<AbstractText>The prevalence of childhood obesity is increasing and, it brings co-morbidities like hypertension. However, it is still not clear whether some obese individuals are hypertensive and others do not. <em>Nesfatin</em>-<em>1</em> is a recently discovered anorexigenic peptide which also has effects on blood pressure. Our aim is to evaluate the relationship between obesity-related hypertension and <em>Nesfatin</em>-<em>1</em>.</AbstractText><AbstractText>For this cross-sectional study 87 obese children were included. The patients were divided into two groups as hypertensive (n=30) and normotensive (n=57) obese. We used the American Academy of Pediatrics guidelines to diagnose hypertension. Blood samples were collected after <em>1</em>2 hours of fasting to examine the levels of <em>Nesfatin</em>-<em>1</em>. We also evaluated the serum trace elements of the patients besides the routine blood tests.</AbstractText><AbstractText>Body mass index (BMI), weight and serum <em>Nesfatin</em>-<em>1</em> were higher in the hypertensive group (p=0.002, p=0.00<em>1</em>, and p=0.007 respectively). There was no difference between serum zinc levels but copper levels were significantly lower in the hypertensive group (p=0.248, p=0.007, respectively). There was a positive correlation between blood pressure and BMI and weight z scores and a negative correlation with Cu. The optimal cut-off value of <em>Nesfatin</em>-<em>1</em> to predict hypertension was found to be ><em>1</em>.8 ng/ml, with specificity of 7<em>1</em>.9% and sensitivity of 96.7% (AUC=0.703; 95% CI, 0.577-0.809; p=0.002). In the multiple logistic regression analysis <em>Nesfatin</em>-<em>1</em> (OR=<em>1</em>.<em>1</em>03, 95% CI: <em>1</em>.039-<em>1</em>.<em>1</em>7<em>1</em>, p=0.00<em>1</em>), Cu (OR=0.947, 95% CI: 0.9<em>1</em>5-0.979, p=0.00<em>1</em>) and BMI for age z score (OR=56.277, 95% CI: 5.79<em>1</em>-546.907, p=0.00<em>1</em>) still remained significant predictors of hypertension.</AbstractText><AbstractText>We found <em>Nesfatin</em>-<em>1</em> was higher and <em>Nesfatin</em>-<em>1</em> levels independently predict hypertension in obese subjects.</AbstractText>

NUCB2/<em>nesfatin</em>-<em>1</em> is first known to be expressed in the hypothalamus while controlling appetite and energy metabolism. However, recent studies have shown that NUCB2/<em>nesfatin</em>-<em>1</em> was expressed in the various organs as well as the hypothalamus. Our previous reports also demonstrated that NUCB2/<em>nesfatin</em>-<em>1</em> was expressed in the ovary, testis, pituitary gland, lung, kidney, and stomach of fetal and adult mice. However, the role of NUCB2/<em>nesfatin</em>-<em>1</em> in mouse fetus remains unknown. Thus, the aim of this study was to investigate whether NUCB2/nestatin-<em>1</em> is expressed in mouse fetus at the developmental stage in which organogenesis begins. To do this, we performed <i>in situ</i> hybridization (ISH) and immunohistochemistry (IHC) staining to examine the distribution of NUCB2 mRNA and <em>nesfatin</em>-<em>1</em> protein in the mouse fetal organs during early developmental stages, especially at embryonic day (E) <em>1</em>0.5. As a result of ISH, NUCB2 mRNA positive signals were more frequent in the liver, but there were relatively few positive signals in heart. On the other hand, no positive signals were detected in other organs. These ISH results were validated by IHC staining and qRT-PCR analysis. Expression of <em>nesfatin</em>-<em>1</em> protein detected by IHC staining was similar to that of NUCB2 mRNA detected by ISH in the liver and heart. In addition, the levels of NUCB2 mRNA expression analyzed by qRT-PCR were significantly increased in the liver and heart compared to other organs of the mouse fetus at E<em>1</em>3.5, whereas its level was extensively decreased in the liver, but increased in the lung, stomach, and kidney of the mouse fetus at E<em>1</em>7.5. These results suggest that NUCB2/<em>nesfatin</em>-<em>1</em> may play an important role in liver and heart development and physiological functions in the developmental process of mouse fetus. Further studies are needed on the function of NUCB2/<em>nesfatin</em>-<em>1</em>, which is highly expressed in the various organs, including liver and heart during mouse development.

The brain receives information on the body's fuel supply through a bewildering array of chemical messengers that signal either negative or positive energy balance. <em>Nesfatin</em>-<em>1</em>, a secreted protein of previously unknown function, acts as a satiety factor. <em>Nesfatin</em>-<em>1</em> suppresses appetite in both the short term and the long term, is made by neurons in brain centers that regulate energy balance and might act via melanocortin pathways. <em>Nesfatin</em>-<em>1</em> is the latest addition to the surprisingly large number of chemical messengers telling the body that the tank is full.

<em>Nesfatin</em>-<em>1</em> is a newly discovered satiety molecule expressed mainly in the hypothalamic nuclei. It suppresses both short-term and long-term appetite. Six synthetic deoxyoligonucleotides overlapped by PCR encoding <em>nesfatin</em>-<em>1</em> were cloned into a pET28a vector after the hexa-histidine-tagged multiple cloning sites sequence with an enterokinase recognition site incorporated in-between. The recombinant plasmid was transformed into Escherichia coli strain Rosetta to express the fusion protein, which constituted 27% of the total cell proteins. After purified by Ni-sepharose affinity chromatography, the fusion protein was treated with enterokinase to release <em>nesfatin</em>-<em>1</em>. The <em>nesfatin</em>-<em>1</em> sample was further purified with reverse-phase high performance liquid chromatography (HPLC), and its molecular weight was determined by mass spectrometry. The biological activities of recombinant <em>nesfatin</em>-<em>1</em> were also assessed using in vivo animal models. The method described here promises to produce about 8 mg biologically active <em>nesfatin</em>-<em>1</em> with homogeneity over 98% from <em>1</em>-L shaking flask culture of E. coli, which can be considered as an easy and cost-effective way to synthesize <em>nesfatin</em>-<em>1</em>.

OBJECTIVE

This study aimed to investigate the possible relationship between plasma concentrations of <em>nesfatin</em> <em>1</em> and first attack psychosis.

METHODS

Totally, 32 patients with the first episode psychosis and 33 randomly selected weight- and body mass index-matched healthy volunteers admitted to Mustafa Kemal University, Faculty of Medicine, Training and Research Hospital, Psychiatry outpatient clinic were included. Healthy control subjects were matched in terms of weight and body mass index (BMI). The Positive and Negative Syndrome Scale (PANNS) was applied to the patient group. The enzyme-linked immunosorbent assay (ELISA) method was used to measure plasma <em>nesfatin</em> <em>1</em> levels.

RESULTS

The mean <em>nesfatin</em> <em>1</em> level was lower in the patients with the first attack psychosis (0.60 ± <em>1</em>.00 ng/mL) than in the control group (0.75 ± <em>1</em>.07 ng/mL).However it did not reach statistical significance (t = -0.567, p = 0.573). There was no statistically significant correlation between plasma <em>nesfatin</em> <em>1</em> levels and total PANNS scores in the patient group (r = -0.262, p = 0.<em>1</em>48).

CONCLUSIONS

Our study was the first to investigate the <em>nesfatin</em> <em>1</em> levels in patients with the first episode psychosis. Based on our study results, <em>nesfatin</em> <em>1</em> might be related to some central nervous system pathologies, including the severity of a psychiatric disorder; however, further large-scale studies are required to establish a conclusion (Tab. <em>1</em>, Ref. 2<em>1</em>).

<em>Nesfatin</em>-<em>1</em>, a newly discovered adipokine, inhibits inflammatory response. Inflammation is involved in the mechanism of atrial fibrillation (AF). We aim to determine the association between serum <em>nesfatin</em>-<em>1</em> concentrations and AF. A population of 200 patients with AF and <em>1</em>08 patients without AF were enrolled in this study. These patients were divided into three subgroups of paroxysmal AF, persistent AF, and permanent AF. Serum <em>nesfatin</em>-<em>1</em> concentrations were lower in AF patients than in controls. Logistic regression analysis showed that serum <em>nesfatin</em>-<em>1</em> concentrations were inversely associated with AF. Serum <em>nesfatin</em>-<em>1</em> concentrations in permanent AF patients decreased compared with those in persistent and paroxysmal AF groups. In addition, persistent AF patients showed reduced serum <em>nesfatin</em>-<em>1</em> concentrations compared with paroxysmal AF subjects. Serum <em>nesfatin</em>-<em>1</em> concentrations were negatively correlated with left atrial diameter. In conclusion, serum <em>nesfatin</em>-<em>1</em> concentrations were inversely correlated with AF development.

OBJECTIVE

Saxagliptin as one of dipeptidyl peptidase-4 (DPP-4) inhibitors can effectively improve glycaemic control in type 2 diabetes mellitus, and <em>nesfatin</em>-<em>1</em> is regarded as a very important factor in regulating feeding behavior and energy homeostasis. In this trial, we observed the effect of saxagliptin on regulating <em>nesfatin</em>-<em>1</em> secretion and ameliorating insulin resistance and metabolic profiles in type 2 diabetes mellitus.

METHODS

One hundred two type 2 diabetes participants (M/F = 48/54) were investigated. Fifty-one (M/F = 24/27) of them as the treatment group were treated with oral glucose-lowering agents including saxagliptin, the other 5<em>1</em> (M/F = 24/27) as the control group were treated with oral glucose-lowering agents excluding any DPP-4 inhibitors. The parameters of serum <em>nesfatin</em>-<em>1</em>, C-peptide, homeostasis model assessment-β (HOMA-β) function, HOMA insulin resistance (HOMA-IR), glycosylated hemoglobin A<em>1</em>c (HbA<em>1</em>c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), body mass index (BMI), and blood pressure (BP) at baseline, month 3, 6, and <em>1</em>2 were observed and compared respectively.

RESULTS

Saxagliptin significantly upregulated <em>nesfatin</em>-<em>1</em> secretion (P < 0.00<em>1</em> at 3-, 6-, and <em>1</em>2-months vs. baseline), increased serum C-peptide (P < 0.05, 0.00<em>1</em>, and 0.00<em>1</em> at 3-, 6-, and <em>1</em>2-months vs. baseline), improved HOMA-IR and function of HOMA-β (P < 0.00<em>1</em> at 3-, 6-, and <em>1</em>2-months vs. baseline) and metabolic profiles (P < 0.00<em>1</em> with HbA<em>1</em>c at 3-, 6- and <em>1</em>2-months; P < 0.00<em>1</em> with LDL-C at 6- and <em>1</em>2-months; P < 0.00<em>1</em> and 0.0<em>1</em> with HDL-C at 6- and <em>1</em>2-months vs. baseline), declined BMI (P < 0.05 at 6- and <em>1</em>2-months vs. baseline) and BP (P < 0.00<em>1</em> with systolic BP (SBP), and mean BP at 6- and <em>1</em>2-months, P < 0.0<em>1</em> with diastolic BP at 6- and <em>1</em>2-months vs. baseline).

CONCLUSIONS

Saxagliptin could upregulate <em>nesfatin</em>-<em>1</em> secretion and ameliorate insulin resistance and metabolic profiles in type 2 diabetes mellitus. Saxagliptin had the potential to play fundamental by upregulating <em>nesfatin</em>-<em>1</em> secretion besides lowering glucose by inhibiting the degradation of glucagon-like peptide-<em>1</em>.

BACKGROUND

In the literature, the relationship between appetite regulating peptides and alcohol craving is on the debate.

OBJECTIVE

This study aims to investigate serum level of NUCB2/<em>nesfatin</em>-<em>1</em>, which is discovered as appetite-related neuropeptide, in patients with alcohol dependence who were in craving and abstaining phase and to compare with healthy controls.

METHODS

Research, Treatment, and Training Center for Alcohol and Substance Dependence, (AMATEM) Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Istanbul, case-control and prospective study design were used.

METHODS

Chi-square, Mann-Whitney U, paired samples, independent samples t- and Pearson correlation tests were used for analysis.

METHODS

Forty-three patients with alcohol dependence who have been admitted for detoxification and thirty healthy controls were included in the study. The blood samples were drawn after the <em>1</em>st day of admission and postdetoxification treatment in inpatients who reached to abstinence period and from 30 healthy controls. The Penn Alcohol Craving Scale and the Obsessive Compulsive Drinking Scale were applied to detect craving scores.

RESULTS

Initial serum NUCB2/<em>nesfatin</em>-<em>1</em> levels in patients were significantly lower than in the healthy control group (P < 0.00<em>1</em>). The NUCB2/<em>nesfatin</em>-<em>1</em> level of initial phase was significantly lower than abstinence phase (P = 0.027). No correlation was found between craving scores and NUCB2/<em>nesfatin</em>-<em>1</em> level (P>> 0.05).

CONCLUSIONS

This study is the first that showed significant differences of serum NUCB2/<em>nesfatin</em>-<em>1</em> level according to different stages of alcohol dependence. Plasma NUCB2/<em>nesfatin</em>-<em>1</em> levels were lower in highest craving phase and tended to normalize after abstinence. Since we could not find a correlation between craving and NUCB2/<em>nesfatin</em>-<em>1</em> levels, the increase of NUCB2/<em>nesfatin</em>-<em>1</em> in abstinence phase might have been resulted from other reasons apart from craving.

<em>Nesfatin</em>-<em>1</em> is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of <em>nesfatin</em>-<em>1</em> significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central <em>nesfatin</em>-<em>1</em> remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by <em>nesfatin</em>-<em>1</em> is mediated by the central melanocortin pathway, which was previously reported to mediate central <em>nesfatin</em>-<em>1</em>´s effects on feeding and numerous other physiological functions. With the application of direct calorimetry, we found that intracerebroventricular <em>nesfatin</em>-<em>1</em> (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9<em>1</em><em>1</em>9. Interestingly, the <em>nesfatin</em>-<em>1</em>-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular <em>nesfatin</em>-<em>1</em> (<em>1</em>00 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, <em>nesfatin</em>-<em>1</em> upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein <em>1</em> and peroxisome proliferator-activated receptor gamma coactivator-<em>1</em> alpha mRNA in the iBAT. Overall, we clearly demonstrate that <em>nesfatin</em>-<em>1</em> requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure.

<em>Nesfatin</em>-<em>1</em> is a well-established anorexigenic peptide. Recent studies indicated an association between <em>nesfatin</em>-<em>1</em> and anxiety/depression-like behavior. However, it is unclear whether this effect is retained in obesity. The aim was to investigate the effect of <em>nesfatin</em>-<em>1</em>_30-59-the active core of <em>nesfatin</em>-<em>1</em>-on anxiety and depression-like behavior in normal weight (NW) and diet-induced (DIO) obese rats. Male rats were intracerebroventricularly (ICV) cannulated and received <em>nesfatin</em>-<em>1</em>_30-59 (0.<em>1</em>, 0.3, or 0.9 nmol/rat) or vehicle 30 min before testing. <em>Nesfatin</em>-<em>1</em>_30-59 at a dose of 0.3 nmol reduced sucrose consumption in the sucrose preference test in NW rats compared to vehicle (⁻33%, <i>p</i> < 0.05), indicating depression-like/anhedonic behavior. This dose was used for all following experiments. <em>Nesfatin</em>-<em>1</em>_30-59 also reduced cookie intake during the novelty-induced hypophagia test (-62%, <i>p</i> < 0.05). Moreover, <em>nesfatin</em>-<em>1</em>_30-59 reduced the number of entries into the center zone in the open field test (-45%, <i>p</i> < 0.0<em>1</em>) and the visits of open arms in the elevated zero maze test (-39%, <i>p</i> < 0.0<em>1</em>) in NW rats indicating anxiety. Interestingly, DIO rats showed no behavioral alterations after the injection of <em>nesfatin</em>-<em>1</em>_30-59 (<i>p</i> > 0.05). These results indicate an implication of <em>nesfatin</em>-<em>1</em>_30-59 in the mediation of anxiety and depression-like behavior/anhedonia under normal weight conditions, while in DIO rats, a desensitization might occur.

Both <em>nesfatin</em>-<em>1</em> and cannabinoid systems involved in the regulation of sleep, metabolism, and food intake. The relationship between cannabinoid system and <em>nesfatin</em>-<em>1</em> levels remains to be elucidated. This study investigated <em>nesfatin</em>-<em>1</em> and insulin resistance in 72-h rapid eye movement (REM) sleep-deprived mice under the effects of cannabinoid, and cannabinoid receptors CB<em>1</em>R and CB2R blocking. Sixty mice were exposed to 72-h sleep deprivation. Groups and drug administrations were as follows: Group <em>1</em> (control) received injection of vehicle. Group 2 received WIN 55,2<em>1</em>2,2. Group 3 received AM25<em>1</em> (CB<em>1</em>R antagonist) followed by WIN 55,2<em>1</em>2,2 injection. Group 4 received SR<em>1</em>44528 (CB2R antagonist) followed by WIN 55,2<em>1</em>2,2 injection. Group 5 received only AM25<em>1</em>. Group 6 received only SR<em>1</em>44528. Blood samples were collected <em>1</em> h after drug administration and prepared for biochemical measurements. Glucose levels were measured by glucometer, whereas insulin and <em>nesfatin</em>-<em>1</em> levels were measured by ELISA. Central <em>nesfatin</em>-<em>1</em> was also assessed using immunohistochemistry. One-way analysis of variance together with post hoc Tukey's test was used for inter-group comparisons. Serum <em>nesfatin</em>-<em>1</em> levels were comparable in all study groups. Brain <em>nesfatin</em>-<em>1</em> immune-positive cell count was lower in WIN group compared to controls. The administration of CB<em>1</em>R or CB2R antagonist prevented reduction in <em>nesfatin</em>-<em>1</em>-positive cell count. Insulin resistance was higher in WINCB2 and CB2 groups than in control and WINCB<em>1</em> groups. Cannabinoid treatment reduced <em>nesfatin</em>-<em>1</em> immunoreactivity in the central nervous system and this effect was prevented by either CB<em>1</em>R or CB2R antagonist pretreatment. Insulin resistance might be related to CB2 receptor activation which was independent from central <em>nesfatin</em>-<em>1</em> immunoreactivity.

Because obesity is a risk factor for many serious illnesses such as diabetes, better understandings of obesity and eating disorders have been attracting attention in neurobiology, psychiatry, and neuroeconomics. This paper presents future study directions by unifying (i) economic theory of addiction and obesity [4-6], and (ii) recent empirical findings in neuroeconomics and neurobiology of obesity and addiction. It is suggested that neurobiological substrates such as adiponectin, dopamine (D2 receptors), endocannabinoids, ghrelin, leptin, <em>nesfatin</em>-<em>1</em>, norepinephrine, orexin, oxytocin, serotonin, vasopressin, CCK, GLP-<em>1</em>, MCH, PYY, and stress hormones (e.g., CRF) in the brain (e.g., OFC, VTA, NAcc, and the hypothalamus) may determine parameters in the economic theory of obesity. Also, the importance of introducing time-inconsistent and gain/loss-asymmetrical temporal discounting (intertemporal choice) models based on Tsallis' statistics and incorporating time-perception parameters into the neuroeconomic theory is emphasized. Future directions in the application of the theory to studies in neuroeconomics and neuropsychiatry of obesity at the molecular level, which may help medical/psychopharmacological treatments of obesity (e.g., with sibutramine), are discussed.

Food intake is regulated by vagal afferent signals from the stomach. <em>Nesfatin</em>-<em>1</em> is an anorexigenic peptide produced within the gastrointestinal tract and has well defined central effects. We aimed to determine if <em>nesfatin</em>-<em>1</em> can modulate gastric vagal afferent signals in the periphery and further whether this is altered in different nutritional states. Female C57BL/6J mice were fed either a standard laboratory diet (SLD) or a high fat diet (HFD) for <em>1</em>2 weeks or fasted overnight. Plasma nucleobindin-2 (NUCB2; <em>nesfatin</em>-<em>1</em> precursor)/<em>nesfatin</em>-<em>1</em> levels were assayed, the expression of NUCB2 in the gastric mucosa and adipose tissue was assessed using real-time quantitative reverse-transcription polymerase chain reaction. An in vitro preparation was used to determine the effect of <em>nesfatin</em>-<em>1</em> on gastric vagal afferent mechanosensitivity. HFD mice exhibited an increased body weight and adiposity. Plasma NUCB2/<em>nesfatin</em>-<em>1</em> levels were unchanged between any of the groups of mice. NUCB2 mRNA was detected in the gastric mucosa and gonadal fat of SLD, HFD and fasted mice with no difference in mRNA abundance between groups in either tissue. In SLD and fasted mice <em>nesfatin</em>-<em>1</em> potentiated mucosal receptor mechanosensitivity, an effect not observed in HFD mice. Tension receptor mechanosensitivity was unaffected by <em>nesfatin</em>-<em>1</em> in SLD and fasted mice, but was inhibited in HFD mice. In conclusion, <em>Nesfatin</em>-<em>1</em> modulates gastric vagal afferent mechanosensitivity in a nutritional state dependent manner.

Ghrelin and <em>nesfatin</em>-<em>1</em> are regulators of blood glucose and energy balance. Prohormone convertases (PCs) enable processing of ghrelin and <em>nesfatin</em>-<em>1</em> from its precursors. An acylation, enabled by ghrelin O-acyl transferase (GOAT) is critical for many of the biological actions of ghrelin. To date, there is no research on the developmental expression of GOAT, and the co-expression of both NUCB2/<em>nesfatin</em>-<em>1</em> and prohormone convertases in the pancreas. The objective of this research was to immunolocalize ghrelin, GOAT, NUCB2/<em>nesfatin</em>-<em>1</em>, PC<em>1</em>/3 and PC2 in the pancreas during fetal and postnatal periods of Sprague Dawley (SD) rats using immunohistochemical analysis. GOAT mRNA in the rat pancreas during development was also determined. In the pancreas, not all islet cells immunopositive for GOAT are immunoreactive for ghrelin on postnatal (P) days 20, 27 and adult. GOAT mRNA expression in the pancreas at P27 was higher than the expression levels in rest of the developmental stages tested. Both PC<em>1</em>/3 and PC2 are co-expressed with NUCB2/<em>nesfatin</em>-<em>1</em> on embryonic (E) day E2<em>1</em>, P<em>1</em>3, P20. While similar co-localization was also found in P27 for NUCB2/<em>nesfatin</em>-<em>1</em> and PC<em>1</em>/3, NUCB2/<em>nesfatin</em>-<em>1</em> and PC2 were found in distinct populations of cells in P27. Some ghrelin and GOAT positive cells stained for <em>nesfatin</em>-<em>1</em> as well. Meanwhile, no co-localization of somatostatin and glucaon with <em>nesfatin</em>-<em>1</em> was found in the pancreas of SD rats. Our findings suggest that the endocrine pancreas can produce and process precursors of ghrelin and <em>nesfatin</em>-<em>1</em> to make bioactive forms of both peptides.

Stress is known to cause severe adverse effects in the human gastrointestinal tract including mucosal microbleedings and erosions or even gastric ulceration but the mechanism of these complications has not been fully elucidated. The pathogenesis of stress-induced gastric damage involves the fall in Gastric Blood Flow (GBF), an increase in gastric acid secretion and gastric motility, enhanced adrenergic and cholinergic nerve activity and the rise in gastric mucosal generation of reactive oxygen species. The gastric mucosal defense mechanisms against the deleterious effect of stress include the activation of the hypothalamic-pituitary-adrenal axis which has been linked with glucocorticoids release capable of counteracting of stress-induced gastric lesions. Here we summarize the novel gastroprotective mechanisms against stress damage exhibited by angiotensin-(<em>1</em>-7), the newly discovered metabolite of Renin-Angiotensin System (RAS), the gaseous mediators such as nitric oxide (NO), hydrogen sulfide (H2S) or Carbon Monoxide (CO), and the food intake controlling peptides ghrelin, <em>nesfatin</em>- <em>1</em> and apelin possibly acting via brain-gut axis. These bioactive molecules such as RAS vasoactive metabolite angiotensin-(<em>1</em>-7) and appetite peptides have been shown to afford gastroprotective effect against stressinduced gastric lesions mainly mediated by an increase in gastric microcirculation. Gaseous mediators protect the gastric mucosa against stress lesions by mechanism involving the activation of PG/COX and CO/HO-<em>1</em> biosynthetic pathways, and their anti-inflammatory and anti-oxidizing properties. Thus, these new components add new mechanistic aspects to the common cooperation of NO/NO-synthase, PG/COX systems and vasoactive sensory neuropeptides including CGRP but their gastroprotective efficacy against experimental stress ulcerogenesis requires the confirmation in human clinical trials.

Adipokines and other biomarkers were previously identified with roles in energy expenditure, appetite, satiety, and adiposity. Therefore, we investigated whether dietary weight loss-induced changes in adipokines and other biomarkers known to play a role in weight regulation or energy expenditure could predict weight regain in people with overweight and obesity. In this randomized controlled trial 26 males and 30 females (BMI: 28-35 kg/m2) followed either a low-calorie diet (LCD; <em>1</em>250 kcal/day) for <em>1</em>2 weeks or a very-low-calorie diet (VLCD; 500 kcal/day) for 5 weeks followed by a weight stable period of 4 weeks (dietary intervention (DI) period) and a 9-month follow-up period. Blood samples were taken before and after each period to measure FFA, TAG, total cholesterol, insulin, glucose, angiotensin-converting enzyme (ACE) activity, IL-6, RBP4, apelin, leptin, adiponectin, vaspin, and <em>nesfatin</em>-<em>1</em> concentrations. Weight loss was similar between groups (LCD: -8.2 ± 0.5 kg; VLCD: -8.9 ± 0.4 kg, P = 0.30). Only changes in ACE activity, FFA and RBP4 concentrations during DI were correlated with weight regain in the whole group (r = -0.299, P = 0.030, r = -0.274, P = 0.047, and r = 0.357, P = 0.008, respectively). Together they explained 28% (r = 0.532) of weight regain variation. Dietary weight loss-induced changes in ACE activity, FFA and RBP4 independently contribute to weight regain prediction.

Neurons in the hypothalamus function to regulate the state of the animal during both learned and innate behaviors, and alterations in hypothalamic development may contribute to pathological conditions such as anxiety, depression or obesity. Despite many studies of hypothalamic development and function, the link between embryonic development and innate behaviors remains unexplored. Here, focusing on the embryonically expressed homeodomain-containing gene Developing Brain Homeobox <em>1</em> (Dbx<em>1</em>), we explored the relationship between embryonic lineage, post-natal neuronal identity and lineage-specific responses to innate cues. We found that Dbx<em>1</em> is widely expressed across multiple developing hypothalamic subdomains. Using standard and inducible fate-mapping to trace the Dbx<em>1</em>-derived neurons, we identified their contribution to specific neuronal subtypes across hypothalamic nuclei and further mapped their activation patterns in response to a series of well-defined innate behaviors.

Dbx<em>1</em>-derived neurons occupy multiple postnatal hypothalamic nuclei including the lateral hypothalamus (LH), arcuate nucleus (Arc) and the ventral medial hypothalamus (VMH). Within these nuclei, Dbx<em>1</em> (+) progenitors generate a large proportion of the Pmch-, Nesfatin-, Cart-, Hcrt-, Agrp- and ERα-expressing neuronal populations, and to a lesser extent the Pomc-, TH- and Aromatase-expressing populations. Inducible fate-mapping reveals distinct temporal windows for development of the Dbx<em>1</em>-derived LH and Arc populations, with Agrp(+) and Cart(+) populations in the Arc arising early (E7.5-E9.5), while Pmch(+) and Hcrt(+) populations in the LH derived from progenitors expressing Dbx<em>1</em> later (E9.5-E<em>1</em><em>1</em>.5). Moreover, as revealed by c-Fos labeling, Dbx<em>1</em>-derived cells in male and female LH, Arc and VMH are responsive during mating and aggression. In contrast, Dbx<em>1</em>-lineage cells in the Arc and LH have a broader behavioral tuning, which includes responding to fasting and predator odor cues.

We define a novel fate map of the hypothalamus with respect to Dbx<em>1</em> expression in hypothalamic progenitor zones. We demonstrate that in a temporally regulated manner, Dbx<em>1</em>-derived neurons contribute to molecularly distinct neuronal populations in the LH, Arc and VMH that have been implicated in a variety of hypothalamic-driven behaviors. Consistent with this, Dbx<em>1</em>-derived neurons in the LH, Arc and VMH are activated during stress and other innate behavioral responses, implicating their involvement in these diverse behaviors.

Free and bound phenolics were extracted from the fibre fraction of wholemeal (W) wheat and barley (B) cookies which had been fortified with <em>1</em>5% blackcurrant powder. Blackcurrant enriched cookies contained between 55 and 66 % higher total phenolics respectively compared control cookies. Ferulic acid in wheat and barley cookie extracts, and quercetin and kaempferol-3-glucoside in wheat cookies with <em>1</em>5% blackcurrant were the dominant phenolic acids. Cellular antioxidant activity was higher in samples with blackcurrant inclusion when evaluated in a cancer cell HepG2 model. Inhibition of cell proliferation was lower for the phenolic samples from cookies with blackcurrant addition. These samples suppressed the regulation of inflammatory cytokine IL-<em>1</em>β (about 3 to 4-fold), IL-6 (about 2-fold) and transcription signalling factor NF-kB (about 2-fold) and showed an up-regulation of the satiety gene NUCB-2/<em>nesfatin</em>-<em>1</em> (about 4-fold) in compared with control samples.

Food intake is a complex, multifaceted process that involves the integration of numerous nutritional signals and behavioral outputs. Dozens of centrally acting peptide hormones that contribute to the control of appetite and food intake have been identified. Two recently described peptide hormones, neuronostatin and <em>nesfatin</em>-<em>1</em>, both act in the brain to induce anorexia, albeit through potentially different mechanisms. In this chapter, the central circuits mediating the anorexigenic effect of these two hormones, their interaction with the central melanocortin and oxytocin systems, and the physiological relevance of these hormones in appetite control are described and an integrated model of hypothalamic control of energy intake is presented.

OBJECTIVE

To investigate serum concentration of <em>nesfatin</em>-<em>1</em> in underweight children who have poor appetite, and its association with anthropometric markers of malnutrition.

METHODS

We recruited 50 underweight children and adolescents (aged 2-<em>1</em>8 years) who presented with loss of appetite. Thirty age- and sex-matched controls were also included in the study. Fasting serum <em>nesfatin</em>-<em>1</em> concentrations were measured by using Enzyme-Linked Immunosorbent Assay (ELISA) technique.

RESULTS

Mean <em>nesfatin</em>-<em>1</em> level was significantly higher in underweight children when compared to controls (p<0.00<em>1</em>). There was no correlation between serum <em>nesfatin</em>-<em>1</em> levels and anthropometrics markers.

CONCLUSIONS

Our results suggest that <em>nesfatin</em>-<em>1</em> might have an important role in regulation of food intake and pathogenesis of loss of appetite in children.

<AbstractText>Ongoing high mortality due to necrotizing enterocolitis (NEC) necessitates the investigation of novel treatments to improve the outcome of the affected newborns. The aim was to elucidate the potential therapeutic impact of the <em>nesfatin</em>-<em>1</em>, a peptide with anti-inflammatory and anti-apoptotic effects in several inflammatory processes, on NEC-induced newborn rats.</AbstractText><AbstractText>Sprague-Dawley pups were separated from their mothers, fed with a hyperosmolar formula and exposed to hypoxia, while control pups had no intervention. NEC-induced pups received saline or <em>nesfatin</em>-<em>1</em> (0.2 μg/kg/day) for 3 days, while some <em>nesfatin</em>-<em>1</em> treated pups were injected with capsaicin (50 μg/g) for the chemical ablation of afferent neurons. On the 4th day, clinical state and macroscopic gut assessments were made. In intestines, immunohistochemical staining of cycloxygenase-2 (COX-2), nuclear factor (NF)-κB-p65 (RelA), vascular endothelial growth factor (VEGF), claudin-3 and zonula occludens-<em>1</em> (ZO-<em>1</em>) were performed, while gene expressions of COX-2, occludin, claudin-3, NF-κB-p65 (RelA) and VEGF were determined using q-PCR. In fecal samples, relative abundance of bacteria was quantified by q-PCR. Biochemical evaluation of oxidant/antioxidant parameters was performed in both intestinal and cerebral tissues.</AbstractText><AbstractText>Claudin-3 and ZO-<em>1</em> immunoreactivity scores were significantly elevated in the <em>nesfatin</em>-<em>1</em> treated control pups. <em>Nesfatin</em>-<em>1</em> reduced NEC-induced high macroscopic and clinical scores, inhibited NF-κB-65 pathway and maintained the balance of oxidant/antioxidant systems. NEC increased the abundance of Proteobacteria with a concomitant reduction in Actinobacteria and Bacteroidetes, while <em>nesfatin</em>-<em>1</em> treatment reversed these alterations. Modulatory effects of <em>nesfatin</em>-<em>1</em> on microbiota and oxidative injury were partially reversed by capsaicin. Immunohistochemistry demonstrated that <em>nesfatin</em>-<em>1</em> abolished NEC-induced reduction in claudin-3. Gene expressions of COX-2, NF-κB, occludin and claudin-3 were elevated in saline-treated NEC pups, while these up-regulated mRNA levels were not further altered in <em>nesfatin</em>-<em>1</em>-treated NEC pups.</AbstractText><AbstractText><em>Nesfatin</em>-<em>1</em> could be regarded as a potential preventive agent for the treatment of NEC.</AbstractText>

Background Although specific role players are currently unknown, contribution of inflammatory mediators has been suggested in the pathophysiology of idiopathic intracranial hypertension (IIH), which is a disease more prevalent in obese female individuals of childbearing age. We aimed to investigate the levels of adipokines and cytokines to demonstrate possible markers for inflammation that participate in IIH pathophysiology and their association with clinical features of IIH. Methods IIH patients, diagnosed according to the revised criteria, and age-, gender- and body mass index (BMI)-matched healthy controls were enrolled in this study. Serum samples were evaluated for insulin-like growth factor <em>1</em>, insulin, <em>nesfatin</em>, adiponectin, interleukin (IL)-<em>1</em>β, IL-6, IL-8, leptin, plasminogen activator inhibitor type-<em>1</em>, resistin, tumour necrosis factor-alpha (TNF-α) and monocyte chemotactic protein <em>1</em> via enzyme-linked immunosorbent assay or multiplex immunoassays. Results IL-<em>1</em>β level was significantly higher ( p = 0.0<em>1</em>2), and IL-8 and TNF-α levels were significantly lower in the IIH group ( p < 0.00<em>1</em> and p = 0.008, respectively) compared to the control group. There were no correlations between the cytokine/adipokine levels and age, BMI, disease duration, and cerebrospinal fluid oligoclonal bands. There were also no significant differences in cytokine and adipokine levels between IIH patients regarding visual impairment. However, statistically significant differences were found between IIH patients with relapse versus healthy controls regarding IL-<em>1</em>β ( p = 0.007), IL-8 ( p = 0.00<em>1</em>) and TNF-α ( p = 0.0<em>1</em>7) levels. Other investigated cytokines and adipokines showed no significant alterations in IIH patients investigated in the remission period. Conclusion Altered serum levels of IL-<em>1</em>β, IL-8 and TNF-α seem to be associated with IIH pathogenesis, and these cytokines may be used as prognostic markers in IIH to predict relapse.

The anorexigenic neuropeptide NEFA/nucleobindin 2 (NUCB2)/<em>nesfatin</em>-<em>1</em>-containing neurons are distributed in the brain regions involved in feeding regulation. In spite of the growing knowledge of its physiological functions through extensive studies, its molecular mechanism of reaction, including its receptor, remains unknown. NUCB2/<em>nesfatin</em>-<em>1</em> is also involved in various peripheral regulations, including glucose homeostasis. In pancreatic beta-cells, NUCB2/<em>nesfatin</em>-<em>1</em> is reported to enhance glucose-stimulated insulin secretion (GSIS) but its exact mechanism remains unknown. To clarify this mechanism, we measured the effect of <em>nesfatin</em>-<em>1</em> on the electrical activity of pancreatic beta-cells. Using mouse primary beta cells, we measured changes in the ATP-sensitive K+ (KATP) channel current, the voltage-gated K+ (Kv) channel current, and insulin secretion upon application of <em>nesfatin</em>-<em>1</em>. <em>Nesfatin</em>-<em>1</em> inhibited the Kv channel, but KATP channel activity was unaffected. <em>Nesfatin</em>-<em>1</em> enhanced insulin secretion to a same level as Kv channel blocker tetraethylammonium (TEA). The effect was not further enhanced when <em>nesfatin</em>-<em>1</em> and TEA were applied simultaneously. The inhibition binding assay with [<em>1</em>25I]<em>nesfatin</em>-<em>1</em> in Kv2.<em>1</em> channels, major contributor of Kv current in beta cell, expressing HEK239 cells indicated the binding of <em>nesfatin</em>-<em>1</em> on Kv2.<em>1</em> channel. Because Kv channel inhibition enhances insulin secretion under high glucose conditions, our present data suggest a possible mechanism of <em>nesfatin</em>-<em>1</em> on enhancing GSIS through regulation of ion channels rather than its unidentified receptor.

<em>Nesfatin</em>-<em>1</em> is an 82 amino acids peptide processed from its precursor nucleobindin-2 (NUCB2). Accumulating evidences have shown that the <em>nesfatin</em>-<em>1</em>/NUCB2 localized in the paraventricular nucleus (PVN) of the hypothalamus regulates food intake and energy metabolism. However, the factors that regulate <em>nesfatin</em>-<em>1</em>/NUCB2 neurons in PVN are less defined. In the hypothalamic feeding center, the second-order neurons in PVN are extensively projected by the first-order neurons in the arcuate nucleus (ARC), the representatives of which are orexigenic neuropeptide Y (NPY) and anorexigenic α-melanocyte-stimulating hormone (α-MSH) neurons. The present study explored whether NPY and α-MSH regulate the PVN <em>nesfatin</em>-<em>1</em>/NUCB2 neurons. This was achieved by cytosolic Ca ([Ca]i) imaging, followed by <em>nesfatin</em>-<em>1</em>/NUCB2 immunostaining in single neurons isolated from PVN. The moderate increase in [Ca]i with 5 mM glucose was suppressed by NPY, but further increased by α-MSH in the PVN neurons that were shown to be immunoreactive to <em>nesfatin</em>-<em>1</em>/NUCB2. The majority (60%) of <em>nesfatin</em>-<em>1</em>/NUCB2 neurons in PVN responded to NPY and/or α-MSH. Confocal immunohistochemical images showed that both NPY and α-MSH neuronal terminals contacted <em>nesfatin</em>-<em>1</em>/NUCB2 neurons in PVN. These data show that NPY inhibits and α-MSH activates PVN <em>nesfatin</em>-<em>1</em>/NUCB2 neurons, presenting dual and reciprocal neuro-circuits from ARC to PVN, possibly contributing toward the balanced regulation of feeding.