<em>Nesfatin</em>-<em>1</em> acts on the hypothalamus and regulates the autonomic nervous system. However, the hypothalamic mechanisms of <em>nesfatin</em>-<em>1</em> on the autonomic nervous system are not well understood. In this study, we found that intracerebroventricular (ICV) administration of <em>nesfatin</em>-<em>1</em> increased the extracellular signal-regulated kinase (ERK) activity in rats. Furthermore, the activity of sympathetic nerves, in the kidneys, liver, and white adipose tissue (WAT), and blood pressure was stimulated by the ICV injection of <em>nesfatin</em>-<em>1</em>, and these effects were abolished owing to pharmacological inhibition of ERK. Renal sympathoexcitatory and hypertensive effects were also observed with <em>nesfatin</em>-<em>1</em> microinjection into the paraventricular hypothalamic nucleus (PVN). Moreover, <em>nesfatin</em>-<em>1</em> increased the number of phospho (p)-ERK<em>1</em>/2-positive neurons in the PVN and coexpression of the protein in neurons expressing corticotropin-releasing hormone (CRH). Pharmacological blockade of CRH signaling inhibited renal sympathetic and hypertensive responses to <em>nesfatin</em>-<em>1</em>. Finally, sympathetic stimulation of WAT and increased p-ERK<em>1</em>/2 levels in response to <em>nesfatin</em>-<em>1</em> were preserved in obese animals such as rats that were fed a high-fat diet and leptin receptor-deficient Zucker fatty rats. These findings indicate that <em>nesfatin</em>-<em>1</em> regulates the autonomic nervous system through ERK signaling in PVN-CRH neurons to maintain cardiovascular function and that the antiobesity effect of <em>nesfatin</em>-<em>1</em> is mediated by hypothalamic ERK-dependent sympathoexcitation in obese animals.

Nutritional status influences hormone secretion from specialized enteroendocrine cells within the gut mucosa. These hormones regulate food intake by mediating information to central neurocircuitries in the brainstem and forebrain (eg, hypothalamic nuclei). Intestinal enteroendocrine cells were believed to be the main source of gut peptides regulating food intake. However, recent evidence highlights a specific endocrine cell within the oxyntic glands of the stomach as an important player in appetite control. Acylated ghrelin is the only known orexigenic hormone peripherally produced in gastric X/A-like cells and centrally acting to stimulate food intake. Recent advances led to the assumption that des-acylated ghrelin, coreleased with acylated ghrelin, is also involved in regulating food intake. This, and the novel observation that <em>nesfatin</em>-<em>1</em>, which inhibits food intake, is expressed in ghrelin-producing cells of the stomach, supports an important role for gastric X/A-like cells in regulating food intake. Another peptide, obestatin, was initially described as a ghrelin gene product inhibiting food intake, but subsequent studies produced controversial data and its action as an anorexic factor is doubtful. Importantly, synergistic interactions between ghrelin and intestinal peptides seem to orchestrate food intake and body weight regulation, which may have implications for understanding mechanisms leading to the treatment of obesity.

BACKGROUND

Peroxisome proliferator-activated receptor gamma (PPARγ) has direct and indirect function in adipokines production process. We aimed to assess the possible influence of circulating PPARγ on relative risk of metabolic syndrome and also examine the association between circulating PPARγ and adipokines levels among obese subjects.

METHODS

A total of 96 obese subjects (body mass index (BMI) ≥30) were included in the current cross-sectional study. We assessed the body composition with the use of Body Composition Analyzer BC-4<em>1</em>8MA - Tanita. The MetS (metabolic syndrome) was defined based on the National Cholesterol Education Program Adult Treatment Panel III. All baseline blood samples were obtained following an overnight fasting. Serum concentrations of adipokines including Retinol binding protein 4 (RBP4), omentin-<em>1</em>, vaspin, progranulin, <em>nesfatin</em>-<em>1</em> and circulating PPARγ was measured with the use of an enzyme-linked immunosorbent assay method. Statistical analyses were performed using software package used for statistical analysis (SPSS).

RESULTS

We found main association between circulating PPARγ and body composition in obese population. The risk of metabolic syndrome in subjects with higher concentration of PPARγ was <em>1</em>.9 fold in compared with lower concentration of PPARγ after adjustment for age, sex and BMI. There was significant association between PPARγ and adipokines, specially <em>nesfatin</em>-<em>1</em> and progranulin. Defined adipokines pattern among participants demonstrated the markedly higher concentration of vaspin, RBP4 and <em>nesfatin</em>-<em>1</em> in participants with MetS compared to non-MetS subjects.

CONCLUSIONS

It appears all of studied adipokines might have association with PPARγ level and might simultaneously be involve in some common pathway to make susceptible obese subjects for MetS.

<em>Nesfatin</em>-<em>1</em> is an anorexigenic peptide that controls feeding behavior and glucose homeostasis. However, there is little data that exists regarding <em>nesfatin</em>-<em>1</em> secretion in obese children and young adolescents. The aim of this study is to investigate serum <em>nesfatin</em>-<em>1</em> in childhood and adolescent obesity and to study potential correlations with food intake, anthropometric indices, body composition and insulin resistance. Forty obese children and adolescents and 40 healthy control subjects were studied. Anthropometric measurements were assessed, dietary food intake was evaluated based on 3-days food record and body composition indices were evaluated using bioelectrical impedance analysis. Lipid profile, fasting blood sugar, fasting insulin and HOMA-IR were measured. Fasting serum <em>nesfatin</em>-<em>1</em> was quantitatively assayed by ELISA. Serum <em>nesfatin</em>-<em>1</em> was significantly higher in obese group (2.49±<em>1</em>.96 ng/ml) than in control group (0.70±0.8<em>1</em> ng/ml), P=0.00<em>1</em>. Positive correlations with serum insulin (P=0.00<em>1</em>), HOMA-IR (P=0.000), BMI-SDS (P=0.04), body fat % (P=0.000), fat mass (P=0.000), fat free mass (P=0.03), CHO % (P=0.000), and saturated fat % (P=0.0<em>1</em>) were found. While significant negative correlation with protein % (P=0.000) was observed. In conclusion, our results denote that <em>nesfatin</em>-<em>1</em> might have an important role in regulation of food intake and pathogenesis of insulin resistance in obese children and young adolescents.

OBJECTIVE

To explore the role of <em>nesfatin</em>-<em>1</em> on irritable bowel syndrome (IBS)-like visceral hypersensitivity.

METHODS

The animal model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8-2<em>1</em>. Experiments were performed when rats became adults. The visceral sensitivity of rats was evaluated by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activity of the external oblique muscle to graded colorectal distension. The content of <em>nesfatin</em>-<em>1</em> in serum was determined using enzyme-linked immunosorbent assay. After implantation of an intracerebroventricular (ICV) cannula and two electrodes into the external oblique muscle, model rats were randomly divided into four groups. Animals then received ICV injection of 8 μg of anti-<em>nesfatin</em>-<em>1</em>/nucleobindin-2 (NUCB2), 50 μg of α-helical corticotropin releasing factor (CRF) 9-4<em>1</em> (non-selective CRF receptor antagonist), 50 μg of NBI-279<em>1</em>4 (selective CRF<em>1</em> receptor antagonist) or 5 μL of vehicle. After <em>1</em> h of ICV administration, visceral sensitivity of each group was measured again, and comparisons between groups were made.

RESULTS

Rats treated with AA showed higher mean AWR scores and EMG activity at all distension pressures compared with controls (P < 0.05). On histopathologic examination, no evidence of inflammation or abnormalities in structure were noted in the colon of either control or AA-treated groups. Myeloperoxidase values were not significantly different between the two groups. The level of <em>nesfatin</em>-<em>1</em> in serum was significantly higher in the AA-treated group than in the control group (5.34 ± 0.37 ng/mL vs 4.8<em>1</em> ± 0.42 ng/mL, P < 0.0<em>1</em>). Compared with rats injected with vehicle, rats which received ICV anti-<em>nesfatin</em>-<em>1</em>/NUCB2, α-helical CRF9-4<em>1</em> or NBI-279<em>1</em>4 showed decreased mean AWR scores and EMG activity at all distension pressures (P < 0.05).

CONCLUSIONS

Nesfatin-<em>1</em> may be associated with IBS-like visceral hypersensitivity, which may be implicated in brain CRF/CRF<em>1</em> signaling pathways.

Although, the exact mechanisms underlying the development of the metabolic syndrome (MetS) are not still completely understood, obesity, circulated peptide hormone levels and their interaction with genetic factors are considered largely responsible. The purpose of this study is to explore how the levels of ghrelin, obestatin (OBS) and NUCB2/<em>nesfatin</em>-<em>1</em> (NES)/NUCB2 change in serum and the reproductive tissues of female and male rats with fructose-induced metabolic syndrome, and whether the levels of each hormone is correlated with the hormones involved with fertility. Experiments were conducted on 5-week-old Sprague-Dawley male and female rats assigned to either a control group or a MetS group. Controls were fed standard rat food and water ad libitum, while the MetS group was fed standard food with <em>1</em>0% (v/v) fructose solution added to their drinking water for <em>1</em>2 weeks with a <em>1</em>2/<em>1</em>2h photoperiod circle. Then, all animals were sacrificed after a one night fast. Peptides levels in the serum and reproductive tissues of rats were studied using the ELISA method while the immunoreactivity of reproductive system peptide hormones were shown by immunohistochemical staining method. Furthermore, the other biochemical parameters were measured using Konelab-60 equipment and infertility hormones were measured with Immulite2000. Fasting serum insulin, glucose, triglyceride, alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) levels were statistically significantly higher, and the amount of high density lipoprotein cholesterol (HDL-C) was significantly lower, in the MetS groups. Serum and tissue supernatant NES levels were significantly higher in the rats with MetS than the control group. Ghrelin, OBS and NES were expressed in the cytoplasm, concentrated around the apical parts of the epithelial cells in the reproductive tissues of the rats. The amounts of ghrelin were lower in the reproductive tissues of the animals with MetS, while NES levels in the same tissues increased. Obestatin also decreased, though not in the seminal glands.

<em>Nesfatin</em>-<em>1</em> was recently identified in the rat brain as a potential post-translational processing product derived from nucleobindin2 (NUCB2). The first biological action identified for <em>nesfatin</em>-<em>1</em> was the reduction of nocturnal food intake in rats. The anorexigenic effect of <em>nesfatin</em>-<em>1</em> was corroborated by several independent laboratories and is now established as a physiological action of this peptide based on the regulation of brain NUCB2/<em>nesfatin</em>-<em>1</em> under different metabolic conditions and the stimulation of food intake and body weight when endogenous brain NUCB2/<em>nesfatin</em>-<em>1</em> is blocked. <em>Nesfatin</em>-<em>1</em> 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 <em>nesfatin</em>-<em>1</em> has been established so far to involve several downstream mechanisms including H<em>1</em>, CRF2, TRH, oxytocin as well as melanocortin-3/4 receptor signaling pathways. This intricate embedding of NUCB2/<em>nesfatin</em>-<em>1</em> 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 <em>nesfatin</em>-<em>1</em> in modulating the nocturnal food intake. Although our knowledge on the regulation and effects of NUCB2/<em>nesfatin</em>-<em>1</em> 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 <em>nesfatin</em>-<em>1</em> release as well as the identification, localization and regulation of the <em>nesfatin</em>-<em>1</em> receptor.

Nesfatin is an anti-inflammatory molecule that reduces atherosclerotic cardiovascular risk. By contrast, visfatin has pro-inflammatory properties and is pro-atherogenic. We examined the potential impact of nesfatin and visfatin on atherosclerotic disease in 232 (113 black and 119 white) consecutive rheumatoid arthritis (RA) patients from 2 centers. Independent relationships of nesfatin and visfatin concentrations with metabolic risk factors, endothelial activation, carotid atherosclerosis and altered plaque stability were determined in multivariable regression models. Rheumatoid factor (RF) positivity was associated with both nesfatin (β = 0.650, p < 0.0001) and visfatin levels (β = 0.157, p = 0.03). Visfatin concentrations were related to increased diastolic blood pressure (β = 4.536, p = 0.01) and diabetes prevalence (β = 0.092, p = 0.04). Nesfatin levels were associated with reduced carotid intima-media thickness (β = -0.017, p = 0.008). Nesfatin (β = 0.116, p = 0.001) and visfatin concentrations (β = 0.234, p = 0.001) were related to those of matrix metalloproteinase-2 (MMP-2), a plaque stability mediator. Nesfatin and visfatin concentrations were directly correlated (Spearman's rho = 0.516). The nesfatin-MMP-2 and visfatin-MMP-2 relations were both stronger in RF negative compared to RF positive patients (interaction p = 0.01 and p = 0.04, respectively). Nesfatin is associated with reduced atherosclerosis and increased plaque stability mediator levels in RA. Visfatin is related to adverse cardio-metabolic risk in RA. Increased MMP-2 expression in relation to visfatin may represent a compensatory mechanism aimed at reducing cardiovascular risk in RA.

BACKGROUND

There is insufficient information about the appetite-related hormones orexin-A, <em>nesfatin</em>-<em>1</em>, agouti-related peptide (AgRP), and neuropeptide Y (NPY) in hyperthyroidism. The aim of the present study was to investigate the effects of hyperthyroidism on the basal metabolic rate (BMR) and energy intake, orexin-A, <em>nesfatin</em>-<em>1</em>, AgRP, NPY, and leptin levels in the circulation, and their relationship with each other and on appetite.

METHODS

In this prospective study, patients were evaluated in hyperthyroid and euthyroid states in comparison with healthy subjects. Twenty-one patients with overt hyperthyroidism and 33 healthy controls were included in the study.

RESULTS

Daily energy intake in the hyperthyroid state was found to be higher than that in the euthyroid state patient group (p=0.039). BMR was higher in hyperthyroid patients than the control group (p=0.0<em>1</em>8). Orexin-A was lower and <em>nesfatin</em>-<em>1</em> was higher in hyperthyroid patients compared to the controls (p<0.00<em>1</em>), whereas orexin-A increased and <em>nesfatin</em>-<em>1</em> decreased after euthyroidism (p=0.003, p<0.00<em>1</em>). No differences were found in the AgRP, NPY, and leptin levels between the hyperthyroid and euthyroid states and controls (p>0.05). Orexin-A correlated negatively with <em>nesfatin</em>-<em>1</em> (p=0.042), BMR (p=0.0<em>1</em>3), free triiodothyronine (fT3; p<0.00<em>1</em>), and free thyroxine (fT4; p<0.00<em>1</em>) and positively with thyrotropin (TSH; p<0.00<em>1</em>). Nesfatin-<em>1</em> correlated negatively with orexin-A (p=0.042) and TSH (p<0.00<em>1</em>) and positively with fT3 (p=0.005) and fT4 (p=0.00<em>1</em>). In the regression analysis, "diagnosis of hyperthyroidism" was the main factor affecting orexin-A (p<0.00<em>1</em>).

CONCLUSIONS

Although it seems that no relationship exists among orexin-A, <em>nesfatin</em>-<em>1</em>, and increased appetite in hyperthyroidism, the orexin-A and <em>nesfatin</em>-<em>1</em> levels are markedly affected by hyperthyroidism.

OBJECTIVE

Exercise training is an effective method of weight management, and knowing about its influence on the hormones involved in the regulation of food intake and inflammation could be useful for body weight management. Therefore, the purpose of this study was to compare the effects of 6 weeks of high-intensity interval training (HIIT) and moderate-intensity continuous exercise training (MCT) on <em>nesfatin</em>-<em>1</em>, interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α).

METHODS

Thirty sedentary overweight men (Mean±SD; age, 25±<em>1</em> years) were divided into three (n=<em>1</em>0) body mass index-matched groups. The participants in the training groups performed either HIIT or MCT protocols 3 days per week for 6 weeks followed by a week of detraining.

RESULTS

Plasma IL-6 and TNF-α did not significantly change after training, but <em>nesfatin</em> increased significantly only with HIIT compared with the control group (p<0.05). In addition, fasting glucose, insulin, and homeostasis model estimated insulin resistance (HOMA-IR), decreased significantly following both HIIT and MCT training (p<0.05). After a detraining period, the plasma <em>nesfatin</em>-<em>1</em> did not return to pre-training levels in the HIIT group.

CONCLUSIONS

Both the HIIT and MCT groups had similar effects on inflammatory markers and insulin resistance in men who are overweight, but the HIIT seems to have better anorectic effects (as indicated by nesfatin) compared with MCT.

BACKGROUND

<em>Nesfatin</em>-<em>1</em>, recently identified as a satiety regulator, elicits an anti-atherosclerosis effect. Our study was designed to determine whether there is an association between serum <em>nesfatin</em>-<em>1</em> and the development and severity of peripheral arterial disease (PAD) in patients with type 2 diabetes mellitus (T2DM).

METHODS

This cross-sectional study included 355 T2DM patients (200 without PAD and <em>1</em>55 with PAD).

RESULTS

T2DM patients with PAD exhibited marked lower serum <em>nesfatin</em>-<em>1</em> concentrations than those without PAD. Multivariable logistic regression analysis indicated an inverse association of serum <em>nesfatin</em>-<em>1</em> concentrations with the development of PAD in T2DM patients (OR 0.008, 95% CI 0.002 to 0.028; P<0.00<em>1</em>). Simple linear regression analysis showed a marked correlation between serum <em>nesfatin</em>-<em>1</em> concentrations and body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), C-reactive protein (CRP), and ankle-brachial index (ABI) in T2DM patients. By contrast, multivariable analysis showed only BMI and ABI as independent correlates of serum <em>nesfatin</em>-<em>1</em>.

CONCLUSIONS

Our study shows an association of serum <em>nesfatin</em>-<em>1</em> concentrations and the development and severity of PAD in T2DM patients.

BACKGROUND

<em>Nesfatin</em>-<em>1</em>, a member of the adipokine family, has been detected in synovial fluid (SF) from OA patients. This study aimed to determine whether there is a marked correlation of <em>nesfatin</em>-<em>1</em> levels in serum and SF of knee OA patients with the disease severity of OA.

METHODS

This cross-sectional research enrolled 202 knee OA subjects. The Kellgren-Lawrence grading system was utilized to evaluate the severity of knee OA.

RESULTS

Elevated <em>nesfatin</em>-<em>1</em> concentrations in serum were found in knee OA patients compared with the controls. <em>Nesfatin</em>-<em>1</em> concentrations were markedly elevated with increased KL grades. Serum and SF <em>nesfatin</em>-<em>1</em> concentrations were both significantly associated with the disease severity evaluated by KL grading criteria.

CONCLUSIONS

Our investigation indicates a marked association of serum and SF <em>nesfatin</em>-<em>1</em> concentrations with OA disease severity.

Several peptides are produced and released from endocrine cells scattered within the gastric oxyntic and the small intestinal mucosa. These peptide hormones are crucially involved in the regulation of gastrointestinal functions and food intake by conveying their information to central regulatory sites located in the brainstem as well as in the forebrain, such as hypothalamic nuclei. So far, ghrelin is the only known hormone that is peripherally produced in gastric X/A-like cells and centrally acting to stimulate food intake, whereas the suppression of feeding seems to be much more redundantly controlled by a number of gut peptides. Cholecystokinin produced in the duodenum is a well established anorexigenic hormone that interacts with ghrelin to modulate food intake indicating a regulatory network located at the first site of contact with nutrients in the stomach and upper small intestine. In addition, a number of peptides including leptin, urocortin 2, amylin and glucagon-like peptide <em>1</em> interact synergistically with CCK to potentiate its satiety signaling effect. New developments have led to the identification of additional peptides in X/A-like cells either derived from the pro-ghrelin gene by alternative splicing and posttranslational processing (obestatin) or a distinct gene (nucleobindin2/<em>nesfatin</em>-<em>1</em>) which have been investigated for their influence on food intake.

BACKGROUND

<em>Nesfatin</em>-<em>1</em> is a novel 82-amino acid anorectic peptide. Acute injection of <em>nesfatin</em>-<em>1</em> into the third brain ventricle reduces food consumption during the dark phase in rats. <em>Nesfatin</em>-<em>1</em> is also expressed in gastric X/A-like cells in the peripheral tissues. <em>Nesfatin</em>-<em>1</em> has been reported to reduce gastric and duodenal motility and to delay gastric emptying.

OBJECTIVE

In the present study, we investigated the effects of <em>nesfatin</em>-<em>1</em> on gastrointestinal motility in conscious dogs.

METHODS

Force transducers were implanted onto the serosal surfaces of the gastric bodies, gastric antra, duodena, and jejuna of healthy beagle dogs, and gastrointestinal motility was monitored. We evaluated the effects of <em>nesfatin</em>-<em>1</em> on gastrointestinal motility and on the circulating levels of <em>nesfatin</em>-<em>1</em> in the fasted and fed states.

RESULTS

The intravenous administration of <em>nesfatin</em>-<em>1</em> reduced gastric contractions and inhibited cyclical interdigestive migrating contractions in the fasted state. In the fasted state, circulating levels of <em>nesfatin</em>-<em>1</em> tended to increase during late phase I. In addition, the kinetics of the circulating levels of <em>nesfatin</em>-<em>1</em> were opposite to those of ghrelin during the fasted state.

CONCLUSIONS

<em>Nesfatin</em>-<em>1</em> regulates gastrointestinal motility, and, in particular, it inhibits gastric contractions in the fasted state. Interdigestive migrating contractions may be regulated by interactions between <em>nesfatin</em>-<em>1</em>, ghrelin, and motilin.

The present study was designed to evaluate the cardioprotective effects of <em>nesfatin</em>-<em>1</em>, a novel peptide with anorexigenic properties, in rats with isoproterenol (ISO)-induced myocardial infarction (MI), and to further investigate the role of Akt/GSK-3β signaling pathway in the protective effect of <em>nesfatin</em>-<em>1</em>. To induce MI, ISO was subcutaneously injected into the rats for two consecutive days at a dosage of 85mg/kg/day. ISO-induced myocardial damage was indicated by elevated levels of cardiac specific troponin-T, enhanced myocardial expression of proinflammatory cytokines (interleukin-<em>1</em>β, interleukin-6 and tumor necrosis factor-α), and increased number of cells with apoptotic and necrotic appearance in the myocardial tissue. Levels of p-Akt/Akt and p-GSK-3β/GSK-3β significantly decreased in heart tissue after ISO-induced MI. However, intraperitoneal administration of <em>nesfatin</em>-<em>1</em> (<em>1</em>0μg/kg/day) elicited a significant cardioprotective activity by lowering the levels of cardiac troponin-T and proinflammatory cytokines, indicating the protective effect of <em>nesfatin</em>-<em>1</em> against ISO-induced MI. The biochemical findings were further confirmed by histopathological examination, which was demonstrated by reduced number of apoptotic and necrotic cells. Moreover, expressions of p-Akt/Akt and p-GSK-3β/GSK-3β in the myocardium of MI group rats were significantly increased by <em>nesfatin</em>-<em>1</em> administration, suggesting that <em>nesfatin</em>-<em>1</em>, which appears to possess anti-apoptotic and anti-inflammatory properties, may confer protection against ISO-induced MI via an Akt/GSK-3β-dependent mechanism.

Mucosal balance impairment, bacterial over-proliferation, cytokines, inflammatory mediators are known as responsible for inflammatory bowel disease. Besides known anorexigenic, neuroprotective, and anti-apoptotic effects, the major effect of <em>nesfatin</em>-<em>1</em> on colitis is unknown. Our aim was to investigate the possible anti-inflammatory effects of <em>nesfatin</em>-<em>1</em> in acetic acid induced colitis model and potential underlying mechanisms. Male Spraque-Dawley rats were anesthetized by intraperitoneal ketamine (<em>1</em>00 mg/kg) and chlorpromazine (0.75 mg/kg). For <em>nesfatin</em>-<em>1</em> and antagonist applications some of the rats were intracerebroventricularly (i.c.v.) cannulated. In colitis group, intrarectally (i.r.) 4% acetic acid solution (<em>1</em> ml) and <em>1</em>0 minutes later i.c.v. <em>nesfatin</em>-<em>1</em> (0.05 μg/5 μl) or vehicle (5 μl) were administered. Treatments continued for 3 days. In control group, physiological saline solution was used intrarectally. To identify the underlying effective mechanism of <em>nesfatin</em>-<em>1</em>, rats were divided into 3 subgroups, 5 minutes following colitis induction; i.c.v. atosiban (oxytocin receptor antagonist), SHU9<em>1</em><em>1</em>9 (melanocortin receptor antagonist) or GHSR-<em>1</em>a antagonist (ghrelin receptor antagonist) were administered, 5 minutes later <em>nesfatin</em>-<em>1</em> was administered for 3 days. On the fourth day, rats were decapitated, and colon tissues were sampled. Macroscopic and microscopic damage scores of distal colon, and colonic tissue malondialdehyde, glutathione, myeloperoxidase, superoxide dismutase, catalase, luminol and lucigenin chemiluminescence measurements were analysed. The increased myeloperoxidase activity, malondialdehyde levels, luminol and lucigenin chemiluminescence measurements, macroscopic and microscopic damage scores with colitis induction (P < 0.05 - 0.00<em>1</em>) were decreased with <em>nesfatin</em>-<em>1</em> treatment (P < 0.05 - 0.00<em>1</em>). <em>Nesfatin</em>-<em>1</em> may show this effect by inhibiting neutrophil infiltration through tissues and by decreasing formation of free oxygen radicals. Atosiban and GHSR-<em>1</em>a administration alleviated the protective effect of <em>nesfatin</em>-<em>1</em> from microscopic and oxidant damage parameters and lipid peroxidation (P < 0.05 - 0.00<em>1</em>). The results of the study suggest that <em>nesfatin</em>-<em>1</em> had a protective effect from colitis induction, and the anti-inflammatory and antioxidant effects of <em>nesfatin</em>-<em>1</em> on colitis might occur via oxytocin and ghrelin receptors.

Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors <em>nesfatin</em>-<em>1</em>, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour. <em>Nesfatin</em>-<em>1</em>, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centres. Moreover, in patients suffered from anxiety and anorexia nervosa a significant, sex-related changes in the plasma neuropeptide levels occurred. It should be therefore taken into account that the targeted pharmacomodulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders. This article reviews recent evidence dealing with the hypothetical role of these new factors in the anxiety-related circuits and pathophysiology of anorexia nervosa.

OBJECTIVE

The aim of the present study was to evaluate the plasma <em>nesfatin</em>-<em>1</em>, corticosterone, and inflammatory cytokine (IL-6, CRP, and TNF-α) concentrations cross-sectionally in patients with major depressive disorder.

METHODS

Subjects in the patient group were randomly selected from the Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. Healthy control subjects were matched in terms of weight and body mass index. The Hamilton Depression Rating Scale (HAM-D) was used to evaluate both groups. ELISAs were used for the measurement of plasma <em>nesfatin</em>-<em>1</em>, corticosterone, IL-6, CRP, and TNF-α levels.

RESULTS

The HAM-D scores and average <em>nesfatin</em>-<em>1</em>, corticosterone, IL-6, and CRP levels were significantly higher in patients with major depressive disorder than those in the control group. Positive correlation was found between <em>nesfatin</em>-<em>1</em> and corticosterone (r = 0.305, P = 0.007), IL-6 (r = 0.333, P = 0.003), and CRP (r = 0.244, P = 0.034) concentrations.

CONCLUSIONS

Increased plasma <em>nesfatin</em>-<em>1</em> levels may be associated with corticosterone, IL-6, and CRP levels in patients with major depressive disorder.

Obesity often results from hyperphagia and involves rhythm disorder. Circadian feeding pattern is suggested to be implicated in energy homeostasis while its disorder in obesity. However, the mechanism underlying circadian feeding is little known. PVN is considered a regulatory center for feeding and circadian activities of hormone release and autonomic nerve. Nucleobindin2 (NUCB2) and its processing product <em>nesfatin</em>-<em>1</em> (NUCB2/<em>nesfatin</em>-<em>1</em>) are localized in the hypothalamic paraventricular nucleus (PVN) and implicated in regulation of feeding. This study aimed to clarify whether the PVN NUCB2/<em>nesfatin</em>-<em>1</em> expression exhibits diurnal rhythm and, if so, whether it is related to circadian feeding. Here we show that NUCB2 mRNA expression in the PVN rises during early light phase (LP) in parallel with suppression of food intake. Immunoneutralization of PVN NUCB2/<em>nesfatin</em>-<em>1</em> with anti-<em>nesfatin</em>-<em>1</em> IgG during LP, but not dark phase, increased food intake. PVN-selective shRNA-induced knockdown of NUCB2 mRNA expression elevated food intake. Furthermore, the rise of PVN NUCB2 mRNA during LP was blunted in Zucker-fatty obese rats which exhibited LP-preferential hyperphagia. The increases in food intake during LP and 24h were significantly corrected by intracerebroventricular injection of <em>nesfatin</em>-<em>1</em> during LP. These results reveal the diurnal rhythm of PVN NUCB2 mRNA expression characterized by early LP rise, which may serve as a factor to limit LP food intake, contributing to circadian feeding. Furthermore, impaired NUCB2/<em>nesfatin</em>-<em>1</em> rhythm may be related to dysregulated feeding pattern and hyperphagia in Zucker-fatty rats.

The roles of leptin, <em>nesfatin</em>-<em>1</em> and kisspeptin in the regulation of food intake and/or reproduction are well known; however, the interactions between these hormones remain unclear, especially in humans. The aim of this study was to determine the roles of leptin, <em>nesfatin</em>-<em>1</em> and kisspeptin in pre- and postmenopausal obese and non-obese women. The study included 83 women who were divided into four groups based on menopausal status and body mass index. The leptin level was significantly higher in the obese women than in the non-obese women (p < 0.05), but did not differ significantly between pre- and postmenopausal women (p>> 0.05). The <em>nesfatin</em>-<em>1</em> and kisspeptin-<em>1</em> levels did not differ significantly between any of the study groups (p>> 0.05). The present findings show that <em>nesfatin</em>-<em>1</em> and kisspeptin levels are not affected by obesity or menopausal status.

Gestational diabetes mellitus (GDM) is considered to be one of the most frequent medical complication observed among pregnant women. The role of adipokines in the pathogenesis of GDM remains strictly unknown. Different adipokines have been studied throughout gestation, and they have been proposed as biomarkers of GDM and other pregnancy-related complications; however, there is no biomarker reported for GDM screening at present. The aim of this study was to evaluate serum <em>nesfatin</em>-<em>1</em> and vaspin levels in GDM and non-GDM women, to characterize the correlation between these adipokines, and to assess the potential role of circulating adipokines in the prediction of risk of gestational diabetes mellitus. Serum concentrations of <em>nesfatin</em>-<em>1</em> and vaspin were measured in <em>1</em>53 women with GDM, and in 84 patients with uncomplicated pregnancy by enzyme-linked immunosorbent assay (ELISA) kits, according to the manufacturer's instructions. Circulating levels of <em>nesfatin</em>-<em>1</em> and vaspin were significantly lower in the GDM group than in the control group. <em>Nesfatin</em>-<em>1</em> levels were negatively correlated with vaspin levels. The results of this study point out the possible role of <em>nesfatin</em>-<em>1</em> and vaspin as potential novel biomarkers for the prediction and early diagnosis of GDM. Further studies are necessary to evaluate the influence of <em>nesfatin</em>-<em>1</em> and vaspin on glucose metabolism in the early stages of GDM.

Nucleobindin-2 is a 420-amino-acid EF-hand calcium-binding protein that undergoes proteolytic processing to generate an 82-amino-acid amino-terminal peptide termed <em>nesfatin</em>-<em>1</em>. To determine whether nucleobindin-2 has any biological function, nucleobindin-2 was either overexpressed or knocked down by short hairpin RNA in cultured CHO cells expressing the human insulin and epidermal growth factor (EGF) receptors (CHO/IE) and in 3T3-L<em>1</em> cells. Reduction in nucleobindin-2 expression inhibited EGF-stimulated MAPK kinase (S2<em>1</em>7/S22<em>1</em>) and Erk phosphorylation (T202/Y204). In contrast, there was no significant effect on EGF-stimulated EGF receptor phosphorylation, EGF receptor internalization, or 52-kDa Shc and c-Raf phosphorylation. Although kinase suppressor of Ras-<em>1</em> and protein phosphatase 2A expression was not changed, intracellular calcium concentrations and PP2A activity was significantly increased in nucleobindin-2 knocked-down cells. Concomitant with these alterations in EGF-stimulated signaling, cell proliferation was significantly reduced in nucleobindin-2 knocked-down cells. Moreover, reduced nucleobindin-2 expression in 3T3-L<em>1</em> preadipocytes resulted in a greater extent of 3T3-L<em>1</em> cell adipocyte differentiation. Taken together, these data indicate that nucleobindin-2 regulates EGF-stimulated MAPK kinase/Erk signaling, cell proliferation, and adipocyte differentiation.

Although the novel satiety peptide <em>nesfatin</em>-<em>1</em> has been shown to regulate gastric motility, the underlying mechanisms have yet to be elucidated. The study aimed to explore the effects of <em>nesfatin</em>-<em>1</em> on ghrelin-responsive gastric distension (GD) neurons in the arcuate nucleus (Arc), and potential regulation mechanisms of gastric motility by the paraventricular nucleus (PVN). Single-unit discharges in the Arc were recorded extracellularly, and gastric motility in conscious rats was monitored during the administration of <em>nesfatin</em>-<em>1</em> to the Arc or electrical stimulation of the PVN. Retrograde tracing and fluo-immunohistochemistry staining were used to determine NUCB2/<em>nesfatin</em>-<em>1</em> neuronal projections. <em>Nesfatin</em>-<em>1</em> inhibited most of the ghrelin-responsive GD-excitatory neurons, but excited ghrelin-responsive GD-inhibitory neurons in the Arc. Gastric motility was significantly reduced by <em>nesfatin</em>-<em>1</em> administration to the Arc in a dose-dependent manner. The firing activity in the Arc and changes to gastric motility were partly reduced by SHU9<em>1</em><em>1</em>9, an antagonist of melanocortin 3/4 receptors. Electrical stimulation of PVN excited most of the ghrelin-responsive GD neurons in the Arc and promoted gastric motility. Nonetheless, pretreatment with an anti-NUCB2/<em>nesfatin</em>-<em>1</em> antibody in the Arc further increased the firing rate of most of the ghrelin-responsive GD-excitatory neurons and decreased the ghrelin-responsive GD-inhibitory neurons following electrical stimulation of the PVN. Gastric motility was enhanced by pretreatment with an anti-NUCB2/<em>nesfatin</em>-<em>1</em> antibody in the Arc following PVN stimulation. Furthermore, NUCB2/<em>nesfatin</em>-<em>1</em>/fluorogold double-labeled neurons were detected in the PVN. These results suggest that <em>nesfatin</em>-<em>1</em> could serve as an inhibitory factor in the Arc to regulate gastric motility via the melanocortin pathway. The PVN could be involved in the regulation of the Arc in gastric activity.

<em>Nesfatin</em>-<em>1</em> is the N-terminal fragment of nucleobindin-2 (NUCB2) that was identified as a novel satiety molecule in rodents. The protein is reported to exert anorexigenic effects and appears to play an important role in hypothalamic pathways regulating energy homeostasis and food intake. In this study, we hypothesized that mutations in the <em>nesfatin</em> encoding gene NUCB2 might cause obesity in humans. Therefore, we screened the entire coding region of the NUCB2 gene for mutations in a population of 47<em>1</em> obese children and adolescents. Mutation analysis of NUCB2 identified a total of seven sequence variants of which four were previously reported as polymorphisms. The remaining three variants included ex9+6G>C, L<em>1</em>25H and K<em>1</em>78X and were found in 3 unrelated individuals in the obese population only (0.6%). Biochemical experiments including ELISA and western blot were performed on plasma samples of the obese patient carrying the nonsense mutation K<em>1</em>78X. However, neither NUCB2/<em>nesfatin</em>-<em>1</em> immunoreactive plasma levels of the patient, nor expression of full length NUCB2 differed significantly from matched obese control individuals. In conclusion, we have identified the first genetic variants in the NUCB2 gene in obese individuals, although further functional characterization will be essential to verify disease causality of the mutations.