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Andreas Stengel - One of the best experts on this subject based on the ideXlab platform.
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Nesfatin-130-59 Injected Intracerebroventricularly Increases Anxiety, Depression-Like Behavior, and Anhedonia in Normal Weight Rats.
Nutrients, 2018Co-Authors: Stephanie Gladys Kühne, Martha A. Schalla, Tiemo Friedrich, Marion Rivalan, Peter Kobelt, Miriam Goebel-stengel, York Winter, Matthias Rose, Melissa Long, Andreas StengelAbstract:Nesfatin-1 is a well-established anorexigenic peptide. Recent studies indicated an association between Nesfatin-1 and anxiety/depression-like behavior. However, it is unclear whether this effect is retained in obesity. The aim was to investigate the effect of Nesfatin-130-59—the active core of Nesfatin-1—on anxiety and depression-like behavior in normal weight (NW) and diet-induced (DIO) obese rats. Male rats were intracerebroventricularly (ICV) cannulated and received Nesfatin-130-59 (0.1, 0.3, or 0.9 nmol/rat) or vehicle 30 min before testing. Nesfatin-130-59 at a dose of 0.3 nmol reduced sucrose consumption in the sucrose preference test in NW rats compared to vehicle (–33%, p 0.05). These results indicate an implication of Nesfatin-130-59 in the mediation of anxiety and depression-like behavior/anhedonia under normal weight conditions, while in DIO rats, a desensitization might occur.
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Peripheral and central localization of the Nesfatin-1 receptor using autoradiography in rats
Biochemical and biophysical research communications, 2016Co-Authors: Philip Prinz, Miriam Goebel-stengel, Matthias Rose, Burghard F Klapp, Pauline Teuffel, Andreas StengelAbstract:Nesfatin-1 was recently identified and introduced as food intake-regulatory hormone. Soon thereafter, mounting evidence indicated a much broader role for Nesfatin-1 with an involvement in the regulation of food intake, gastrointestinal motility, glucose homeostasis, blood pressure and stress. Despite the growing knowledge on the physiological regulation and functions of Nesfatin-1, the receptor mediating these effects remains to be characterized. Therefore, the aim of this study was to investigate the peripheral and central localization of the Nesfatin-1 receptor by autoradiography. Male Sprague-Dawley rats were used and peripheral as well as brain tissue was processed for (125)I-Nesfatin-1 autoradiography. In peripheral tissues, an autoradiographic signal was observed in the gastric mucosa of corpus and antrum, in duodenum, jejunum and ileum, while no signal was detected in the colon. Preabsorption of (125)I-Nesfatin-1 with non-labeled Nesfatin-1 greatly diminished the autoradiographic signal in the stomach indicating specificity (-32%, p
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Nesfatin-1: an affair of the heart.
Endocrinology, 2013Co-Authors: Andreas StengelAbstract:Nesfatin-1 is an 82-amino acid peptide that was identified in 2006 in the rat hypothalamus by Mori and coworkers (1). The polypeptide is proteolytically cleaved from its precursor protein, nucleobindin2 (NUCB2) and named after its initially described function to reduce food intake after third-brain ventricular injection in rats [nucleobindin 2 encoded satiety and fat influencing protein (Nesfatin-1)] (1). NUCB2 can be cleaved into three polypeptides: Nesfatin-1, nesfatin-2, and nesfatin-3, whereas an anorexigenic effect has so far been described only for Nesfatin-1 (1). The brain-inhibitory effect on food intake was confirmed by several independent groups in rodent models (2, 3) as well as nonmammalian vertebrates (4). These initial data fostered research on this peptide, and as observed for many brain peptides before, the role of Nesfatin-1 is not restricted to one effect (inhibition of food intake) but also comprises the inhibition of gastric emptying (2) and water intake (5), the modulation of stress-related endocrine and anxiogenic responses (6, 7) and sympathetic outflow (8) and also an involvement in reproduction (9). After the initial reports all focused on NUCB2/Nesfatin-1 as a brain peptide, subsequent studies investigated the expression of this peptide in the periphery and detected high levels in the gastric mucosa (10), pancreas (11), adipocytes (12), gonads (13), and blood (14). Interestingly, the levels in the stomach were even higher than those detected in the brain (10), indicating a predominant expression of NUCB2/Nesfatin-1 in the periphery. Possible functions attributed to peripheral Nesfatin-1 encompassed the modulation of food intake (15), adipogenesis (12), and an involvement in the regulation of glucose homeostasis (16–18). Recently one study reported the expression of NUCB2/ Nesfatin-1 in rat cardiac extracts (19). These data were corroborated and extended by a study of Feijoo-Bandin et al published in this issue of Endocrinology (20). The authors present a comprehensive set of experiments using a truly translational approach by means of studying mouse, rat, and human cardiac tissues. First, they show that NUCB2 mRNA is expressed in mouse, human, and rat heart occurring in both atrial and ventricular cardiomyocytes (20). Interestingly, although in mouse and rat, NUCB2 mRNA expression levels are markedly lower in the heart compared with the stomach [the presumed major source of peripheral NUCB2/Nesfatin-1 (10)], expression levels are similar in the heart and stomach of humans (20), giving rise to an important role of heart-derived NUCB2/ Nesfatin-1 in humans. This expression was also confirmed at the protein level. It is important to note that so far the mature, fully processed 82-amino acid Nesfatin-1 has been described only in cerebrospinal fluid of rats (1), rat heart (19), and human plasma using a Nesfatin-1 specific sandwich-type ELISA (14). All other studies did not distinguish between full-length NUCB2 and Nesfatin-1 or detected the precursor protein, NUCB2, only in tissue extracts (4, 10, 21), whereas exogenous synthetic Nesfatin-1 was clearly visible on the Western blot (10). In addition, because NUCB2 is functionally active (1), this led to the assumption that NUCB2 might not be processed at all or might be cleaved more distant from its production site. However, in the present study of Feijoo-Bandin et al (20), mature Nesfatin-1 was clearly detectable by Western blot as a 9.5-kDa band in protein samples from mouse, rat, and human cardiomyocytes, indicating the processing of NUCB2 into Nesfatin-1 within the heart. This hypothesis was further
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Role of Brain NUCB2/Nesfatin-1 in the Regulation of Food Intake
Current pharmaceutical design, 2013Co-Authors: Andreas Stengel, Yvette TacheAbstract:Nesfatin-1 was recently identified in the rat brain as a potential post-translational processing product derived from nucleobindin2 (NUCB2). The first biological action identified for Nesfatin-1 was the reduction of nocturnal food intake in rats. The anorexigenic effect of Nesfatin-1 was corroborated by several independent laboratories and is now established as a physiological action of this peptide based on the regulation of brain NUCB2/Nesfatin-1 under different metabolic conditions and the stimulation of food intake and body weight when endogenous brain NUCB2/Nesfatin-1 is blocked. Nesfatin-1 shows extensive co-localization with various other, predominantly food intake inhibitory, hypothalamic peptides including corticotropin-releasing factor (CRF), oxytocin, cholecystokinin, proopiomelanocortin, -αmelanocyte stimulating hormone (α-MSH), thyrotropin-releasing hormone (TRH), the orexigenic neuropeptide Y and brain biogenic amines, histamine, serotonin, and catecholamines. The food intake suppressing effect of centrally injected Nesfatin-1 has been established so far to involve several downstream mechanisms including H1, CRF2, TRH, oxytocin as well as melanocortin-3/4 receptor signaling pathways. This intricate embedding of NUCB2/Nesfatin-1 in central food intake regulatory pathways recruited during the dark phase corresponding to the eating period in rodents, unlike the orexigenic response to a fast, points towards a role for Nesfatin-1 in modulating the nocturnal food intake. Although our knowledge on the regulation and effects of NUCB2/Nesfatin-1 as a new anorexic peptide markedly increased during the past five years, several important gaps of knowledge remain to be filled in the near future such as the regulation of NUCB2 processing and Nesfatin-1 release as well as the identification, localization and regulation of the Nesfatin-1 receptor.
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Minireview: Nesfatin-1—An Emerging New Player in the Brain-Gut, Endocrine, and Metabolic Axis
Endocrinology, 2011Co-Authors: Andreas Stengel, Yvette TacheAbstract:Nesfatin-1 is a recently identified 82-amino-acid peptide derived from the precursor protein, nucleobindin2 (NUCB2). The brain distribution of NUCB2/Nesfatin-1 at the mRNA and protein level along with functional studies in rodents support a role for NUCB2/Nesfatin-1 as a novel satiety molecule acting through leptin-independent mechanisms. In addition, Nesfatin-1 induces a wide spectrum of central actions to stimulate the pituitary-adrenal axis and sympathetic nervous system and influences visceral functions and emotion. These central actions combined with the activation of NUCB2/Nesfatin-1 neurons in the brain by various stressors are indicative of a role in the adaptive response under stressful conditions. In the periphery, evidence is mounting that Nesfatin-1 exerts a direct glucose-dependent insulinotropic action on β-cells of the pancreatic islets. However, the cellular mechanisms of Nesfatin-1's action remain poorly understood, partly because the receptor through which Nesfatin-1 exerts its pleiotropic actions is yet to be identified.
Masatomo Mori - One of the best experts on this subject based on the ideXlab platform.
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central blockage of nesfatin 1 has anxiolytic effects but does not prevent corticotropin releasing factor induced anxiety in male rats
Biochemical and Biophysical Research Communications, 2020Co-Authors: Martha A. Schalla, Stephanie Gladys Kühne, Tiemo Friedrich, Marion Rivalan, Peter Kobelt, York Winter, Masatomo Mori, Miriam Goebelstengel, M Long, Matthias RoseAbstract:Abstract Nesfatin-1, a pleotropic peptide, was recently implicated in the regulation of anxiety and depression-like behavior in rats. However, the underlying mechanisms remain unclear so far. Thus, this study aimed to investigate the role of endogenous Nesfatin-1 in the mediation of anxiety and depression-like behavior induced by corticotropin-releasing factor (CRF). Therefore, normal weight male intracerebroventricularly (icv) cannulated Sprague Dawley rats received two consecutive icv injections of anti-Nesfatin-1 antibody or IgG control antibody followed by CRF or saline, before being exposed to a behavioral test. In the elevated zero maze test, assessing anxiety and explorative behavior, blockade of Nesfatin-1 using an anti-Nesfatin-1 antibody under basal conditions increased the number of entries into the open arms compared to control antibody/vehicle (1.6-fold, p 0.05). In summary, CRF tended to increase anxiety and explorative behavior an effect not altered by blockade of Nesfatin-1, whereas no significant effect of CRF on anhedonia was observed. Blockade of endogenous Nesfatin-1 significantly decreased anxiety-like behavior giving rise to a physiological role of brain Nesfatin-1 in the mediation of anxiety.
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Nesfatin-1 inhibits voltage gated K+ channels in pancreatic beta cells
Peptides, 2017Co-Authors: Yuko Maejima, Masatomo Mori, Shoichiro Horita, Daisuke Kobayashi, Miho Aoki, Rie O’hashi, Ryota Imai, Kazuho Sakamoto, Katsuya Takasu, Kazuma OgawaAbstract:The anorexigenic neuropeptide NEFA/nucleobindin 2 (NUCB2)/Nesfatin-1-containing neurons are distributed in the brain regions involved in feeding regulation. In spite of the growing knowledge of its physiological functions through extensive studies, its molecular mechanism of reaction, including its receptor, remains unknown. NUCB2/Nesfatin-1 is also involved in various peripheral regulations, including glucose homeostasis. In pancreatic beta-cells, NUCB2/Nesfatin-1 is reported to enhance glucose-stimulated insulin secretion (GSIS) but its exact mechanism remains unknown. To clarify this mechanism, we measured the effect of Nesfatin-1 on the electrical activity of pancreatic beta-cells. Using mouse primary beta cells, we measured changes in the ATP-sensitive K+ (KATP) channel current, the voltage-gated K+ (Kv) channel current, and insulin secretion upon application of Nesfatin-1. Nesfatin-1 inhibited the Kv channel, but KATP channel activity was unaffected. Nesfatin-1 enhanced insulin secretion to a same level as Kv channel blocker tetraethylammonium (TEA). The effect was not further enhanced when Nesfatin-1 and TEA were applied simultaneously. The inhibition binding assay with [125I]Nesfatin-1 in Kv2.1 channels, major contributor of Kv current in beta cell, expressing HEK239 cells indicated the binding of Nesfatin-1 on Kv2.1 channel. Because Kv channel inhibition enhances insulin secretion under high glucose conditions, our present data suggest a possible mechanism of Nesfatin-1 on enhancing GSIS through regulation of ion channels rather than its unidentified receptor.
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Nesfatin-1: Its Role in the Diagnosis and Treatment of Obesity and Some Psychiatric Disorders
Methods in molecular biology (Clifton N.J.), 2012Co-Authors: Hiroyuki Shimizu, Masatomo MoriAbstract:We discovered a new anorexigenic protein, nesfatin/nucleobindin-2 (NUCB2), which includes an EF-hand, calcium-binding motif. Nesfatin/NUCB2 is converted to Nesfatin-1, which may be a physiologically active form in the body. Centrally and systemically administered Nesfatin-1 inhibits appetite and body weight gain in rodents. The mid-segment of Nesfatin-1 appears to be important in the inhibition of food intake. Intranasal administration of the mid-segment inhibits appetite. Nesfatin-1 may also be involved in the regulation of gastrointestinal function and insulin secretion. We have summarized the recent progress in the research of Nesfatin-1.
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Nesfatin-1 stimulates renal sympathetic nerve activity in rats.
Neuroreport, 2011Co-Authors: Mamoru Tanida, Masatomo MoriAbstract:Earlier examination reported that central injection of Nesfatin-1 elevated blood pressure and suppressed food intake in conscious rats. In this study, we analyzed the effects of the intracerebroventricular injection of Nesfatin-1 on the sympathetic nerve outflow to the kidney in urethane-anesthetized rats. An intracerebroventricular injection of Nesfatin-1 significantly stimulated renal sympathetic nerve activity and blood pressure in a dose-dependent manner. Moreover, we examined the role of the melanocortin system on the sympathoexcitation caused by the Nesfatin-1 injection. Pretreatment with the melanocortin-3/4 receptor antagonist, SHU9119, abolished the increase in nerve activity and blood pressure induced by Nesfatin-1. Thus, the stimulating effects of Nesfatin-1 administration on the sympathetic nerve activity of the kidney may depend on the central melanocortin system.
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nesfatin 1 evokes ca2 signaling in isolated vagal afferent neurons via ca2 influx through n type channels
Biochemical and Biophysical Research Communications, 2009Co-Authors: Yusaku Iwasaki, Hiroyuki Shimizu, Masatomo Mori, Hajime Nakabayashi, Masafumi Kakei, Toshihiko YadaAbstract:Abstract Nesfatin-1, processed from nucleobindin 2, is an anorexigenic peptide expressed in the brain and several peripheral tissues including the stomach and pancreas. Peripheral, as well as intracerebroventricular, administration of Nesfatin-1 suppresses feeding behavior, though underlying mechanisms are unknown. In this study, we examined effects of Nesfatin-1 on cytosolic Ca2+ concentration ([Ca2+]i) in the neurons isolated from the vagal afferent nodose ganglion of mice. Nesfatin-1 at 10−10–10−8 M increased [Ca2+]i in the isolated neurons in a concentration-dependent manner, and at 10−8 M it increased [Ca2+]i in 33 out of 263 (12.5%) neurons. These responses were inhibited under Ca2+-free conditions and by N-type Ca2+ channel blocker, ω-conotoxin GVIA. All the Nesfatin-1-responsive neurons also exhibited [Ca2+]i responses to capsaicin and cholecystokinin-8. These results provide direct evidence that Nesfatin-1 activates vagal afferent neurons by stimulating Ca2+ influx through N-type channels, demonstrating the machinery through which peripheral Nesfatin-1 can convey signals to the brain.
Yvette Tache - One of the best experts on this subject based on the ideXlab platform.
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Role of Brain NUCB2/Nesfatin-1 in the Regulation of Food Intake
Current pharmaceutical design, 2013Co-Authors: Andreas Stengel, Yvette TacheAbstract:Nesfatin-1 was recently identified in the rat brain as a potential post-translational processing product derived from nucleobindin2 (NUCB2). The first biological action identified for Nesfatin-1 was the reduction of nocturnal food intake in rats. The anorexigenic effect of Nesfatin-1 was corroborated by several independent laboratories and is now established as a physiological action of this peptide based on the regulation of brain NUCB2/Nesfatin-1 under different metabolic conditions and the stimulation of food intake and body weight when endogenous brain NUCB2/Nesfatin-1 is blocked. Nesfatin-1 shows extensive co-localization with various other, predominantly food intake inhibitory, hypothalamic peptides including corticotropin-releasing factor (CRF), oxytocin, cholecystokinin, proopiomelanocortin, -αmelanocyte stimulating hormone (α-MSH), thyrotropin-releasing hormone (TRH), the orexigenic neuropeptide Y and brain biogenic amines, histamine, serotonin, and catecholamines. The food intake suppressing effect of centrally injected Nesfatin-1 has been established so far to involve several downstream mechanisms including H1, CRF2, TRH, oxytocin as well as melanocortin-3/4 receptor signaling pathways. This intricate embedding of NUCB2/Nesfatin-1 in central food intake regulatory pathways recruited during the dark phase corresponding to the eating period in rodents, unlike the orexigenic response to a fast, points towards a role for Nesfatin-1 in modulating the nocturnal food intake. Although our knowledge on the regulation and effects of NUCB2/Nesfatin-1 as a new anorexic peptide markedly increased during the past five years, several important gaps of knowledge remain to be filled in the near future such as the regulation of NUCB2 processing and Nesfatin-1 release as well as the identification, localization and regulation of the Nesfatin-1 receptor.
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Minireview: Nesfatin-1—An Emerging New Player in the Brain-Gut, Endocrine, and Metabolic Axis
Endocrinology, 2011Co-Authors: Andreas Stengel, Yvette TacheAbstract:Nesfatin-1 is a recently identified 82-amino-acid peptide derived from the precursor protein, nucleobindin2 (NUCB2). The brain distribution of NUCB2/Nesfatin-1 at the mRNA and protein level along with functional studies in rodents support a role for NUCB2/Nesfatin-1 as a novel satiety molecule acting through leptin-independent mechanisms. In addition, Nesfatin-1 induces a wide spectrum of central actions to stimulate the pituitary-adrenal axis and sympathetic nervous system and influences visceral functions and emotion. These central actions combined with the activation of NUCB2/Nesfatin-1 neurons in the brain by various stressors are indicative of a role in the adaptive response under stressful conditions. In the periphery, evidence is mounting that Nesfatin-1 exerts a direct glucose-dependent insulinotropic action on β-cells of the pancreatic islets. However, the cellular mechanisms of Nesfatin-1's action remain poorly understood, partly because the receptor through which Nesfatin-1 exerts its pleiotropic actions is yet to be identified.
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Localization of Nesfatin-1 neurons in the mouse brain and functional implication.
Brain research, 2011Co-Authors: Miriam Goebel-stengel, Andreas Stengel, Lixin Wang, Yvette TacheAbstract:Nesfatin-1 reduces food intake when injected centrally in rodents. We recently described wide distribution of nucleobindin2 (NUCB2)/Nesfatin-1 immunoreactivity in rat brain autonomic nuclei activated by various stressors. We used C57BL/6 mice to localize brain NUCB2/Nesfatin-1 immunoreactivity and assessed activation of NUCB2/nesfatin 1 neurons after water avoidance stress (WAS). Gastric emptying of a non-nutrient liquid was also determined. NUCB2/Nesfatin-1 immunoreactivity was detected in cortical areas including piriform, insular, cingulate and somatomotor cortices, the limbic system including amygdaloid nuclei, hippocampus and septum, the basal ganglia, bed nucleus of the stria terminalis, the thalamus including paraventricular and parafascicular nuclei, the hypothalamus including supraoptic, periventricular, paraventricular (PVN), arcuate nuclei and ventromedial and lateral hypothalamic areas. Intensely labeled NUCB2/Nesfatin-1 neurons were detected in a previously undefined region which we named intermediate dorsomedial hypothalamus. In the brainstem, NUCB2/Nesfatin-1 immunoreactivity was detected in the raphe nuclei, Edinger-Westphal nucleus, locus coeruleus (LC), lateral parabrachial nucleus, ventrolateral medulla (VLM) and dorsal vagal complex. WAS induced Fos expression in 35% of NUCB2/Nesfatin-1-immunoreactive neurons in the PVN, 50% in the LC, 54% in the rostral raphe pallidus, 58% in the VLM, 39% in the middle part of the nucleus of the solitary tract (NTS) and 33% in the caudal NTS. Nesfatin-1 injected intracerebroventricularly significantly decreased gastric emptying. These data showed that NUCB2/Nesfatin-1 immunoreactivity is distributed in mouse brain areas involved in the regulation of stress response and visceral functions activated by an acute psychological stressor suggesting that Nesfatin-1 might play a role in the efferent component of the stress response.
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nesfatin 1 a novel inhibitory regulator of food intake and body weight
Obesity Reviews, 2011Co-Authors: Andreas Stengel, Miriam Goebel, Yvette TacheAbstract:The protein nucleobindin 2 (NUCB2) or NEFA (DNA binding/EF-hand/acidic amino acid rich region) was identified over a decade ago and implicated in intracellular processes. New developments came with the report that post-translational processing of hypothalamic NUCB2 may result in Nesfatin-1, nesfatin-2 and nesfatin-3 and convergent studies showing that Nesfatin-1 and full length NUCB2 injected in the brain potently inhibit the dark phase food intake in rodents including leptin receptor deficient Zucker rats. Nesfatin-1 also reduces body weight gain, suggesting a role as a new anorexigenic factor and modulator of energy balance. In light of the obesity epidemic and its associated diseases, underlying new mechanisms regulating food intake may be promising targets in the drug treatment of obese patients particularly as the vast majority of them display reduced leptin sensitivity or leptin resistance while Nesfatin-1’s mechanism of action is leptin independent. Although much progress on the localization of NUCB2/Nesfatin-1 in the brain and periphery as well as on the understanding of Nesfatin-1’s anorexic effect have been achieved during the past three years, several important mechanisms have yet to be unraveled such as the identification of the Nesfatin-1 receptor and the regulation of NUCB2 processing and Nesfatin-1 release.
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Nesfatin-1 - role as possible new potent regulator of food intake.
Regulatory Peptides, 2010Co-Authors: Andreas Stengel, Yvette TacheAbstract:Abstract Nesfatin-1 is an 82 amino acid peptide recently discovered in the brain which is derived from nucleobindin2 (NUCB2), a protein that is highly conserved across mammalian species. Nesfatin-1 has received much attention over the past two years due to its reproducible food intake-reducing effect that is linked with recruitment of other hypothalamic peptides regulating feeding behavior. A growing amount of evidence also supports that various stressors activate fore- and hindbrain NUCB2/Nesfatin-1 circuitries. In this review, we outline the central nervous system distribution of NUCB2/Nesfatin-1, and recent developments on the peripheral expression of NUCB2/Nesfatin-1, in particular its co-localization with ghrelin in gastric X/A-like cells and insulin in s-cells of the endocrine pancreas. Functional studies related to the characteristics of Nesfatin-1's inhibitory effects on dark phase food intake are detailed as well as the central activation of NUCB2/Nesfatin-1 immunopositive neurons in the response to psychological, immune and visceral stressors. Lastly, potential clinical implications of targeting NUCB2/Nesfatin-1 signaling and existing gaps in knowledge to ascertain the role and mechanisms of action of Nesfatin-1 are presented.
Hiroyuki Shimizu - One of the best experts on this subject based on the ideXlab platform.
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Nesfatin-1 suppresses peripheral arterial remodeling without elevating blood pressure in mice
Bioscientifica, 2019Co-Authors: Yusaku Mori, Hiroyuki Shimizu, Hideki Kushima, Tomomi Saito, Munenori Hiromura, Michishige Terasaki, Masakazu Koshibu, Hirokazu Ohtaki, Tsutomu HiranoAbstract:Nesfatin-1 is a novel anorexic peptide hormone that also exerts cardiovascular protective effects in rodent models. However, Nesfatin-1 treatment at high doses also exerts vasopressor effects, which potentially limits its therapeutic application. Here, we evaluated the vasoprotective and vasopressor effects of nesfatin -1 at different doses in mouse models. Wild-type mice and those with the transgene nucleobindin-2, a precursor of Nesfatin-1, were employed. Wild-type mice were randomly assigned to treatment with vehicle or Nesfatin-1 at 0.2, 2.0 or 10 μg/kg/day (Nes-0.2, Nes-2, Nes-10, respectively). Subsequently, mice underwent femoral artery wire injury to induce arterial remodeling. After 4 weeks, injured arteries were collected for morphometric analysis. Compared with vehicle, Nesfatin-1 treatments at 2.0 and 10 μg/kg/day decreased body weights and elevated plasma Nesfatin-1 levels with no changes in systolic blood pressure. Furthermore, these treatments reduced neointimal hyperplasia without inducing undesirable remodeling in injured arteries. However, Nesfatin-1 treatment at 0.2 μg/kg/day was insufficient to elevate plasma Nesfatin-1 levels and showed no vascular effects. In nucleobindin-2- transgenic mice, blood pressure was slightly higher but neointimal area was lower than those observed in littermate controls. In cultured human vascular endothelial cells, Nesfatin-1 concentration-dependently increased nitric oxide production. Additionally, Nesfatin-1 increased AMP-activated protein kinase phosphorylation, which was abolished by inhibiting liver kinase B1. We thus demonstrated that Nesfatin-1 treatment at appropriate doses suppressed arterial remodeling without affecting blood pressure. Our findings indicate that Nesfatin-1 can be a therapeutic target for improved treatment of peripheral artery disease
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Possible Involvement of Anorexigenic Protein, Nesfatin/Nucleobindin-2 (NUCB2) in Blood Pressure Regulation by Regulating Water Reabsorption in Renal Collecting Duct
Journal of Cytology and Histology, 2014Co-Authors: Hiroyuki Shimizu, Aya OsakiAbstract:Nesfatin/nucleobindin-2 (NUCB2), a precursor protein of anorexigenic protein, Nesfatin-1, is ubiquitously expressed in the body. The finding that peripheral administration of Nesfatin-1 increases blood pressure indicates a possible involvement of Nesfatin-1 in the regulation of blood pressure. The present studies were undertaken to investigate a possible involvement of nesfatin/NUCB2 in the regulation of blood pressure. The immunoreactivity against nesfatin/NUCB2 was selectively found in vascular endothelial cells of aorta, pulmonary artery and renal artery, cardiac muscle and skeletal striated muscle cells, but not in vascular smooth muscle cells at all. Furthermore, the immunoreactivity against nesfatin/NUCB2 was selectively found in renal collecting duct cells, which contain aquaporin (AQP)-2 and/or epithelial sodium channel (ENaC). In medullary collecting ducts, cells expressing nesfatin/ NUCB2 co-expressed AQP-2, but did not co-expressed AQP-2 in renal cortical collecting ducts. On the other hand, collecting ductal cells expressing ENaC were totally compatible with those expressing nesfatin/NUCB2 in both renal medullary and cortical collecting ducts. Thus, there is a possibility that nesfatin/NUCB2 is involved in the regulation of blood pressure through increased water reabsorption in the kidney.
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Nesfatin-1: Its Role in the Diagnosis and Treatment of Obesity and Some Psychiatric Disorders
Methods in molecular biology (Clifton N.J.), 2012Co-Authors: Hiroyuki Shimizu, Masatomo MoriAbstract:We discovered a new anorexigenic protein, nesfatin/nucleobindin-2 (NUCB2), which includes an EF-hand, calcium-binding motif. Nesfatin/NUCB2 is converted to Nesfatin-1, which may be a physiologically active form in the body. Centrally and systemically administered Nesfatin-1 inhibits appetite and body weight gain in rodents. The mid-segment of Nesfatin-1 appears to be important in the inhibition of food intake. Intranasal administration of the mid-segment inhibits appetite. Nesfatin-1 may also be involved in the regulation of gastrointestinal function and insulin secretion. We have summarized the recent progress in the research of Nesfatin-1.
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nesfatin 1 evokes ca2 signaling in isolated vagal afferent neurons via ca2 influx through n type channels
Biochemical and Biophysical Research Communications, 2009Co-Authors: Yusaku Iwasaki, Hiroyuki Shimizu, Masatomo Mori, Hajime Nakabayashi, Masafumi Kakei, Toshihiko YadaAbstract:Abstract Nesfatin-1, processed from nucleobindin 2, is an anorexigenic peptide expressed in the brain and several peripheral tissues including the stomach and pancreas. Peripheral, as well as intracerebroventricular, administration of Nesfatin-1 suppresses feeding behavior, though underlying mechanisms are unknown. In this study, we examined effects of Nesfatin-1 on cytosolic Ca2+ concentration ([Ca2+]i) in the neurons isolated from the vagal afferent nodose ganglion of mice. Nesfatin-1 at 10−10–10−8 M increased [Ca2+]i in the isolated neurons in a concentration-dependent manner, and at 10−8 M it increased [Ca2+]i in 33 out of 263 (12.5%) neurons. These responses were inhibited under Ca2+-free conditions and by N-type Ca2+ channel blocker, ω-conotoxin GVIA. All the Nesfatin-1-responsive neurons also exhibited [Ca2+]i responses to capsaicin and cholecystokinin-8. These results provide direct evidence that Nesfatin-1 activates vagal afferent neurons by stimulating Ca2+ influx through N-type channels, demonstrating the machinery through which peripheral Nesfatin-1 can convey signals to the brain.
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Nesfatin-1: an overview and future clinical application.
Endocrine journal, 2009Co-Authors: Hiroyuki Shimizu, Shuichi Okada, Sinsuke Oh-i, Masatomo MoriAbstract:Nesfatin/nucleobindin 2 (NUCB2) is expressed in the appetite-control hypothalamic nuclei and brainstem nuclei. Nesfatin/NUCB2 expression in the paraventricular nucleus of the hypothalamus was modulated by starvation and refeeding. Intracerebroventricular administration of Nesfatin-1 dose-dependently inhibited food intake for 6 hours in male Wistar and leptin resistant, Zucker fatty rats. Intraperitoneal administration of Nesfatin-1 and its mid-segment (M30) dosedependentlyinhibited food intake for 3 hours in male ICR mice. Intraperitoneal administration of M30 also decreased foodintake in leptin-resistant, genetically obese (ob/ob), diabetic (db/db) mice and mice fed a 45% high fat diet for 28 days. Intraperitoneal administration of M30 increased proopiomelanocortin and cocaine- and amphetamine- related peptide mRNA expression in the nucleus of the solitary tract of mice. In addition, intranasal administration of Nesfatin-1 significantly inhibited food intake for 6 hours in male Wistar rats. We summarize recent observations about Nesfatin-1, and attempt to present future direction of Nesfatin-1 research for developing a new anti-obesity treatment.
Suraj Unniappan - One of the best experts on this subject based on the ideXlab platform.
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Loss of Nucleobindin-2/Nesfatin-1 increases lipopolysaccharide-induced murine acute lung inflammation
Cell and Tissue Research, 2021Co-Authors: Jasmine Hui, Suraj Unniappan, Gurpreet Kaur Aulakh, Baljit SinghAbstract:NUCB2/Nesfatin-1 is expressed in variety of tissues. Treatment with Nesfatin-1 reduces inflammation in rat models of subarachnoid hemorrhage-induced oxidative brain damage and traumatic brain injury as well as myocardial injury. There is only one study showing anti-inflammatory actions of Nesfatin-1 on acute lung inflammation. To more precisely determine the role of NUCB2/Nesfatin-1 in acute lung inflammation, we conducted a study using NUCB2/Nesfatin-1 knockout (NKO) mice as well as neutrophils isolated from the bone marrows of WT and NKO mice. Our findings suggest that the absence of NUCB2/Nesfatin-1 significantly increases the accumulation of adherent neutrophils by approximately 3 times compared with WT within LPS-treated lungs. Integrating this with observations from both BALF and neutrophil cytokine expression, we propose that although neutrophils lacking NUCB2/Nesfatin-1 individually secrete less pro-inflammatory cytokines compared with stimulated WT cells, the result of knocking out NUCB2/Nesfatin-1 is net pro-inflammatory. No change was found in NUCB2/Nesfatin-1 mRNA or protein expression comparing WT LPS and PBS-treated samples. Taken together, our results show that NUCB2/Nesfatin-1 is constitutively expressed in mouse lungs and neutrophils and demonstrates anti-inflammatory properties in mouse lungs during acute lung injury, by inhibiting adherent neutrophil accumulation and inflammatory cytokine expression.
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Nesfatin-1 suppresses fish reproductive axis and gonadal steroidogenesis.
Reproduction (Cambridge England), 2020Co-Authors: Jithine Jayakumar Rajeswari, Suraj UnniappanAbstract:Nesfatin-1 is a naturally occurring orphan ligand in fish and mammals. Research in our lab resulted in the identification of an inhibitory role for Nesfatin-1 on pituitary hormones (goldfish) and oocyte maturation (zebrafish). The present study is an extension of these original findings and aimed to determine whether Nesfatin-1 has any additional effects on HPG genes in male and female goldfish. We found that a single i.p. injection of synthetic Nesfatin-1 (50 ng/g body weight) downregulated the expression of salmon gonadotropin-releasing hormone (sgnrh), chicken gnrh-II (cgnrh-II), kisspeptin receptor (gpr54a) and brain aromatase (cyp19a1b) mRNAs in the hypothalamus of both male and female goldfish at 15 min post-administration. In the pituitary of both males and females, Nesfatin-1 reduced luteinizing hormone beta (lhβ) and follicle stimulating hormone beta (fshβ) mRNA expression at 60 min and gpr54a mRNA at 15 min. Similarly, the gonadotropin receptors lhr and fshr were downregulated in the gonads. Meanwhile, gonadotropin inhibiting hormone (gnih), gnih receptor, kisspeptin 1 (kiss1) and gpr54a mRNA expression in the gonads were increased post-Nesfatin-1 treatment. Nesfatin-1 negatively influences the star, cytochrome P450 family 11 subfamily A member 1, anti-mullerian hormone and aromatase mRNAs. In agreement with these results, Nesfatin-1 reduced plasma estradiol and testosterone in female and male goldfish circulation at 60 min post-injection. The information generated through this research further solidified Nesfatin-1 as an inhibitor of reproductive hormones in fish. Targeting Nesfatin-1 and related peptides could yield beneficial effects in fish reproduction and aquaculture.
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Nesfatin-1 regulates glucoregulatory genes in rainbow trout (Oncorhynchus mykiss).
Comparative biochemistry and physiology. Part A Molecular & integrative physiology, 2019Co-Authors: Juan Ignacio Bertucci, Ayelén Melisa Blanco, Suraj UnniappanAbstract:Abstract The aim of this work was to determine if the anorexigen Nesfatin-1 modulates the expression of genes involved in glucoregulation in rainbow trout. First, the Nesfatin-1 sequence from trout was confirmed. Second, the effects of 0.1, 1 and 10 nM Nesfatin-1 on insulin, glucagon, igf-I, igf-II, glut1, glut2, glut4 and sglt1 expression were tested in cultured liver, gut, muscle and adipose tissue. In liver, the expression of insulin and glucagon isoforms X1 increased after 2 h of incubation with 0.1 nM Nesfatin-1, while insulin and glucagon X2 expression increased after 4 h with 1 nM treatment. All Nesfatin-1 doses tested decreased glut2 expression after 4 h. In adipose tissue, all Nesfatin-1 concentrations reduced insulin X1 expression at 30 min, and 1 nM Nesfatin-1 increased insulin X2 expression at 4 h. In gut, 0.1, 1 and 10 nM Nesfatin-1 decreased glut2 and sglt1 mRNA levels after 240 min of incubation. In muscle, 0.1 nM Nesfatin-1 increased the expression of igf-I after 240 min. The expression of igf-II in muscle increased after 30 min of incubation with 1 and 10 nM Nesfatin-1 and after 120 min of incubation with 0.1 and 1 nM Nesfatin-1. Expression of glut1 and sglt1 in muscle increased after 240 min of incubation with 0.1 nM Nesfatin-1 and after 120 min with 0.1 and 10 nM Nesfatin-1, respectively. These results suggest that Nesfatin-1 could decrease the gut intake of dietary glucose, and increase its uptake in glucoregulatory tissues such as liver and muscle of rainbow trout.
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Nesfatin-1 Regulates Feeding, Glucosensing and Lipid Metabolism in Rainbow Trout.
Frontiers in endocrinology, 2018Co-Authors: Ayelén Melisa Blanco, Juan Ignacio Bertucci, Cristina Velasco, José L. Soengas, Suraj UnniappanAbstract:Nesfatin-1 is an 82 amino acid peptide that has been involved in a wide variety of physiological functions in both mammals and fish. This study aimed to elucidate the role of Nesfatin-1 on rainbow trout food intake, and its putative effects on glucose and fatty acid sensing systems. Intracerebroventricular administration of 25 ng/g Nesfatin-1 resulted in a significant inhibition of appetite, likely mediated by the activation of central POMC and CART. Nesfatin-1 stimulated the glucosensing machinery (changes in sglt1, g6pase, gsase, and gnat3 mRNA expression) in the hindbrain and hypothalamus. Central fatty acid sensing mechanisms were unaltered by Nesfatin-1, but this peptide altered the expression of mRNAs encoding factors regulating lipid metabolism (fat/cd36, acly, mcd, fas, lpl, pparα, and pparγ), suggesting that Nesfatin-1 promotes lipid accumulation in neurons. In the liver, intracerebroventricular Nesfatin-1 treatment resulted in decreased capacity for glucose use and lipogenesis, and increased the potential of fatty acid oxidation. Altogether, the present results demonstrate that Nesfatin-1 is involved in the homeostatic regulation of food intake and metabolism in fish.
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Tissue-specific expression and circulating concentrations of Nesfatin-1 in domestic animals.
Domestic animal endocrinology, 2018Co-Authors: K.a. Morton, Ayelén Melisa Blanco, L. Hargreaves, Sima Mortazavi, Lynn P. Weber, Suraj UnniappanAbstract:Abstract Nesfatin-1 is a naturally occurring 82–amino acid protein encoded in the precursor nucleobindin-2 (NUCB2) and has been implicated in multiple physiological functions, including food intake and blood glucose regulation. This study aimed to characterize Nesfatin-1 in domestic species, especially cats (Felis catus), dogs (Canis lupus familiaris), and pigs (Sus scrofa). Our in silico analysis demonstrated that the NUCB2/Nesfatin-1 amino acid sequence, especially the bioactive core region of the peptide, is very highly conserved (more than 90% identity) in domestic animals. Expression of mRNAs encoding NUCB2/Nesfatin-1 was detected in the cat, dog, and pig stomach and pancreas. Immunohistochemistry revealed the presence of Nesfatin-1 in the gastric mucosa of the stomach of dogs, cats, and pigs, and in the pancreatic islet β-cells of dogs and pigs. No Nesfatin-1 immunoreactivity was found in the cat pancreas. Nesfatin-1 was detected in the serum of dog, cat, pig, bison, cow, horse, sheep, and chicken. Circulating Nesfatin-1 in male and female dogs remained unchanged at 60 min after glucose administration, suggesting a lack of meal responsiveness in Nesfatin-1 secretion in this species. The presence of Nesfatin-1 in the gastric and endocrine pancreatic tissues suggests possible roles for this peptide in the metabolism of domestic animals. Future research should focus on elucidating the species-specific functions and mechanisms of action of Nesfatin-1 in health and disease of domestic animals.