<em>Nesfatin</em>/nucleobindin-2 (nesf/NUCB2), a precursor of the anorexigenic protein <em>nesfatin</em>-<em>1</em>, is selectively expressed in the hypothalamic nuclei, which are central to the regulation of the autonomic nervous system. The present study sought to investigate the involvement of nesf/NUCB2 in the regulation of blood pressure and ingestive behavior, by using nesf/NUCB2-transgenic (Tg) mice. Blood pressure and heart rates were measured under conscious and unconscious conditions. Twenty-four-hour water intake and urine volume of male nesf/NUCB2-Tg mice and their littermates in metabolic cages were measured. After killing, kidney weight was measured and the mRNA expression of epithelial sodium channel (ENaC)-α and ENaC-γ was measured in the hypothalamus and kidney with real-time PCR. Systolic, diastolic and mean blood pressure were significantly higher in nesf/NUCB2-Tg mice, but pulse rate was not affected in conscious mice. In contrast, isoflurane anesthesia prevented an increase in blood pressure in the nesf/NUCB2-Tg mice. Twenty-four-hour water intake and urine volume were significantly higher in the nesf/NUCB2-Tg mice than in their non-Tg littermates. Urine sodium concentration was significantly lower in the nesf/NUCB2-Tg mice, although the serum sodium concentration and urine sodium excretion were not different between the genotypes. Kidney weight was significantly higher in the nesf/NUCB2-Tg mice than their non-Tg littermates, although there were no clear differences in the kidney histological findings between genotypes. The mRNA expression of ENaC-γ, but not ENaC-α, was decreased in the hypothalami of nesf/NUCB2-Tg mice. Our data suggested that Nesf/NUCB2 is involved in the regulation of blood pressure in the brain.

<em>Nesfatin</em>-<em>1</em>, a peptide whose receptor is yet to be identified, has been shown to be involved in the modulation of feeding, stress, and metabolic responses. Recently, increasing evidence has supported a modulatory role of <em>nesfatin</em>-<em>1</em> in cardiovascular activity. We have previously reported that <em>nesfatin</em>-<em>1</em> causes an increase in blood pressure in normotensive and hypotensive rats by increasing plasma catecholamine, vasopressin, and renin levels. Recent reports suggest that <em>nesfatin</em>-<em>1</em> may activate the central cholinergic system. However, there is no evidence showing an interaction between central <em>nesfatin</em>-<em>1</em> and the cholinergic system. Therefore, this study aimed to determine whether the central cholinergic system may have a functional role in the <em>nesfatin</em>-<em>1</em>-induced cardiovascular effect observed in normotensive rats. Intracerebroventricular injection of <em>nesfatin</em>-<em>1</em> caused short-term increases in mean arterial pressure and heart rate responses including bradycardic/tachycardic phases in normotensive animals. Central injection of <em>nesfatin</em>-<em>1</em> increased the acetylcholine and choline levels in the posterior hypothalamus, as shown in microdialysis studies. Central pretreatment with the cholinergic muscarinic receptor antagonist atropine and/or nicotinic receptor antagonist mecamylamine blocked <em>nesfatin</em>-<em>1</em>-induced cardiovascular effects. In conclusion, the results show that centrally administered <em>nesfatin</em>-<em>1</em> produces a pressor effect on blood pressure and heart rate responses including bradycardic/tachycardic phases in normotensive rats. Moreover, according to our findings, the central cholinergic system can modulate <em>nesfatin</em>-<em>1</em>-evoked cardiovascular activity.

<AbstractText>In this review, authors have selected from literature the most recent and suggestive studies on therapy of nonalcoholic fatty liver disease (NAFLD). The selected interventions regulate the action of gastrointestinal peptides, such as gastric inhibitory polypeptide (GIP), <em>nesfatin</em>, peptide YY, cholecystokinin, and glucagon-like peptide <em>1</em> (GLP-<em>1</em>). These hormones have been found frequently modified in obesity and/or type 2 diabetes mellitus, morbidities mostly associated with NAFLD. This disease has a very high prevalence worldwide and could evolve in a more severe form, that is, nonalcoholic steatohepatitis, characterized by inflammation and fibrosis. The findings shown by this article describe the metabolic effects of new drugs, mainly but not only, as well of some old substances.</AbstractText><AbstractText>Recent approaches, in animal models or in humans, use synthetic GLP-<em>1</em> receptor agonists, a centrally administered antibody neutralizing GIP receptor, curcumin, compound being active on <em>nesfatin</em>, resveratrol (antiinflammatory agent), and Ginseg, both of them acting on <em>nesfatin</em>, a cholecystokinin receptor analogue, and finally coffee functioning on YY peptide.</AbstractText><AbstractText>The implications of the presented findings, if they are confirmed in larger clinical trials, likely open the door to future application in clinical practice. In fact, nowadays, patients have only diet and article (incl abstract and keywords) exercise as well accepted recommendations. Thus, there are unmet needs to find substances that could really improve the progression of nonalcoholic steatohepatitis toward liver cirrhosis and hepatocellular carcinoma.</AbstractText>

There is growing evidence that vagus nerve stimulation (VNS) exerts a suppressive effect on both short- and long-term feeding in animal models. We previously showed that VNS with high-frequency (<em>1</em>0 Hz) electrical impulses decreased food intake and body weight in rats. In the present study, we investigated the effect of VNS with a low frequency (<em>1</em> Hz) on the serum lipid concentrations, feeding behavior and appetite in rats fed a high-fat diet. The levels of appetite-regulating peptides were also assessed. Adult male Wistar rats were subcutaneously implanted with a microstimulator (MS) and fed a high-fat diet throughout the entire study period (42 days). The left vagus nerve was stimulated subdiaphragmatically by rectangular electrical pulses (<em>1</em>0 ms, 200 mV, <em>1</em> Hz, <em>1</em>2 h a day) generated by the MS. The daily food intake and body weight were measured each morning. At the end of the experiments, the serum glucose, cholesterol, triglycerides, low-density lipoproteins, high-density lipoproteins, ghrelin, leptin and <em>nesfatin</em>-<em>1</em> concentrations were measured. The adipose tissue content was evaluated by the assessment of the weight of the epididymal fat pads. Chronic VNS significantly decreased food intake, body weight gain and epididymal fat pad weight. VNS also lowered the total plasma cholesterol concentrations and triglyceride levels. Finally, the serum concentrations of <em>nesfatin</em>-<em>1</em> were elevated, leptin levels were decreased, and ghrelin levels remained unchanged after VNS. The study demonstrates that chronic electrical VNS exerts anorexigenic effects, lowering the blood concentration of lipids. Increased <em>nesfatin</em>-<em>1</em> levels may contribute to these effects.

The stomach is responsible for the processing of nutrients as well as for the secretion of various hormones which are involved in many activities throughout the gastrointestinal tract. Experimental adult male Wistar rats (<i>n</i> = 6) underwent a modified gastrectomy, while control rats (<i>n</i> = 6) were sham-operated. After six weeks, changes in small intestine (including histomorphometrical parameters of the enteric nervous plexuses) and liver morphology, immunolocalization of leptin, ghrelin and <em>nesfatin</em>-<em>1</em> as well as proteins forming adherens and tight junctions (E-cadherin, zonula occludens-<em>1</em>, occludin, marvelD3) in intestinal mucosa were evaluated. A number of effects on small intestine morphology, enteric nervous system ganglia, hormones and proteins expression were found, showing intestinal enteroplasticity and neuroplasticity associated with changes in gastrointestinal tract condition. The functional changes in intestinal mucosa and the enteric nervous system could be responsible for the altered intestinal barrier and hormonal responses following gastrectomy. The results suggest that more complicated regulatory mechanisms than that of compensatory mucosal hypertrophy alone are involved.

Keywords: enteroendocrine cells; gastrectomy; gut hormones; small intestine; stomach; tight junction.

The purpose of this study was to determine the levels of leptin, ghrelin, and <em>nesfatin</em>-<em>1</em> to elucidate the causes of poor appetite and growth retardation in patients receiving methylphenidate therapy for attention deficit hyperactivity disorder. The study was performed on 89 male subjects; 48 patients and 4<em>1</em> healthy controls, aged 7-<em>1</em>4 years. Following treatment, patients' leptin levels increased and ghrelin levels decreased while no significant change was found in <em>nesfatin</em>-<em>1</em> levels. Of the 48 patients, 34 developed lack of appetite. In patients who developed lack of appetite, body weight SDS, body mass index (BMI), and BMI SDS were statistically significantly reduced; moreover, height SDS was reduced, though not to a statistically significant extent. This study attempted to elucidate the mechanisms that mediate the association between methylphenidate and appetite and growth, for which no studies have yet to be published.

Growth hormone (GH), mainly produced from the pituitary somatotrophs is a key endocrine regulator of somatic growth. GH, a pleiotropic hormone, is also involved in regulating vital processes, including nutrition, reproduction, physical activity, neuroprotection, immunity, and osmotic pressure in vertebrates. The dysregulation of the pituitary GH and hepatic insulin-like growth factors (IGFs) affects many cellular processes associated with growth promotion, including protein synthesis, cell proliferation and metabolism, leading to growth disorders. The metabolic and growth effects of GH have interesting applications in different fields, including the livestock industry and aquaculture. The latest discoveries on new regulators of pituitary GH synthesis and secretion deserve our attention. These novel regulators include the stimulators adropin, klotho, and the fibroblast growth factors, as well as the inhibitors, nucleobindin-encoded peptides (<em>nesfatin</em>-<em>1</em> and <em>nesfatin</em>-<em>1</em>-like peptide) and irisin. This review aims for a comparative analysis of our current understanding of the endocrine regulation of GH from the pituitary of vertebrates. In addition, we will consider useful pharmacological molecules (i.e. stimulators and inhibitors of the GH signaling pathways) that are important in studying GH and somatotroph biology. The main goal of this review is to provide an overview and update on GH regulators in 2020. While an extensive review of each of the GH regulators and an in-depth analysis of specifics are beyond its scope, we have compiled information on the main endogenous and pharmacological regulators to facilitate an easy access. Overall, this review aims to serve as a resource on GH endocrinology for a beginner to intermediate level knowledge seeker on this topic.

Keywords: cell signaling; growth hormone; hormones; neuropeptides; pituitary; somatotrophs cells; vertebrates.

<strong class="sub-title"> Objective: </strong> Recent studies have investigated the circulating adipocyte fatty acid binding protein (FABP4), <em>nesfatin</em>-<em>1</em>, and osteocalcin (OC) concentrations in women diagnosed with gestational diabetes mellitus (GDM), but the findings prove to be conflicting. The objective of this research was to systematically assess the relationship of circulating levels of above adipokines with GDM.

<strong class="sub-title"> Methods: </strong> Pubmed, Embase, Web of Science, Cochrane library, OVID, and Scopus were performed to locate articles published up to January 3<em>1</em>, 2020. Pooled standard mean differences (SMDs) with 95% confidence intervals (CIs), and 95% predictive intervals (PIs) were calculated by random-effects models to compare levels of adipokines between GDM cases and control groups. Cumulative and single-arm meta-analyses were also performed.

<strong class="sub-title"> Results: </strong> Thirty-one studies comprising 4590 participants were included. No significant differences were found between GDM women and healthy controls in circulating <em>nesfatin</em>-<em>1</em> levels (4.56 vs. 5.02 ng/mL; SMD = - 0.<em>1</em><em>1</em>, 95% CI -0.6<em>1</em>-0.38, 95% PI -<em>1</em>.63-<em>1</em>.4<em>1</em>). Nevertheless, circulating FABP4 and OC levels observed in GDM women outnumbered normal controls (FABP4, 23.68 vs. <em>1</em>6.04 ng/mL; SMD = 2.99, 95% CI 2.28-3.69, 95% PI 0.28-5.7<em>1</em>; OC, 52.34 vs. 5<em>1</em>.04 ng/mL; SMD = 0.68, 95% CI 0.3<em>1</em>-<em>1</em>.05, 95% PI -0.48-<em>1</em>.84). The cumulative meta-analysis showed that the SMDs of circulating FABP4 and OC levels had stabilized between the two groups.

<strong class="sub-title"> Conclusions: </strong> Elevated circulating FABP4 and OC levels were observed in GDM women, but <em>nesfatin</em>-<em>1</em> levels did not change, the PI of OC crossed the no-effect threshold. The results suggested that FABP4 is more suitable as a biomarker of GDM compared to OC in a future study, which is useful in identifying pregnant women who are likely to develop GDM and providing prompt management strategies.

<strong class="sub-title"> Keywords: </strong> Adipokines; Adipose tissue; Biomarker; FABP4; Gestational diabetes mellitus; Nesfatin-<em>1</em>; Osteocalcin.

The last two decades of research has established histamine (HA) as a neurotransmitter. Since H3R antagonists are known to modulate several neurotransmitters besides HA, H3R antagonists have shown potential for the treatment of different central nervous system disorders, including depression. However, molecular mechanisms underlying the beneficial effects of H3R antagonism in depression are not clear, yet. In the present study, we investigated the antidepressant potential of ciproxifan, a selective H3R antagonist, in chronic unpredictable stress (CUS) model of depression in C57BL/6 J mice. We observed that chronic treatment of CUS mice with ciproxifan (3 mg/kg i.p.; for three weeks) alleviates depression-like symptoms such as helplessness measured by forced swim and tail suspension test (FST and TST), anhedonia measured by sucrose preference test (SPT) and social deficit measured in social behavior test. Chronic ciproxifan treatment restored CUS induced BDNF expression in the prefrontal cortex (PFC) and hippocampus. We also observed that ciproxifan modulates CUS induced NUCB2/<em>nesfatin</em>-<em>1</em> and CRH expression in the hypothalamus and plasma corticosterone. We also determined the direct effect of HA on BDNF expression in neurons by western blotting and immunocytochemistry, and found that HA significantly induced BDNF expression, which was blocked by the H4R selective antagonist, but not by other HA receptor selective antagonists. Furthermore, ciproxifan significantly modulated NMDA glutamate receptor subunits NR2B and NR2A. Thus, these results suggest that increased HA signaling in the brain produces antidepressant-like effects in mice and modulates BDNF expression and HPA-axis.

OBJECTIVE

The goal of this study was to compare levels of acyl and des-acyl ghrelin, obestatin, <em>nesfatin</em>-<em>1</em> and leptin in healthy gravidas to hyperemesis gravidarum (HG) patients.

METHODS

Twenty pregnant women with HG and twenty healthy pregnant women all of similar ages, BMI and all at similar pregnancy development comprised the study cohort. Fasting serum samples were obtained and measured for acyl and des-acyl ghrelin, leptin, obestatin and <em>nesfatin</em>-<em>1</em>.

RESULTS

Nesfatin-<em>1</em> concentrations in the HG group were higher compared to the control group whereas; leptin concentrations during pregnancy were lower in the HG group as compared to the control group. The two groups did not differ with regard to acyl and des-acyl ghrelin and obestatin.

CONCLUSIONS

This pilot study suggests a possible role of leptin and <em>nesfatin</em>-<em>1</em>, which might be involved in the pathology of the disease.

The gastric X/A-like cell was long thought to be restricted to the production of acyl ghrelin. However, the subsequent years witnessed the discovery of other peptide products derived from this cell, namely desacyl ghrelin, obestatin and <em>nesfatin</em>-<em>1</em>. While the role of obestatin remains highly questionable and is very critically discussed in the literature, besides acyl ghrelin also desacyl ghrelin and <em>nesfatin</em>-<em>1</em> have been implicated in the regulation of food intake. As observed for several other peptide hormones before, ghrelin and <em>nesfatin</em>-<em>1</em> are not restricted to one function but rather exert pleiotropic actions including effects on gastrointestinal motility, thermogenesis, lipid and glucose homeostasis, stress mediation, cardiovascular as well as reproductive functions. These often counter-regulatory effects of <em>nesfatin</em>-<em>1</em> and ghrelin will be discussed in the present review.

OBJECTIVE

To evaluate <em>Nesfatin</em>-<em>1</em> levels in patients with and without intrauterine growth restriction and to analyze the correlation between <em>Nesfatin</em>-<em>1</em> levels and fetal birth weights.

METHODS

This study comprised a total of 8<em>1</em> cases; 4<em>1</em> patients with IUGR and 40 healthy cases. Demographic data, pregnancy weeks, fetal birth weights and <em>Nesfatin</em>-<em>1</em> levels were all recorded. The <em>Nesfatin</em>-<em>1</em> levels were compared between the groups and the correlation between fetal birth weights and <em>Nesfatin</em>-<em>1</em> levels was analyzed.

RESULTS

No statistical significant difference was determined between the groups in terms of demographic data (p>> 0.05). Average birth weights were determined as 3420 ± 259 g in the control group and 204<em>1</em> ± 350 g in the IUGR group, which was found to be statistically unequal (p = 0.00<em>1</em>). The average <em>Nesfatin</em> levels in the control group were 0.069 ± 0.0<em>1</em><em>1</em> and 0.094 ± 0.042 in the IUGR group. This difference was statistically unequal (p = 0.00<em>1</em>). While no correlation was determined between <em>Nesfatin</em> levels and fetal birthweights in the control group (r = -0.034 versus p = 0.836), in the IUGR group and when all the cases were evaluated together, a statistically moderately significant negative correlation was determined (r = -0.469, p = 0.002 and r = -0.25<em>1</em>, p = 0.024, respectively).

CONCLUSIONS

Although intrauterine growth is a multifactorial process, the effect mechanism has not yet been established. The results of this study offer some indications about the possible effect of <em>Nesfatin</em> <em>1</em> on fetal growth.

BACKGROUND

<em>Nesfatin</em>-<em>1</em> is implicated to possess an anti-inflammatory effect.

OBJECTIVE

The aim of our study is to investigate whether abnormal serum levels of nesfatin-<em>1</em> are associated with the presence and severity of preeclampsia.

METHODS

A total of <em>1</em>20 women with preeclampsia and 92 women with uncomplicated pregnancies were enrolled in this study.

RESULTS

Women with preeclampsia showed significantly reduced levels of serum nesfatin-<em>1</em> levels than women with uncomplicated pregnancies. Serum nesfatin-<em>1</em> levels were significantly decreased in women with severe preeclampsia compared with women with mild preeclampsia.

CONCLUSIONS

Decreased serum nesfatin-<em>1</em> levels are associated with the presence and severity of preeclampsia.

The placenta is the physiological bridge between mother and fetus and has life-sustaining functions during pregnancy, including metabolic regulation, fetal protection and hormone secretion. Nucleobindin-2 (NUCB2) is a calcium- and DNA-binding protein and precursor of <em>nesfatin</em>-<em>1</em>, a signalling peptide with multiple functions, including regulation of energy homeostasis and glucose transport. These are also key functions of the placenta, yet NUCB2/<em>nesfatin</em>-<em>1</em> expression has never been comprehensively studied in this organ. In the present study, mouse placental samples from Embryonic Day (E) 7.5 to E<em>1</em>7.5 and human chorionic villi from the first and second trimester, as well as term pregnancy, were analysed for NUCB2/<em>nesfatin</em>-<em>1</em> expression by immunohistochemistry with an antiserum that recognised both NUCB2 and <em>nesfatin</em>-<em>1</em>. From E7.5 to E9.5, NUCB2/<em>nesfatin</em>-<em>1</em> was expressed in the ectoplacental cone, then parietal trophoblast giant cells and early spongiotrophoblast. At E<em>1</em>0.5-<em>1</em>2.5, NUCB2/<em>nesfatin</em>-<em>1</em> expression became detectable in the developing labyrinth. From E<em>1</em>2.5 and onwards, NUCB2/<em>nesfatin</em>-<em>1</em> was expressed in the glycogen trophoblast cells, as well as highly expressed in syncytiotrophoblast, sinusoidal trophoblast giant cells and fetal capillary endothelial cells of the labyrinth. In all trimesters of human pregnancy, NUCB2/<em>nesfatin</em>-<em>1</em> was highly expressed in syncytiotrophoblast. In addition, there was a significant increase in NUCB2 expression in human primary trophoblast cells induced to syncytialise. Thus, the haemochorial mammalian placenta is a novel source of NUCB2/<em>nesfatin</em>-<em>1</em> and likely a site of its action, with potential roles in glucose homeostasis and/or nutrient sensing.

In a search for new appetite-controlling signals, the peptide <em>nesfatin</em>-<em>1</em>, expressed in the brain and peripheral tissues of rodents and humans has been reported to regulate feeding by reducing food intake. Recently it has also been reported that <em>nesfatin</em>-<em>1</em> might be involved in regulating the reproductive axis in fishes and mammals, but its expression and physiological role if any, is not yet known in birds. In the present study, localization and expression of <em>nesfatin</em>-<em>1</em> was observed in the testis, ovary and shell gland of poultry species Japanese quail, Coturnix coturnix japonica. Our earlier studies have reported that serotonin precursor 5-HTP and dopamine precursor l-DOPA given 8h apart induces gonadal suppression, when given <em>1</em>2h apart leads to gonadal stimulation while other relationships were found ineffective. In the present study intense ir-<em>nesfatin</em>-<em>1</em> was observed in the regressed ovary (stromal cells) and shell gland (endometrium) of 8-h Japanese quail while in <em>1</em>2-h quail, weak and scarce immunostaining for <em>nesfatin</em>-<em>1</em> was detected in the hyperactive ovary and shell gland compared to control. These findings led us to conclude that, an inverse relationship exists between ovarian activity (both in the control and simulated conditions) and <em>nesfatin</em>-<em>1</em> expression. Present avian study, first of its kind, also suggests the role of <em>nesfatin</em>-<em>1</em> in reproductive regulation possibly via appetite control and energy balance in female Japanese quail and needs to be investigated further in relation to food intake.

<em>Nesfatin</em>-<em>1</em>/NUCB2 is known to take part in the control of the appetite and energy metabolism. Recently, many reports have shown <em>nesfatin</em>-<em>1</em>/NUCB2 expression and function in various organs. We previously demonstrated that <em>nesfatin</em>-<em>1</em>/NUCB2 expression level is higher in the pituitary gland compared to other organs and its expression is regulated by <em>1</em>7β-estradiol and progesterone secreted from the ovary. However, currently no data exist on the expression of <em>nesfatin</em>-<em>1</em>/NUCB2 and its regulation mechanism in the pituitary of male mouse. Therefore, we examined whether <em>nesfatin</em>-<em>1</em>/NUCB2 is expressed in the male mouse pituitary and if its expression is regulated by testosterone. As a result of PCR and western blotting, we found that a large amount of <em>nesfatin</em>-<em>1</em>/NUCB2 was expressed in the pituitary and hypothalamus. The NUCB2 mRNA expression level in the pituitary was decreased after castration, but not in the hypothalamus. In addition, its mRNA expression level in the pituitary was increased after testosterone treatment in the castrated mice, whereas, the expression level in the hypothalamus was significantly decreased after the treatment with testosterone. The in vitro experiment to elucidate the direct effect of testosterone on NUCB2 mRNA expression showed that NUCB2 mRNA expression was significantly decreased with testosterone in cultured hypothalamus tissue, but increased with testosterone in cultured pituitary gland. The present study demonstrated that <em>nesfatin</em>-<em>1</em>/NUCB2 was highly expressed in the male mouse pituitary and was regulated by testosterone. This data suggests that reproductive-endocrine regulation through hypothalamus-pituitary-testis axis may contribute to NUCB2 mRNA expression in the mouse hypothalamus and pituitary gland.

The study was aimed to address the role of <em>nesfatin</em>-<em>1</em> on the sexual maturation of testis during the pubertal transition. The immunostaining of testis suggested <em>nesfatin</em>-<em>1</em> is expressed in Leydig cells with pubertal maturation. The pre-pubertal mice for in vivo study were randomly divided in three groups; (a) control-saline (b) treated with low (0.25 nM) dose of <em>nesfatin</em>-<em>1</em>/gbw/day and (c) treated with high (<em>1</em>.25 nM) dose <em>nesfatin</em>-<em>1</em>/gbw/day. Histological analysis showed that <em>nesfatin</em>-<em>1</em> loaded mice showed facilitated maturation of testis. Western blot analysis on various protein expressions upon injection of <em>nesfatin</em>-<em>1</em> into pre-pubertal mice suggested that expressions of proteins involving steroid hormone production, spermatogenic markers (PCNA, Bcl2, AR), glucose uptake-related proteins (GLUT8 and insulin receptor) and GnRH-R and GPR-54 proteins were facilitated. Both of lactose dehydrogenase activity and lactate levels were increased. The treatment with <em>nesfatin</em>-<em>1</em> also reduced oxidative stress, which further facilitates testicular functions during puberty. The treatment of <em>nesfatin</em>-<em>1</em> on cultured testis also supports in vivo findings as evident by the increased testosterone production and StAR protein expression as well as increased glucose and lactate production. In sum, our data report for the first time the accelerative role of <em>nesfatin</em>-<em>1</em> on spermatogenesis and steroidogenesis of pre-pubertal male mice by directly acting on the testis coupled with the advancement of puberty.

<AbstractText>The present study was aimed to demonstrate the recuperative effect of <em>nesfatin</em>-<em>1</em> on testicular dysfunction in the high-fat diet (HFD)/streptozotocin (STZ)-induced type-2 diabetes mellitus (T2DM) mice.</AbstractText><AbstractText>Three experimental groups were formed: (<em>1</em>) vehicle control (VC), (2) T2DM mice, (3) T2DM + nesf-<em>1</em>. The mice with blood glucose level higher than 300 mg/dL following HFD and a single dose of STZ were used for the experiment. The T2DM mice showed increases in body mass, blood glucose and insulin levels, reductions in spermatogenesis and steroidogenesis, production of antioxidative enzymes, and disturbed lipid profile. These alterations were all ameliorated by administration of <em>nesfatin</em>-<em>1</em> at 20 μg/Kg BW for <em>1</em>5 days. <em>Nesfatin</em>-<em>1</em> treatment also increased the production of testosterone (T), improved insulin sensitivity, and effectively ameliorated the testicular aberrations, and increased spermatogenesis and steroidogenesis. In addition, <em>nesfatin</em>-<em>1</em> treatment upregulated the PCNA and Bcl2 expression and inhibited the caspase-3 and prohibitin expression in T2DM mice. <em>Nesfatin</em>-<em>1</em> increased insulin receptor (IR) and GLUT8 expressions, and lactate production, the changes that further substantiate the increase of energy influx to the testis.</AbstractText><AbstractText>Altogether, the results suggest the ameliorative effect of <em>nesfatin</em>-<em>1</em> against T2DM-associated testicular dysfunctions and improved insulin sensitivity along with promoting T production and fertility in T2DM mice.</AbstractText>

Neuroendocrine regulation of metabolism and reproduction are tightly interlinked. <em>Nesfatin</em>-<em>1</em> is an 82 amino acid metabolic peptide derived from nucleobindin-2 (NUCB2). NUCB2 mRNA and protein significantly increase in the hypothalamus of rats during puberty-to-adult transition. Administration of <em>nesfatin</em>-<em>1</em> modulates circulating LH and testosterone in male rats. However, whether <em>nesfatin</em>-<em>1</em> acts directly on neurons and gonadotropes remain unknown. In addition, whether reproductive hormones of the hypothalamo-pituitary gonadal axis modulate NUCB2/<em>nesfatin</em>-<em>1</em> is unclear. To address these, we employed murine hypothalamic (GT<em>1</em>-7) and pituitary (LβT2) cells in vitro. Nucb2 expression, and NUCB2/<em>nesfatin</em>-<em>1</em> immunoreactivity were observed in both GT<em>1</em>-7 and LβT2 cells, and in the hypothalamus of mice. <em>Nesfatin</em>-<em>1</em> co-localized GnRH in GT<em>1</em>-7 cells, and in the hypothalamic perikarya of mice. Cells were treated with kisspeptin, GnRH, and estradiol and testosterone, as well as <em>nesfatin</em>-<em>1</em> for 2, 6 or 24 hours. Synthetic <em>nesfatin</em>-<em>1</em> increased Kiss<em>1</em>r and Gnrh expression in GT<em>1</em>-7 cells and Lhβ in LβT2. <em>Nesfatin</em>-<em>1</em> increased GnRH and LHβ protein expression in GT<em>1</em>-7 and LβT2 at 6-hour post incubation respectively. Both NUCB2 mRNA and protein were increased in GT<em>1</em>-7 cells treated with kisspeptin. Testosterone increased NUCB2 mRNA and protein expression in GT<em>1</em>-7 and LβT2. <em>1</em>7β-estradiol increased NUCB2 mRNA and protein expression in LβT2. <em>Nesfatin</em>-<em>1</em> acts directly on hypothalamic neurons and gonadotropes to elicit a generally positive influence on the endocrine milieu regulating reproduction in mice. Reproductive hormones, in turn, modulate brain and pituitary NUCB2/<em>nesfatin</em>-<em>1</em>. In conclusion, we provide additional information to designate <em>nesfatin</em>-<em>1</em> as a novel, additional factor that helps reproductive success.

<AbstractText>This case-control study was conducted to investigate the relationship between serum <em>nesfatin</em>-<em>1</em> levels and nutritional status and blood parameters in patients diagnosed with metabolic syndrome.</AbstractText><AbstractText>Thirty patients (case) diagnosed with metabolic syndrome according to National Cholesterol Education Program-Adult Treatment Panel III criteria were included. Thirty healthy subjects (control) matched with patients with metabolic syndrome in terms of age, gender and body mass index were included. Three-day food consumption records were obtained. Anthropometric indices were measured and body composition was determined by bioelectrical impedance method. Biochemical parameters and serum <em>nesfatin</em>-<em>1</em> levels were measured after 8 hours of fasting.</AbstractText><AbstractText>Serum <em>nesfatin</em>-<em>1</em> levels were 0.245±0.272 ng/mL in the case group and 0.528±0.987 ng/mL in the control group (p>0.05). There was a positive significant correlation between serum <em>nesfatin</em>-<em>1</em> levels and body weight, waist and hip circumferences in the case group (p<0.05). Each unit increase in hip circumference measurement affects the levels of <em>nesfatin</em> by 0.0<em>1</em>4 times. In the control group, there was a positive significant correlation between body weight and serum <em>nesfatin</em>-<em>1</em> levels (p<0.05). A significant correlation was detected between HbA<em>1</em>c and serum <em>nesfatin</em>-<em>1</em> levels in the case group (p<0.05). A significant relationship was detected between dietary fibre intake and the serum <em>nesfatin</em>-<em>1</em> levels in the case group (p<0.05).</AbstractText><AbstractText>Anthropometric indices and blood parameters were correlated with serum <em>nesfatin</em>-<em>1</em> levels in patients with metabolic syndrome. More clinical trials may be performed to establish the relationship between serum <em>nesfatin</em>-<em>1</em> levels and nutritional status.</AbstractText>

Nucleobindins (NUCBs) are DNA and calcium binding, secreted proteins with various signaling functions. Two NUCBs, nucleobindin-<em>1</em> (NUCB<em>1</em>) and nucleobindin-2 (NUCB2), were discovered during the <em>1</em>990s. These two peptides are shown to have diverse functions, including the regulation of inflammation and bone formation, among others. In 2006, Oh-I and colleagues discovered that three peptides encoded within the NUCB2 could be processed by prohormone convertases. These peptides were named <em>nesfatin</em>-<em>1</em>, 2 and 3, mainly due to the satiety and fat influencing properties of <em>nesfatin</em>-<em>1</em>. However, it was found that <em>nesfatin</em>-2 and -3 have no such effects. <em>Nesfatin</em>-<em>1</em>, especially its mid-segment, is very highly conserved across vertebrates. Although the receptor(s) that mediate <em>nesfatin</em>-<em>1</em> effects are currently unknown, it is now considered an endogenous peptide with multiple functions, affecting central and peripheral tissues to regulate metabolism, reproduction, endocrine and other functions. We recently identified a <em>nesfatin</em>-<em>1</em>-like peptide (NLP) encoded within the NUCB<em>1</em>. Like <em>nesfatin</em>-<em>1</em>, NLP suppressed feed intake in mice and fish, and stimulated insulin secretion from pancreatic beta cells. There is considerable evidence available to indicate that nucleobindins and its encoded peptides are multifunctional regulators of cell biology and whole animal physiology. This review aims to briefly discuss the structure, distribution, functions and mechanism of action nucleobindins and encoded peptides.

<em>Nesfatin</em>-<em>1</em> is a novel peptide with anorexigenic and anti-hyperglycemic properties. According to previous studies, this multi-functional peptide protects dopaminergic cells against neurotoxicity via anti-apoptotic effects. In addition, <em>Nesfatin</em>-<em>1</em> protects myocardial tissue after myocardial infarction via anti-inflammatory and anti-apoptotic mechanisms. In this study, we investigated the neuroprotective effects of <em>nesfatin</em>-<em>1</em> against cerebral ischemia reperfusion injury in the CA<em>1</em> area of hippocampus in rats. 56 male Wistar rats (240-270 g) were randomly selected and allocated into four groups: (<em>1</em>) sham, (2) <em>nesfatin</em>-<em>1</em>, (3) ischemia/reperfusion, (4) ischemia/reperfusion+<em>nesfatin</em>-<em>1</em>. Cerebral ischemia induced by the occlusion of the common carotid arteries for 20 min was followed by reperfusion. Saline as a vehicle and <em>nesfatin</em>-<em>1</em> (20 μg/kg) were injected intraperitoneally (IP) at the start of cerebral reperfusion. Apoptotic and necrotic cell death was detected by TUNEL and Nissl staining. Malondialdehyde (MDA) and antioxidant enzymes (GSH and SOD) levels were measured by the ELISA method. The results showed that cerebral ischemia increased the apoptotic and necrotic cell death in the CA<em>1</em> area of hippocampus, while, treatment with <em>nesfatin</em>-<em>1</em>significantly reduced apoptotic and necrotic cell death. Moreover, the MDA levels of the hippocampus in ischemic rats were higher, whereas in <em>nesfatin</em>-<em>1</em>-treated rats the MDA levels were decreased. Furthermore, the SOD and GSH levels in the ischemic rats were decreased, whilst in ischemic rats treated with <em>nesfatin</em>-<em>1</em>, the SOD and GSH levels were increased. This study for the first time found that <em>nesfatin</em>-<em>1</em> treatment improves CA<em>1</em> hippocampus injuries after cerebral ischemia through preventing neuronal cell death and enhancement of antioxidant defenses.

The process of spontaneous abortion involves a complex mechanism with various cytokines, growth factors, and hormones during the pregnancy. However, the mechanism underlying spontaneous abortion by pro- and anti-inflammatory cytokines in the serum during the pregnancy is not fully understood. Therefore, the purpose of this study was to examine the relationship between the serum levels of pro- and anti-inflammatory cytokines and spontaneous abortion using the CBA/j × DBA/2 mouse model. Serum levels of pro-inflammatory cytokines, such as IFN-γ, IL-<em>1</em>α and TNF-α were not increased in abortion model mice, but anti-inflammatory cytokines, such as IL-4, IL-<em>1</em>3 and IL-<em>1</em>ra were decreased compared to normal pregnant mice. In addition, serum levels of chemokine, such as SDF-<em>1</em>, G-CSF, M-CSF, IL-<em>1</em>6, KC and MCP-<em>1</em> were decreased in abortion model mice compared to normal pregnant mice. However, the expression levels of <em>nesfatin</em>-<em>1</em>/NUCB2 mRNA and protein in the uteri of implantation sites were significantly higher in abortion model mice than normal pregnant mice. These results suggest that uterine <em>nesfatin</em>-<em>1</em>/NUCB2 expression may be down-regulated by inflammatory cytokines and chemokines in the serum of pregnant mice. Moreover, this study suggests the possibility that <em>nesfatin</em>-<em>1</em>/NUCB2 expressed in the implantation sites may be associated with the maintenance of pregnancy.