OBJECTIVE

<em>Nesfatin</em>-<em>1</em>, an anorexigenic neuropeptide, is expressed mainly in the central nervous system and in some peripheral tissues. The role of <em>nesfatin</em>-<em>1</em> in energy balance has been investigated. Despite the suggestion of a role for <em>nesfatin</em>-<em>1</em> in reproductive function, data are limited on the role of <em>nesfatin</em>-<em>1</em> in human puberty.

METHODS

The aim of this study was to investigate the following: i) the role of <em>nesfatin</em>-<em>1</em> in puberty, and ii) relationship between <em>nesfatin</em>-<em>1</em> and anthropometric measurements and gonadotropin levels in girls with idiopathic central precocious puberty (CPP). Twenty-four girls with CPP (7.68±<em>1</em>.02 years) and 20 female, prepubertal, healthy controls (7.48±0.88 years) were enrolled in the study. All patients with CPP were treated by the intramuscular administration of leuprolide acetate at a daily dose of 3.75 mg for 28 days. <em>Nesfatin</em>-<em>1</em> was measured before and during treatment.

RESULTS

There was no difference in serum <em>nesfatin</em>-<em>1</em> levels in girls with CPP and healthy controls [5.67 (2.5-20.6) mmol/L and 5.75 (2.5<em>1</em>-9.64) mmol/L], respectively. There was a negative correlation between <em>nesfatin</em>-<em>1</em> levels and body weight and body mass index-standard deviation score (p=0.0<em>1</em>, r=-0.83; p=0.025, r=-0.8<em>1</em>, respectively). No correlation was found between <em>nesfatin</em>-<em>1</em> and gonadotropin, estradiol levels, uterine length or endometrial thickness.

CONCLUSIONS

The results of this study suggest that there are no differences between girls with CPP and healthy, prepubertal girls regarding <em>nesfatin</em>-<em>1</em> levels.

Background Hyperemesis gravidarum, which affects 0.3-2.3% of pregnancies, is defined as excessive vomiting during pregnancy and usually starts in week 4 or 5 of gestation. Symptoms include weight loss, dehydration, ketonaemia, ketonuria, fasting acidosis, alkalosis due to hydrochloric acid loss and hypokalaemia and its exact cause is unknown. The present study was undertaken to investigate the relationship between prealbumin, ghrelin, <em>nesfatin</em>-<em>1</em> and obestatin concentrations in pregnancies associated with hyperemesis gravidarum. Methods A total of 40 pregnant females with hyperemesis gravidarum and 38 pregnant females without hyperemesis gravidarum as controls were included in this study. Serum concentrations of prealbumin, ghrelin, obestatin and <em>nesfatin</em>-<em>1</em> were measured. Results There were no significant differences in age, gestational week, gravidity and parity between the two groups. Body mass index was significantly lower in cases than in controls. Serum ghrelin and prealbumin concentrations were significantly lower in cases than in controls ( P <0.05 and P < 0.00<em>1</em>, respectively). There was no significant difference in serum concentrations of obestatin and <em>nesfatin</em>-<em>1</em> between the two groups. There was no significant association between body mass index and serum ghrelin, <em>nesfatin</em>-<em>1</em>, obestatin or prealbumin concentrations in patients with hyperemesis gravidarum. Conclusions Decreased serum concentrations of ghrelin and prealbumin in patients with hyperemesis gravidarum are independent of body mass index. Based on our results, we believe that ghrelin may be considered to play a role in the aetiopathogenesis of hyperemesis gravidarum and that hyperemesis gravidarum may result in disruption of the relationship between <em>nesfatin</em>-<em>1</em> and ghrelin. In addition, we believe that the measurement of serum prealbumin may be used for assessing nutritional status in pregnancy.

NUCB2/<em>nesfatin</em>-<em>1</em> is expressed in the hypothalamus and regulates food intake and energy metabolism. Recent studies showed that NUCB2/<em>nesfatin</em>-<em>1</em> also plays a role in other organs. However, its expression pattern and function in female reproductive organs are unclear. Therefore, we investigated NUCB2/<em>nesfatin</em>-<em>1</em> expression in the ovary and uterus of mice and determined whether it is regulated by gonadotropins and sex steroid hormones. NUCB2 mRNA and <em>nesfatin</em>-<em>1</em> protein were detected in the ovary and uterus of mice. NUCB2/<em>nesfatin</em>-<em>1</em> expression in both organs was highest in the estrus period of the estrus cycle. Administration of pregnant mare serum gonadotropin (PMSG) dose-dependently increased mRNA expression of NUCB2 in the ovary and uterus of mice. On the other hand, mRNA expression of NUCB2 in the uterus was dramatically decreased after ovariectomy and was not increased upon administration of PMSG. Injection of <em>1</em>7β-estradiol upregulated mRNA expression of NUCB2 in the uterus of ovariectomized mice, whereas injection of progesterone did not. These results suggest that NUCB2/<em>nesfatin</em>-<em>1</em> expression in the ovary and uterus of mice is regulated through the hypothalamus-pituitary-ovary axis and that NUCB2/<em>nesfatin</em>-<em>1</em> is a local regulator of ovarian steroidogenesis and uterine function.

Testicular torsion (TT) is a common urological problem in the field of pediatric surgery. The degree and duration of torsion determines the degree of testicular damage; however, its effects on the expression of octanoylated ghrelin and nucleobindin 2 (NUCB2) /<em>nesfatin</em>-<em>1</em> synthetized from testicular tissue remain unclear. We explored the effects of experimentally induced unilateral TT on serum and contralateral testicular tissue ghrelin and NUCB2/<em>nesfatin</em>-<em>1</em> levels, and determined whether N-acetyl cysteine (NAS) treatment had any effects on their expression. A total of 42 Wistar Albino strain rats were divided into 7 groups: Group (G) I control, GII sham, GIII <em>1</em>2-hour torsion, GIV <em>1</em>2-hour torsion + detorsion + <em>1</em>00 mg/kg NAS, GV 24-hour torsion, GVI 24-hour torsion + detorsion + <em>1</em>00 mg/kg NAS, and GVII <em>1</em>00 mg/kg NAS. Octanoylated ghrelin and NUCB2/<em>nesfatin</em>-<em>1</em> concentrations were evaluated in serum using the ELISA method and in testicular tissue with immunohistochemical methods. Immunoreactivity of octanoylated ghrelin significantly increased in GI compared to GIII, GV, and GVI (p<0.05). NUCB2/<em>nesfatin</em>-<em>1</em> immunoreactivity increased in GV and GVIII relative to GI (p<0.05). In the <em>1</em>2-hour torsion group, a significant decrease in octanoylated ghrelin levels with NAS treatment was observed; however, in the 24-hour torsion group, a significant decrease was not observed. In the <em>1</em>2-hour torsion + NAS treatment group, a significant change was not observed in NUCB2/<em>nesfatin</em>-<em>1</em> expression. Following 24-hour torsion, an increase in NUCB2/<em>nesfatin</em>-<em>1</em> levels was observed, and NAS treatment did not reverse this increase. It was determined that increases in the expression of octanoylated ghrelin and NUCB2/<em>nesfatin</em>-<em>1</em>, the latter of which was a result of TT, reflect damage in this tissue. Importantly, NAS treatment could prevent this damage. Thus, there may be a clinical application for the combined use of NAS and octanoylated ghrelin in preventing TT-related infertility.

NUCB2/<em>nesfatin</em>-<em>1</em> known to regulate appetite and energy homeostasis is expressed not only in the hypothalamus, but also in various organs and tissues. Our previous reports also demonstrated that NUCB2/<em>nesfatin</em>-<em>1</em> was expressed in the reproductive organs, including the ovaries, uterus, and testes of mice. However, it is yet known whether NUCB2/<em>nesfatin</em>-<em>1</em> is expressed in the oviduct and how its expression is regulated. Therefore, we investigated the expression of NUCB2/<em>nesfatin</em>-<em>1</em> in the oviduct and its expression is regulated by gonadotropin. Immunohistochemical staining results showed that <em>nesfatin</em>-<em>1</em> protein was localized in epithelial cells of the oviduct. As a result of quantitative real-time PCR (qRT-PCR) and Western blot, NUCB2/<em>nesfatin</em>-<em>1</em> was detected strongly in the oviducts. During the estrus cycle, NUCB2/<em>nesfatin</em>-<em>1</em> expression in the oviducts was markedly higher in the proestrus stage than in other estrus stages. In order to elucidate whether the expression of NUCB2 mRNA is controlled by the gonadotropins, we injected PMSG and hCG and measured NUCB2 mRNA level in the oviduct after injection. Its level was increased in the oviduct after PMSG injection, but no significant change after hCG injection. In addition, NUCB2 mRNA levels were markedly reduced after ovariectomy, while recovered after <em>1</em>7β-estradiol (E2) injection, but not by progesterone (P4). This study demonstrated that NUCB2/<em>nesfatin</em>-<em>1</em> is highly expressed in the oviduct of mouse and its expression is regulated by E2 secreted by the ovaries. These results suggest that NUCB2/<em>nesfatin</em>-<em>1</em> expressed by the oviduct may affect the function of the oviduct regulated by the ovaries.

<em>Nesfatin</em>-<em>1</em> has recently been indicated as a pleiotropic molecule that is primarily involved in the metabolic regulation of reproductive functions acting at hypothalamic level. The aim of this study was to explore the local action of <em>nesfatin</em>-<em>1</em> in swine ovarian follicles. Nucleobindin 2 (NUCB2) was verified using real-time quantitative polymerase chain reaction in swine granulosa cells from different sized follicles and <em>nesfatin</em>-<em>1</em> was localised by immunohistochemistry in sections of the whole porcine ovary. The effects of different concentrations of <em>nesfatin</em>-<em>1</em> on cell growth, steroidogenesis and the redox status of granulosa cells were determined invitro. In addition, the effects of <em>nesfatin</em>-<em>1</em> were evaluated in an angiogenesis bioassay because vessel growth is essential for ovarian follicle function. Immunohistochemistry revealed intense positivity for <em>nesfatin</em>-<em>1</em> in swine granulosa cells in follicles at all developmental stages. Expression of the gene encoding the precursor protein NUCB2 was higher in granulosa cells from large rather than from medium and small follicles. Further, <em>nesfatin</em>-<em>1</em> stimulated cell proliferation and progesterone production and interfered with redox status by modifying nitric oxide production and non-enzyme scavenging activity in granulosa cells from large follicles. Moreover, <em>nesfatin</em>-<em>1</em> exhibited a stimulatory effect on angiogenesis. This study demonstrates, for the first time, that <em>nesfatin</em>-<em>1</em> is physiologically present in the swine ovarian follicle, where it may impair granulosa cell functions.

<em>Nesfatin</em>-<em>1</em> is a naturally occurring orphan ligand in fish and mammals. Research in our lab resulted in the identification of an inhibitory role for <em>nesfatin</em>-<em>1</em> on pituitary hormones (goldfish) and oocyte maturation (zebrafish). The present study is an extension of these original findings, and aimed to determine whether <em>nesfatin</em>-<em>1</em> has any additional effects on HPG genes in male and female goldfish. We found that a single intraperitoneal (I.P) injection of synthetic <em>nesfatin</em>-<em>1</em> (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 (cyp<em>1</em>9a<em>1</em>b) mRNAs in the hypothalamus of both male and female goldfish at <em>1</em>5 minutes post-administration. In the pituitary of both males and females, <em>nesfatin</em>-<em>1</em> reduced luteinizing hormone beta (lhβ) and follicle stimulating hormone beta (fshβ) mRNA expression at 60 minutes, and gpr54a mRNA at <em>1</em>5 minutes. Similarly, the gonadotropin receptors lhr and fshr were downregulated in the gonads. Meanwhile, gonadotropin inhibiting hormone (gnih), gnih receptor, kisspeptin <em>1</em> (kiss<em>1</em>) and gpr54a mRNA expression were in the gonads were increased post <em>nesfatin</em>-<em>1</em> treatment. <em>Nesfatin</em>-<em>1</em> negatively influences the steroidogenic acute regulatory protein, cytochrome P450 family <em>1</em><em>1</em> subfamily A member <em>1</em>, anti-mullerian hormone and aromatase mRNAs. In agreement with these results, <em>nesfatin</em>-<em>1</em> reduced plasma estradiol and testosterone in female and male goldfish circulation at 60 min post injection. The information generated through this research further solidified <em>nesfatin</em>-<em>1</em> as an inhibitor of reproductive hormones in fish. The suppression of <em>nesfatin</em>-<em>1</em> and related peptides could yield beneficial effects in fish reproduction and aquaculture.

Nucleobindin (Nucb)-<em>1</em> and Nucb2 are DNA and Ca2+ binding proteins with multiple functions in vertebrates. Prohormone convertase-mediated processing of Nucb2 results in the production of biologically active <em>nesfatin</em>-<em>1</em>. <em>Nesfatin</em>-<em>1</em> is involved in the regulation of reproduction in many vertebrates, including fish. Our lab originally reported a <em>nesfatin</em>-<em>1</em>-like peptide (Nlp) encoded in Nucb<em>1</em> that exhibits <em>nesfatin</em>-<em>1</em>-like metabolic effects. We hypothesized that Nlp has a suppressive role in the reproductive physiology of fish. In this research, whether Nlp regulates reproductive hormones and oocyte maturation in fish was determined. Single intraperitoneal (I.P) injection of goldfish Nlp (50 ng/g body weight) suppressed salmon and chicken gonadotropin releasing hormone (sgnrh and cgnrh2), gonadotropin inhibiting hormone (gnih) and its receptor (gnihr), kisspeptin and brain aromatase mRNA expression in the hypothalamus of both male and female goldfish. In the pituitary, Nlp decreased mRNAs encoding lhb, fshb and kisspeptin and its receptor, while a significant increase in gnih and gnihr was observed. In the gonads, lh (only in male fish) and fsh receptor mRNAs were also significantly downregulated in Nlp injected fish. Sex-specific modulation of gnih, gnihr and kisspeptin system in the gonads was also observed. Nlp decreased sex steroidogenic enzyme encoding mRNAs, and circulating levels of testosterone and estradiol. In addition, incubation of zebrafish ovarian follicles with Nlp resulted in a reduction in oocyte maturation. These results provide evidence for a robust role for Nlp in regulating reproductive hormones in goldfish, and oocyte maturation in zebrafish, and these effects resemble that of <em>nesfatin</em>-<em>1</em>.

<strong class="sub-title"> Keywords: </strong> HPG axis; <em>Nesfatin</em>-<em>1</em>-like peptide; Nucleobindins; goldfish; <em>nesfatin</em>-<em>1</em>; oocyte maturation; sex steroids.

<em>Nesfatin</em>-<em>1</em> is a novel hormone synthesized in hypothalamus and several other specific organs to regulate eating habits, appetite and is thought to be related to ovarian functions. In our study, we aimed to evaluate the <em>nesfatin</em>-<em>1</em> levels with other metabolic parameters in polycystic ovary syndrome (PCOS), a condition that is known to be related to both ovarian functions and obesity. Study subjects were chosen from the women attended to the Obstetrics and Gynecology Department of Istanbul Bilim University, Avrupa Florence Nightingale Hospital. Thirty-five healthy control subjects and 55 PCOS patients were included. Blood samples were obtained on the 3rd day of the menstrual cycle. Luteinizing hormone (LH), follicle stimulating hormone (FSH), free testosterone (FT), dehydroepiandrosterone sulfate (DHEA-S), insulin, fasting blood glucose (FBG), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), sex hormone binding globulin (SHBG) levels were measured; homeostatic model assessment-insulin resistance (HOMA-IR) value was calculated. The <em>nesfatin</em>-<em>1</em> levels were measured by competitive inhibition ELISA method. Due to our results, PCOS patients were having lower <em>nesfatin</em>-<em>1</em> levels compared to the control group and this was not seemed to be related to body mass index (BMI) levels. This is an important result to be investigated in larger study groups and is related to other metabolic markers.

Phoenixin (PNX) and <em>nesfatin</em>-<em>1</em> are localised in the hypothalamus and the pituitary gland. Moreover, the most of the PNX-expressing neurons in the hypothalamus also co-express <em>nesfatin</em>-<em>1</em>. These outcomes may suggest that there is an interaction between PNX and <em>nesfatin</em>-<em>1</em>, at least in terms of neuroendocrine-mediated regulations. Hence, the study was planned to find out the effects of centrally delivered PNX and <em>nesfatin</em>-<em>1</em> on male sex hormones or to show the interactive association of intracerebroventricularly (ICV) injected PNX+<em>nesfatin</em>-<em>1</em> combination on the release of male hormones. PNX and <em>nesfatin</em>-<em>1</em>, single or together, were delivered ICV to different male Wistar Albino rat groups. Both PNX and <em>nesfatin</em>-<em>1</em> induced a significant enhancement in plasma FSH, LH and testosterone without inducing any alteration in plasma GnRH in the rats. The central combinatorial treatment of both the neuropeptides produced a more potent rise in male plasma hormone levels than treating with single neuropeptide. In summary, our preliminary data show that centrally delivered PNX and <em>nesfatin</em>-<em>1</em> can affect plasma male hormone levels. Moreover, that the combinatorial treatment with both the neuropeptides in male rats leading to a more potent effect on the plasma male hormone levels might suggest that both these neuropeptides act synergistically in terms of regulation of male HPGA.

This study was conducted to explore the beneficial impact of <em>nesfatin</em>-<em>1</em> on reproductive dysfunction induced by nicotine (NT) in male rats with possible modulation of autophagy and pyroptosis signaling pathways. This research was performed on 40 Wistar male rats. They were distributed into four groups: control, normal+<em>nesfatin</em>-<em>1</em>, NT, and NT+<em>nesfatin</em>-<em>1</em>. At the end of the experimental period, the serum was separated for assay of testosterone, FSH and LH. Also, sperm parameters were determined. Histopathological examination of testicular tissue and immunohistochemical analysis was done for mammalian target of rapamycin, AMP-activated protein kinase, and mitogen-activated protein kinases including phosphorylated extracellular signal regulated kinase and phosphorylated cJun N-terminal kinase. Relative gene expression was determined for testicular nucleotide oligomerization domain (NOD)-like receptors proteins and Caspase-<em>1</em>, and autophagy markers including microtubule-associated protein <em>1</em> light chain 3 alpha and Beclin-<em>1</em>. Also, the following testicular parameters were assayed: 3β-hydroxysteroid dehydrogenase, <em>1</em>7β-hydroxysteroid dehydrogenase, malondialdehyde, superoxide dismutase activity, catalase, glucose-6 phosphate dehydrogenase, reactive oxygen species, caspase-3 activity, IL-<em>1</em>β, IL-<em>1</em>8, mitochondrial transmembrane potential and Complex-I activity. The results revealed that the normal+<em>nesfatin</em>-<em>1</em> group showed insignificant changes as compared to the control group. Meanwhile, the NT group exhibited prominent reproductive dysfunction in male rats. On the other hand, in the NT+<em>nesfatin</em>-<em>1</em> group <em>nesfatin</em>-<em>1</em> notably attenuated this reproductive dysfunction as evidenced by improvement of hormonal assay, sperm parameters, histopathological picture, immunohistochemical evaluation and real time relative gene expressions. In conclusion: <em>Nesfatin</em>-<em>1</em> alleviated the impairment of male reproductive functions induced by NT via enhancement of autophagy pathways, suppression of pyroptosis, apoptosis, mitochondrial dysfunction and ROS production. Thus <em>nesfatin</em>-<em>1</em> may offer a novel protective or therapeutic access for treating male infertility.

<strong class="sub-title"> Keywords: </strong> autophagy; <em>nesfatin</em>-<em>1</em>; nicotine; pyroptosis; reproductive dysfunction.

<AbstractText>Major depressive disorder (MDD) is a complex and heterogeneous disorder in which clinical symptoms can widely differ among patients. Neurovegetative symptoms, i.e. decreased or increased appetite, changes in body weight and sleep disturbances, described as 'melancholic' or 'atypical' features of a depressive episode, are the most variable symptoms among patients with MDD. We hypothesized biomarkers differences underlying this neurovegetative variability in major depression.</AbstractText><AbstractText>We systematically reviewed, according to the PRISMA guidelines, the role of specific metabolic, hormonal and inflammatory biomarkers in drug-free MDD patients, that could have neurobiological effects on appetite, weight regulation and circadian rhythms, influencing eating behaviour and sleep patterns. All studies regarding the co-occurrence of disturbed sleep and appetite were examined.</AbstractText><AbstractText>Besides the well-known leptin and ghrelin, other biomarkers such as BDNF, VEGF, NPY, orexin, and the recent discovered <em>nesfatin</em>-<em>1</em> seem to be involved in neurovegetative changes in depressive disorders playing a role in the regulation of affective states, stress reactions and sleep patterns. Interestingly, based on the existing evidence, ghrelin, orexin and <em>nesfatin</em>-<em>1</em> could be linked both to sleep and appetite regulation in depressed patients.</AbstractText><AbstractText>Heterogeneous studies with low sample size.</AbstractText><AbstractText>Despite the wide heterogeneity of results, studies on biomarkers of appetite and sleep in MDD are an interesting field of research to explain the neurobiological substrates of depressive symptoms that deserve further investigation.</AbstractText>

<em>Nesfatin</em>-<em>1</em> plays an important role in the modulation of heart performance. However, it remains unclear how <em>nesfatin</em>-<em>1</em> contributes to cell survival in acute myocardial infarction (MI). A rat model of MI was established via ligation of left anterior descending coronary artery (LAD) for 30 min and 20 µg/kg concentration of <em>nesfatin</em>-<em>1</em> was intraperitoneally infused prior to reperfusion. At 24 h after reperfusion, oxidative stress markers, the expression of caspase3, beclin-<em>1</em>, pro-inflammatory cytokines, and the mRNA levels of Bax and Bcl-2 were evaluated. Results showed that <em>nesfatin</em>-<em>1</em> markedly restored GSH content and SOD activity as well as reduced MDA levels compared to only the MI group (<i>p</i> < .05). Likewise, <em>nesfatin</em>-<em>1</em> contributed to cell survival by inhibiting autophagy and apoptosis markers such as caspase3 and Bax (<i>p</i> < .05). Collectively, these findings support the idea that nasfatin-<em>1</em> can be used as a good candidate to treat MI by targeting oxidative stress, apoptosis, and autophagy.

<strong class="sub-title"> Keywords: </strong> Myocardial infarction; apoptosis; autophagy; <em>nesfatin</em>-<em>1</em>; oxidative stress.

What is the topic of this review? We describe roles of crucial signalling molecules in the paraventricular nucleus of the hypothalamus and highlight recent data suggesting sex-specific changes in the expression of crucial signalling molecules and their receptors, which may underlie sex differences in both cardiovascular and metabolic function. What advances does it highlight? This review highlights the integrative capacity of the paraventricular nucleus in mediating cardiovascular and metabolic effects by integrating information from multiple signalling molecules. It also proposes that these signalling molecules have sex-specific differential gene expression, indicating the importance of considering these differences in our ongoing search to understand the female-male differences in the regulation of crucial autonomic systems. Many traditional cardiovascular hormones have been implicated in metabolic function. Conversely, many hormones traditionally involved in metabolic regulation have an effect on cardiovascular function. Many of these signalling molecules exert such effects through specific actions in the paraventricular nucleus, an integrative autonomic control centre located in the hypothalamus. Here, we focus on four cardiovascular/metabolic peptide hormones that signal within the paraventricular nucleus, namely angiotensin II, orexin, adiponectin and <em>nesfatin</em>-<em>1</em>. Each of these hormones has specific electrophysiological effects on paraventricular nucleus neurons that can be related to its physiological actions. In addition, we introduce preliminary transcriptomic data indicating that the genes for some of these hormones and their receptors have sex-specific differential expression.

NUCB2/<em>nesfatin</em>-<em>1</em> was originally discovered as an anorexigenic peptide. However, recent studies revealed various additional functions including the regulation of inflammation. However, there are no studies that investigated the involvement of NUCB2/<em>nesfatin</em>-<em>1</em> in neuroinflammatory diseases. Here, we aimed to investigate the involvement of NUCB2/<em>nesfatin</em>-<em>1</em> in a representative neuroinflammatory disease, multiple sclerosis (MS). Cerebrospinal fluids (CSF) were collected from 24 MS patients and <em>1</em>0 control subjects and NUCB2/<em>nesfatin</em>-<em>1</em>, proinflammatory cytokines (TNF-α, IL-<em>1</em>β) and anti-inflammatory cytokines (IL-<em>1</em>0, TGF-β) levels were measured by using ELISA assay. Also the expression of NUCB2/<em>nesfatin</em>-<em>1</em> in the CSF of MS patient was investigated by western blot analysis. Expression of NUCB2/<em>nesfatin</em>-<em>1</em> was confirmed in the CSF of the MS patient by western blot analysis. NUCB2/<em>nesfatin</em>-<em>1</em> levels were significantly higher in the CSF of the MS patients. Among the measured cytokines, only IL-<em>1</em>β was lower in the CSF of the MS patients. We report for the first time increased NUCB2/<em>nesfatin</em>-<em>1</em> levels in the CSF of MS patients.

<strong class="sub-title"> Keywords: </strong> NUCB2/<em>nesfatin</em>-<em>1</em>; inflammation; multiple sclerosis.

<b>Background:</b> Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability, and loss of self-sufficiency. <b>Objective:</b> To establish an AD-like mice model, investigate the behavioral performance, and explore the potential mechanism. <b>Methods:</b> Streptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL/6 mice, and the behavioral performance was observed. The serum concentrations of insulin and <em>nesfatin</em>-<em>1</em> were measured by ELISA, and the activation of hippocampal microglia and astrocytes was assessed by immunohistochemistry. The protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the pre-frontal cortex (PFC) was detected via western blotting. <b>Results:</b> The STZ-microinjected model mice showed a slower bodyweight gain and higher serum concentration of insulin and <em>nesfatin</em>-<em>1</em>. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice, together with an increase abundance of Aβ_{<em>1</em>-42} and Tau in the hippocampus and PFC. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-β-catenin/β-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3β (ser9)/GSK-3β were reduced in the hippocampus. <b>Conclusion:</b> A bilateral hippocampal microinjection of STZ could induce not only AD-like behavioral performance in mice, but also adaptive changes of synaptic plasticity against neuroinflammatory and endocrinal injuries. The underlying mechanisms might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC.

<strong class="sub-title"> Keywords: </strong> Alzheimer disease; BDNF; NMDAR; <em>nesfatin</em>-<em>1</em> (NUCB2); streptozotocin.

<em>Nesfatin</em>-<em>1</em>, a satiety molecule processed from nucleobindin2 (NUCB2), is implicated in visceral hypersensitivity in rats and colocalized with 5-hydroxytryptamine (5-HT) in the dorsal raphe nucleus (DRN). Maternal separation (MS) in rats contributes to visceral hypersensitivity via elevated expression of 5-HT in the DRN. Intracerebroventricular injection of <em>nesfatin</em>-<em>1</em> activates DRN 5-HT neurons. In this study, A model of visceral hypersensitivity was developed by subjecting rats to MS. Colorectal distension was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR) scores and electromyogram (EMG) magnitude. MS rats exhibited higher AWR scores and EMG magnitude compared with controls. The numbers of <em>nesfatin</em>-<em>1</em>- and tryptophan hydroxylase (TPH, the rate-limiting enzyme for 5-HT synthesis)-positive cells in the DRN were significantly elevated accordingly. Visceral hypersensitivity was significantly alleviated in MS rats treated with intra-DRN administration of anti-<em>nesfatin</em>-<em>1</em>/NUCB2, accompanied by decreased expression of 5-HT and TPH in the DRN, compared with the vehicle-treated group. In contrast, intra-DRN administration of <em>nesfatin</em>-<em>1</em> into normal adult rats induced visceral hypersensitivity, which correlated with elevated expression of 5-HT and TPH in the DRN. In conclusion, <em>Nesfatin</em>-<em>1</em> has critical effects on visceral hypersensitivity; the underlying mechanisms might be related to the activation of DRN 5-HT neurons.

Homeostatic and hedonic pathways distinctly interact to control food intake. Dysregulations of circuitries controlling hedonic feeding may disrupt homeostatic mechanisms and lead to eating disorders. The anorexigenic peptides nucleobindin-2 (NUCB2)/<em>nesfatin</em>-<em>1</em> may be involved in the interaction of these pathways. The endogenous levels of this peptide are regulated by the feeding state, with reduced levels following fasting and normalized by refeeding. The fasting state is associated with biochemical and behavioral adaptations ultimately leading to enhanced sensitization of reward circuitries towards food reward. Although NUCB2/<em>nesfatin</em>-<em>1</em> is expressed in reward-related brain areas, its role in regulating motivation and preference for nutrients has not yet been investigated. We here report that both dopamine and GABA neurons express NUCB2/<em>nesfatin</em>-<em>1</em> in the VTA. Ex vivo electrophysiological recordings show that <em>nesfatin</em>-<em>1</em> hyperpolarizes dopamine, but not GABA, neurons of the VTA by inducing an outward potassium current. In vivo, central administration of <em>nesfatin</em>-<em>1</em> reduces motivation for food reward in a high-effort condition, sucrose intake and preference. We next adopted a 2-bottle choice procedure, whereby the reward value of sucrose was compared with that of a reference stimulus (sucralose + optogenetic stimulation of VTA dopamine neurons) and found that <em>nesfatin</em>-<em>1</em> fully abolishes the fasting-induced increase in the reward value of sucrose. These findings indicate that <em>nesfatin</em>-<em>1</em> reduces energy intake by negatively modulating dopaminergic neuron activity and, in turn, hedonic aspects of food intake. Since <em>nesfatin</em>-<em>1</em>´s actions are preserved in conditions of leptin resistance, the present findings render the NUCB2/<em>nesfatin</em>-<em>1</em> system an appealing target for the development of novel therapeutical treatments towards obesity.

Since NUCB2 was discovered, the information about NUCB2/<em>nesfatin</em>-<em>1</em> in appetite regulation in both mammals and teleost has been still limited. The present study aims to determine the effects of <em>nesfatin</em>-<em>1</em> on food intake and to explore the appetite mechanism in Siberian sturgeon. In this study, nucb2 cDNA sequence of <em>1</em>57<em>1</em> bp was obtained, and the mRNA expression of nucb2 was abundant in brain and liver. Levels of nucb2 were appreciably increased in brain after feeding <em>1</em> and 3 h, while significantly decreased within fasting <em>1</em>5 days. Except for fasting <em>1</em> day, the expression pattern of nucb2 in the liver was similar to the brain. Acute intraperitoneal (i.p.) injection of <em>nesfatin</em>-<em>1</em> inhibited the food intake during 0-<em>1</em> h in a dose-dependent manner and 50 or <em>1</em>00 ng/g BW <em>nesfatin</em>-<em>1</em> significantly decreased the cumulative food intake during 3 h. The daily food intake and cumulative food intake were remarkably reduced post chronic (7 days) i.p. injection. Moreover, chronic i.p. injection of <em>nesfatin</em>-<em>1</em> affected the expression of appetite factors including cart, apelin and pyy in the brain, stomach and liver with the consistent pattern of change, while the levels of cck, ucn3 and nucb2 in these have different patterns. This study demonstrates that <em>nesfatin</em>-<em>1</em> acts as a satiety factor in reducing the short-term and long-term food intake of Siberian sturgeon. Therefore, the data suggesting <em>nesfatin</em>-<em>1</em> inhibits the appetite through different signal pathways in the central and peripheral endocrine systems of Siberian sturgeon.

Kisspeptin (KP), known as a hypothalamic neuropeptide, plays a critical role in the regulation of not only reproduction but also food intake. The anorectic neuropeptides, <em>nesfatin</em>-<em>1</em> and oxytocin (OXT), are expressed in central nervous system, particulaly in various hypothalamic nuclei, and peripheral tissue. We examined the effects of the intracerebroventricular (icv) administration of KP-<em>1</em>0 on feeding and <em>nesfatin</em>-<em>1</em>-immunoreactive (ir) or OXT-ir neurons in the rat hypothalamus, using Fos double immunohistochemistry in male rats. Cumulative food intake was remarkably decreased 0.5-3 h after icv administration of KP-<em>1</em>0 (6.0 μg) compared to the vehicle treated and the KP-<em>1</em>0 (3.8 μg) treated group. The icv administration of KP-<em>1</em>0 significantly increased the number of <em>nesfatin</em>-<em>1</em>-ir neurons expressing Fos in the supraoptic nucleus (SON), paraventricular nucleus (PVN), arcuate nucleus (ARC), dorsal raphe nucleus, locus coeruleus, and nucleus tractus solitarius. The decreased food intake induced by KP-<em>1</em>0 was significantly attenuated by pretreatment with the icv administration of antisense RNA against nucleobindin-2. After icv administration of KP-<em>1</em>0, the percentages of OXT-ir neurons expressing FOS were remarkably higher in the SON and PVN than for vehicle treatment. The KP-<em>1</em>0-induced anorexia was partially abolished by pretreatment with OXT receptor antagonist (OXTR-A). The percentage of <em>nesfatin</em>-<em>1</em>-ir neurons expressing Fos-ir in the ARC was also decreased by OXTR-A pretreatment. These results indicate that central administration of KP-<em>1</em>0 activates <em>nesfatin</em>-<em>1</em>- and OXT neurons, and may play an important role in the suppression of feeding in male rats.

This study aimed to investigate the potential effects of acute soccer matches performed in morning, afternoon and at night on both <em>nesfatin</em>-<em>1</em> and irisin levels in trained subjects. Total of 20 male subjects performed in soccer matches at three different times of day: morning, afternoon, and night. Pre- and post-match venous blood samples were taken, and levels of both <em>nesfatin</em>-<em>1</em> and irisin were analysed using the enzyme-linked immunosorbent assay (ELISA). Following all matches, the subjects' irisin levels increased significantly in all subjects (p < 0.000<em>1</em>). <em>Nesfatin</em>-<em>1</em> levels were also increased after the matches; however, the increase was statistically significant for morning (P=0.0<em>1</em>) and night-time (p=0.009). The subjects' <em>nesfatin</em>-<em>1</em> levels did not increase in all subjects and decrease of <em>nesfatin</em>-<em>1</em> levels observed in some subjects after matches. This study finds that soccer matches performed different workout times have strong stimulatory effects on irisin levels in all subjects but <em>nesfatin</em>-<em>1</em> response varied among the subjects and it did not change significantly in afternoon match.

The last few decades have seen a major increase in the number of neurotransmitters and neuropeptides recognized as playing a role in brain stem neurocircuits, including those involved in homeostatic functions such as stress responsiveness, gastrointestinal motility, feeding, and/or arousal/wakefulness. This minireview will focus on the known physiological role of three of these novel neuropeptides, i.e., apelin, <em>nesfatin</em>-<em>1</em>, and neuropeptide-S, with a special emphasis on their hypothetical roles in vagal signaling related to gastrointestinal motor functions.