynaptic effect. This effect was reduced in a Ca(2+)-free, or voltage-gated Ca(2+) channel blocker La(3+)-containing Krebs solution and was produced by a galanin type-2/3 receptor (GalR2/R3) agonist, galanin 2-11, but not by a galanin type-1 receptor (GalR1) agonist, M617. Galanin also concentration-dependently produced an outward current at -70 mV (EC(50) = 44 nM), although this appeared to be contaminated by a small inward current. This outward current was mimicked by M617, but not by galanin 2-11. Moreover, galanin reduced monosynaptic Aδ-fiber- and C-fiber-evoked EPSC amplitude; the former reduction was larger than the latter. A similar action was produced by galanin 2-11, but not by M617. Spontaneous and focally evoked inhibitory (GABAergic and glycinergic) transmission was unaffected by galanin. These findings indicate that galanin at lower concentrations enhances the spontaneous release of l-glutamate from nerve terminals by Ca(2+) entry from the external solution following GalR2/R3 activation, whereas galanin at higher concentrations also produces a membrane hyperpolarization by activating GalR1. Moreover, galanin reduces l-glutamate release onto SG neurons from primary afferent fibers by activating GalR2/R3. These effects could partially contribute to the behavioral effect of galanin.

Functional importance of inositol-1,4,5-triphosphate-induced intracellular Ca2+ mobilization in galanin-induced microglial migration.

Galanin (GAL) is a neuropeptide which is up-regulated following neuronal axotomy or inflammation. One subtype of GAL receptor (GalR2) is reported to be expressed in the brain's immune cell population, microglia. In the present study, we investigated the effect of GAL on microglial migration and compared the mechanism with that of bradykinin (BK). GAL significantly increased the migration of rat cultured microglia at 0.1 pM. The GAL-induced signal cascade was partly similar to that induced by BK. It was not dependent on G(i/o) protein but involved activation of protein kinase C, phosphoinositide 3-kinase and Ca(2+)-dependent K(+) channels. However, reverse-mode activation of the Na(+) /Ca(2+) -exchanger 1 was not involved in GAL-induced microglial migration, unlike BK-induced migration. Likewise, nominally-free extracellular Ca(2+) inhibited BK-induced migration but not GAL-induced migration. An inositol-1,4,5-triphosphate receptor antagonist significantly inhibited GAL-induced migration. GAL-induced Ca(2+) signaling did not induce nitric oxide synthase expression, but up-regulated class II major histocompatibility complex expression. These results indicate that activation of inositol-1,4,5-triphosphate receptor and increase in intracellular Ca(2+) are important for GAL-induced migration and immunoreactivity in microglia. The differences in down-stream signal transduction induced by GAL and BK suggest that GAL and BK may control distinct microglial functions under pathological conditions.

Rodent models of varicella-zoster virus neurotropism.

Inoculation of rodents with varicella-zoster virus (VZV) results in a latent infection in dorsal root ganglia with expression of at least five of the six VZV transcripts and one of the viral proteins that are reported to be expressed during latency in human ganglia. Rats develop allodynia and hyperalgesia in the limb distal to the site of injection and the resulting exaggerated withdrawal response to stimuli is reduced by treatment with gabapentin and amitryptyline, but not by antiviral therapy. Inoculation of rats with VZV mutants show that most viral genes are dispensable for latency, but that some genes (e.g., ORF4, 29, and ORF63) that are expressed during latency are important for the establishment of latency in rodents, but not for infection of rodent ganglia. The rodent model for VZV latency allows one to study ganglia removed immediately after death, avoiding the possibility of reactivation, and helps to identify VZV genes required for latency.

Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour.

The bioactive peptides galanin, spexin and kisspeptin have a common ancestral origin and their pathophysiological roles are increasingly the subject of investigation. Evidence suggests that these bioactive peptides play a role in the regulation of metabolism, pancreatic ß-cell function, energy homeostasis, mood and behaviour in several species, including zebrafish, rodents and humans. Galanin signalling suppresses insulin secretion in animal models (but not in humans), is potently obesogenic and plays putative roles governing certain evolutionary behaviours and mood modulation. Spexin decreases insulin secretion and has potent anorectic, analgesic, anxiolytic and antidepressive-like effects in animal models. Kisspeptin modulates glucose-stimulated insulin secretion, food intake and/or energy expenditure in animal models and humans. Furthermore, kisspeptin is implicated in the control of reproductive behaviour in animals, modulation of human sexual and emotional brain processing, and has antidepressive and fear-suppressing effects. In addition, galanin-like peptide is a further member of the galaninergic family that plays emerging key roles in metabolism and behaviour. Therapeutic interventions targeting galanin, spexin and/or kisspeptin signalling pathways could therefore contribute to the treatment of conditions ranging from obesity to mood disorders. However, many gaps and controversies exist, which must be addressed before the therapeutic potential of these bioactive peptides can be established.

Fronto-temporal galanin modulates impulse control.

RATIONALE: The neuropeptide galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised. It works through three subtypes of G-protein-coupled receptors. One of these, the galanin receptor 1 (Gal-R1) subtype, is densely expressed in the ventral hippocampus (vHC) and ventral prefrontal cortex (vPFC); two brain structures that have similar actions on behavioral control. We hypothesize that Gal-R1 contributes to cognitive-control mechanisms that require hippocampal-prefrontal cortical circuitry. OBJECTIVE: To examine the effect of local vHC and vPFC infusions of M617, a Gal-R1 agonist, on inhibitory mechanisms of response control. METHODS: Different cohorts of rats were implanted with bilateral guide cannulae targeting the vPFC or the vHC. Following infusion of the Gal-R1 agonist, we examined the animals' behavior using a touchscreen version of the 5-choice reaction time task (5-choice task). RESULTS: The Gal-R1 agonist produced opposing behaviors in the vPFC and vHC, leading to disruption of impulse control when infused in the vPFC but high impulse control when infused into the vHC. This contrast between areas was accentuated when we added variability to the timing of the stimulus, which led to long decision times and reduced accuracy in the vPFC group but a general improvement in performance accuracy in the vHC group. CONCLUSIONS: These results provide the first evidence of a selective mechanism of Gal-R1-mediated modulation of impulse control in prefrontal-hippocampal circuitry.

Chronic increase of circulating galanin levels induces obesity and marked alterations in lipid metabolism similar to metabolic syndrome.

OBJECTIVE: Galanin (GAL) has a role in the regulation of food intake by way of acting on the central nervous system in rodents. High serum GAL levels have been observed in obese human subjects, suggesting that peripheral GAL has a role in the regulation of energy balance and that elevated circulating GAL levels contribute to the development of obesity and obesity-associated metabolic impairments. Currently, it is not known how chronically increased levels of circulating GAL affect energy balance. The purpose of this study is to clarify the importance of chronically increased levels of circulating GAL on energy balance in a transgenic mouse model. RESEARCH DESIGN AND METHODS: Male wild-type and homozygous galanin transgenic (GAL-Tg) mice were used to study the peripheral effects of a 10-fold increase in circulating GAL on food intake, body weight, lipid metabolism, hepatic steatosis, glucose homeostasis and energy expenditure. RESULTS: In the absence of an orexigenic effect, GAL-Tg mice had increased body weight, visceral adiposity, total serum cholesterol, total serum triglycerides and hyperinsulinemia, as well as impaired glucose tolerance. Compared with wild-type mice, the obese phenotype observed in the GAL-Tg mice was attributed to decreased oxygen consumption and carbon dioxide production, and this effect was independent of any changes in food intake or horizontal activity. In this obese model, GAL contributed to the development of fatty liver disease, which was associated with impaired glucose tolerance, as well as a reduction in heat production and metabolic rate. CONCLUSIONS: Chronically elevated GAL may regulate body weight, metabolic rate, and lipid and carbohydrate metabolism through a mechanism that is independent of feeding regulation. The obese phenotype in the GAL-Tg mice is related to the reduced energy expenditure and insulin resistance. These findings support the hypothesis that increased circulating GAL levels contribute to the development of metabolic syndrome.

Effects of galanin and leptin on gonadotropin-releasing hormone-stimulated luteinizing hormone release from the pituitary.

BACKGROUND: A number of peptides regulate luteinizing hormone (LH) release. In some cases, these peptides exert an effect at the pituitary, to directly regulate LH release and/or to modulate the effects of gonadotropin-releasing hormone (GnRH). A link between nutrition and reproductive function is well established. In this study we investigated the effects of two peptides associated with appetite control, galanin and leptin, on the regulation of LH release from the pituitary. METHODS: Using perifused anterior pituitary tissue from freely fed rats, we investigated the effect of galanin on basal LH release and GnRH-stimulated LH release from pituitaries in a high-estrogen (proestrus) and a low-estrogen (metestrus) environment. In addition, we examined the effect of galanin on LH release following GnRH self-priming. The effect of inhibiting protein synthesis, with cycloheximide, was also studied under these conditions. Finally, the effects of leptin alone and on a galanin-modulated LH response were investigated. RESULTS: There was no detectable effect of leptin, either alone or in conjunction with galanin. We observed that galanin enhanced GnRH stimulation of LH secretion, an effect that was dependent on protein synthesis and on an estrogenized environment. In addition, importantly, galanin also enhanced the LH response in GnRH self-primed pulses. CONCLUSION: Our results provide further details on the effect of galanin on the LH surge, particularly the effect on the response to pulsatile GnRH and the effect of protein production, and thereby indicate a means by which appetite- and nutrition-related peptides may act on the ovulatory cycle at the pituitary.