Nesfatin-1 inhibits proliferation and enhances apoptosis of human adrenocortical H295R cells (original) (raw)
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Role of NUCB2/Nesfatin-1 in the Hypothalamic Control of Energy Homeostasis
Hormone and Metabolic Research, 2013
Hunger and satiety are regulated in a complex fashion by a few food intake stimulatory (orexigenic) and a multitude of inhibitory (anorexigenic) factors produced in the periphery (mainly in the gastrointestinal tract) or directly in the brain. Within the brain, the hypothalamus plays a pivotal role as a production site of food intake regulatory factors. Importantly, this site integrates peripheral and central signaling factors to orchestrate food intake and in the long term body weight. Our knowledge on these regulatory pathways is not static but rather rapidly changing as new factors as well as upand downstream signaling pathways of already known transmitters are uncovered. Hypothalamic nucleobindin2 (NUCB2), the precursor of nesfatin-1, was first described in 2006 and nesfatin-1 found to be a novel anorexigenic modulator of food intake and body weight. The initial report stimulated several groups to investigate the biological actions of nesfatin-1 and subsequent studies delineated the underlying brain mechanisms involved in its food reducing effect. Of interest was the demonstration that NUCB2 also exerts its anorexigenic action in the paraventricular nucleus of the hypothalamus and is regulated at this site by changes in metabolic status with a diurnal rhythm inversely related to that of feeding in rats. The present review describes the current state-of-knowledge on central nesfatin-1's effects on food intake and body weight and highlights important missing links regarding cellular signaling mechanisms involved in nesfatin-1's action.
Minireview: Nesfatin-1—An Emerging New Player in the Brain-Gut, Endocrine, and Metabolic Axis
Endocrinology, 2011
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 nesf...
Paraventricular NUCB2/nesfatin-1 is directly targeted by leptin and mediates its anorexigenic effect
Biochemical and Biophysical Research Communications, 2015
An adipokine leptin plays a central role in the regulation of feeding and energy homeostasis via acting on the hypothalamus. However, its downstream neuronal mechanism is not thoroughly understood. The neurons expressing nucleobindin-2 (NUCB2)-derived nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) have been implicated in feeding and energy homeostasis. The present study aimed to explore the role of PVN NUCB2/nesfatin-1 in the leptin action, by using adeno-associated virus (AAV) vectors encoding shRNA targeting NUCB2 (AAV-NUCB2-shRNA). Leptin directly interacted and increased cytosolic Ca 2+ in single neurons isolated from the PVN, predominantly in NUCB2/nesftin-1-immunoreactive neurons. Treatment with leptin in vivo and in vitro markedly increased NUCB2 mRNA expression in the PVN. Peripheral and central injections of leptin failed to significantly inhibit food intake in mice receiving AAV-NUCB2. These results indicate that PVN NUCB2/nesfatin-1 is directly targeted by leptin, and mediates its anorexigenic effect.
Nesfatin-1: functions and physiology of a novel regulatory peptide
Journal of Endocrinology, 2016
Nesfatin-1 was identified in 2006 as a potent anorexigenic peptide involved in the regulation of homeostatic feeding. It is processed from the precursor-peptide NEFA/nucleobindin 2 (NUCB2), which is expressed both in the central nervous system as well as in the periphery, from where it can access the brain via non-saturable transmembrane diffusion. In hypothalamus and brainstem, nesfatin-1 recruits the oxytocin, the melancortin and other systems to relay its anorexigenic properties. NUCB2/nesfatin-1 peptide expression in reward-related areas suggests that nesfatin-1 might also be involved in hedonic feeding. Besides its initially discovered anorexigenic properties, over the last years, other important functions of nesfatin-1 have been discovered, many of them related to energy homeostasis, e.g. energy expenditure and glucose homeostasis. Nesfatin-1 is not only affecting these physiological processes but also the alterations of the metabolic state (e.g. fat mass, glycemic state) have...
Nesfatin-1 — Role as possible new potent regulator of food intake
Regulatory Peptides, 2010
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 β-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.
Frontiers in Cell and Developmental Biology, 2015
Nesfatin-1, the N-terminal fragment of nucleobindin 2 (NUCB2), is an 82 amino-acid peptide that inhibits food intake and exerts weight-reducing effects. Nesfatin-1 has been proposed as a potential anti-obesity peptide. However, studies to date have mainly focused on the acute satiety effects of centrally administered nesfatin-1. The main objective of our studies was to characterize the long-term/chronic effects of peripheral administration of nesfatin-1 on whole-body energy balance and metabolic partitioning in male Fischer 344 rats. Short-term (1 day) subcutaneous infusion of nesfatin-1 (50 µg/kg body weight/day) using osmotic mini-pumps increased spontaneous physical activity and whole-body fat oxidation during the dark phase. This was accompanied by decreased food intake and basal metabolic rate compared to saline infused controls. On the seventh day of nesfatin-1 infusion, cumulative food intake, and total spontaneous physical activity during the dark phase were significantly reduced and elevated, respectively. Meanwhile, intraperitoneal injection of nesfatin-1 only caused a dark phase specific reduction in food intake and an increase in physical activity. NUCB2 mRNA expression in the brain and stomach, as well as serum NUCB2 concentrations were significantly reduced after 24 h fasting, while a post-prandial increase in serum NUCB2 was found in ad libitum fed rats. Collectively, our results indicate that chronic peripheral administration of nesfatin-1 at the dose tested, results in a sustained reduction in food intake and modulation of whole body energy homeostasis.
Nesfatin-1 immunoreactivity in rat brain and spinal cord autonomic nuclei
Neuroscience Letters, 2009
Nesfatin-1 is one of the peptide products of posttranslational processing of the nucleobindin-2 (NUCB2) gene, suggested to have physiological relevance to suppress food intake and body weight gain in rats. Nesfatin-1-immunoreactive cells have been found in distinct nuclei in the rat brain related to circuitries regulating food intake. Here, we report novel yet undescribed localization of NUCB2/ nesfatin-1 at the mRNA and protein level in the rat central nervous system. Immunohistochemical staining revealed the localization of NUCB2/nesfatin-1 in the piriform and insular cortex, endopiriform nucleus, nucleus accumbens, lateral septum, bed nucleus of stria terminalis, central amygdaloid nucleus, medial preoptic area, dorsal raphe nucleus, ambiguus nucleus, ventrolateral medulla and gigantocellular reticular nucleus, as well as Purkinje-cells of the cerebellum. In the spinal cord, nesfatin-1 immunoreactivity (IR) was found in both sympathetic and parasympathetic preganglionic neuronal groups and in the dorsal area X from lower thoracic to sacral segments. The immunohistochemical results were confirmed by RT-PCR in the central amygdaloid nucleus, nucleus accumbens, cerebellum and lumbar spinal cord microdissected by punch technique. The features and distributions of nesfatin-1 IR and mRNA expression in the brain and spinal cord suggest that NUCB2/ nesfatin-1 could play a wider role in autonomic regulation of visceral-endocrine functions besides food intake.
Nesfatin-1 stimulates the hypothalamus-pituitary-interrenal axis hormones in goldfish
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2021
Stress in vertebrates is mediated by the hypothalamus-pituitary-adrenal (in mammals)/interrenal (in fish) (HPA/I) axis, which produces the corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and corticosteroids, respectively. Nesfatin-1, a novel anorexigenic peptide encoded in the precursor nucleobindin-2 (NUCB2), is increasingly acknowledged as a peptide that influences the stress axis in mammals. The primary aim of this study was to characterize the putative effects of nesfatin-1 on the fish HPI axis, using goldfish ( Carassius auratus) as an animal model. Our results demonstrated that nucb2/nesfatin-1 transcript abundance was detected in the HPI tissues of goldfish, with most abundant expression in the pituitary. NUCB2/nesfatin-1-like immunoreactivity was found in the goldfish hypothalamus, pituitary, and interrenal cells of the head kidney. GPCR12, a putative receptor for nesfatin-1, was also detected in the pituitary and interrenal cells. NUCB2/nesfatin-1-...
Endocrinology, 2010
Nesfatin-1 is a recently identified anorexigenic peptide derived from its precursor protein, nonesterified fatty acid/nucleobindin 2 (NUCB2). Although the hypothalamus is pivotal for the maintenance of energy homeostasis, adipose tissue plays an important role in the integration of metabolic activity and energy balance by communicating with peripheral organs and the brain via adipokines. Currently no data exist on nesfatin-1 expression, regulation, and secretion in adipose tissue. We therefore investigated NUCB2/nesfatin-1 gene and protein expression in human and murine adipose tissue depots. Additionally, the effects of insulin, dexamethasone, and inflammatory cytokines and the impact of food deprivation and obesity on nesfatin-1 expression were studied by quantitative RT-PCR and Western blotting. We present data showing NUCB2 mRNA (P Ͻ 0.001), nesfatin-1 intracellular protein (P Ͻ 0.001), and secretion (P Ͻ 0.01) were significantly higher in sc adipose tissue compared with other depots. Also, nesfatin-1 protein expression was significantly increased in high-fat-fed mice (P Ͻ 0.01) and reduced under food deprivation (P Ͻ 0.01) compared with controls. Stimulation of sc adipose tissue explants with inflammatory cytokines (TNF␣ and IL-6), insulin, and dexamethasone resulted in a marked increase in intracellular nesfatin-1 levels. Furthermore, we present evidence that the secretion of nesfatin-1 into the culture media was dramatically increased during the differentiation of 3T3-L1 preadipocytes into adipocytes (P Ͻ 0.001) and after treatments with TNF-␣, IL-6, insulin, and dexamethasone (P Ͻ 0.01). In addition, circulating nesfatin-1 levels were higher in high-fat-fed mice (P Ͻ 0.05) and showed positive correlation with body mass index in human. We report that nesfatin-1 is a novel depot specific adipokine preferentially produced by sc tissue, with obesity-and food deprivation-regulated expression. (Endocrinology 151: 3169-3180, 2010) O besity is a leading cause of morbidity and mortality worldwide (1) and is known to arise from an imbalance between energy intake and expenditure. The hypothalamus is the key center for integration of long-term energy balance and is a rich source of satiety regulatory peptides. Many of these peptides are also found in peripheral sites such as the gut and adipose tissue in which they play key physiological roles in body weight homeostasis and contribute to the pathophysiology of insulin resistance and its associated metabolic complications in obesity and diabetes (2-4). Nesfatin-1 is a recently described anorexigenic peptide derived from a precursor molecule NUCB2, which contains an amino acid sequence that is highly conserved be
Nesfatin-1, a unique regulatory neuropeptide of the brain
Neuropeptides, 2012
Nesfatin-1, a newly discovered NUCB2-derived satiety neuropeptide is expressed in several neurons of forebrain, hindbrain, brainstem and spinal cord. This novel anorexigenic substance seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. Nesfatin-1 immunoreactive cells are detectable in arcuate (ARC), paraventricular (PVN) and supraoptic nuclei (SON), where the peptide is colocalized with POMC/CART, NPY, oxytocin and vasopressin. The nesfatin-1 molecule interacts with a G-protein coupled receptor and its cytophysiological effect depends on inhibitory hyperpolarization of NPY/AgRP neurons in ARC and melanocortin signaling in PVN. Administration of nesfatin-1 significantly inhibits consumatory behavior and decreases weight gain in experimental animals. These recent findings suggest the evidence for nesfatin-1 involvement in other important brain functions such as reproduction, sleep, cognition and anxiety-or stress-related responses. The neuroprotective and antiapoptotic properties of nesfatin-1 were also reported. From the clinical viewpoint it should be noteworthy, that the serum concentration of nesfatin-1 may be a sensitive marker of epileptic seizures. However, the details of nesfatin-1 physiology ought to be clarified, and it may be considered suitable in the future, as a potential drug in the pharmacotherapy of obesity, especially in patients treated with antipsychotics and antidepressants. On the other hand, some putative nesfatin-1 antagonists may improve eating disorders.