nesfatin-1 is an 82-amino - acid peptide originated from post translational processing of the n - terminal fragment of nucleobindin 2 ( nucb2 ) , a 396-amino - acid protein exceptionally conserved across mammalian species ( oh - i et al . , 2006 ) .
post translational cleavage of nucb-2 appears in the expression of nesfatin-2 fragment ( 85 - 163 ) and nesfatin-3 fragment ( 166 - 396 ) in addition to nesfatin-1 ( oh - i et al . , 2006 ) .
( 2006 ) suggested that nesfatin-1 ( named as acronym for nefa / nucleobindin2-encoded satiety- and fat - influencing protein ) may have physiological importance in regulating food intake .
in fact , nesfatin-1 injected into the third brain ventricle reduces food consumption occurring during the dark phase , whereas nesfatin-2 or nesfatin-3 had no effect ( oh - i et al . , 2006 ) . in the same way , continuous infusion of nesfatin-1
( 5 pmol / day for 10 days into the third brain ventricle ) decreases significantly food intake and body weight gain in rats ( oh - i et al . , 2006 ) .
conversely , third ventricle infusion of a nucb-2 antisense oligonucleotide increases food intake and body weight gain compared with a missense nucb-2 oligonucleotide ( oh - i et al . , 2006 ) . additionally , a 24-h fast decreased the expression of nucb-2 in the paraventricular nucleus ( pvn ) ( oh - i et al . , 2006 ) .  
albayrak et al . , 2013 ) showed high expression level of nesfatin-1/nucb-2 expression in relevant hypothalamic and medullary sites implicated in feeding regulation in rats .
the arcuate nucleus , pvn , and the nucleus of the solitary tract ( nts ) , further supporting the evidence that nesfatin-1 is involved in food intake regulation .  
nesfatin-1 is co - expressed with melanin - concentrating hormone ( mch ) in neurons from the tuberal hypothalamic area ( tha ) which are recruited during sleep states , especially paradoxical sleep ( ps ) ( jego et al . , 2012 ) .
to help decipher the contribution of this contingent of tha neurons to sleep regulatory mechanisms , jego et al .
( 2012 ) thus investigated in rats whether the co - factor nesfatin-1 is also endowed with sleep - modulating properties .
it was found that the disruption of the brain nesfatin-1 signaling achieved by icv administration of nesfatin-1 antiserum or antisense against the nucleobindin2 ( nucb2 ) prohormone suppressed ps with little , if any alteration of slow wave sleep ( sws ) ( jego et al . , 2012 ) .
additionally , the infusion of nesfatin-1 antiserum after a selective ps deprivation , designed for elevating ps needs , severely prevented the ensuing expected ps recovery ( jego et al . , 2012 ) .
( 2012 ) finally demonstrated by using c - fos as an index of neuronal activation that the recruitment of nesfatin-1-immunoreactive neurons within tha is positively correlated to ps but not to sws amounts experienced by rats prior to sacrifice . in conclusion , this work supports a functional contribution of the nesfatin-1 signaling , operated by tha neurons , to ps regulatory mechanisms .
( 2012 ) proposed that these neurons , likely releasing mch as a synergistic factor , constitute an appropriate lever by which the hypothalamus may integrate endogenous signals to adapt the ultradian rhythm and maintenance of ps in a manner dictated by homeostatic needs .
this could be done through the inhibition of downstream targets comprised primarily of the local hypothalamic wake - active orexin- and histamine - containing neurons ( jego et al . , 2012 ) .
activation of brain crf signaling pathways by crf acting on crf1 and crf2 receptors and by selective endogenous crf2 agonists urocortin 2 or 3 ( chen et al . ,
nesfatin-1 injected intracerebroventricularly significantly decreased gastric emptying ( garca - galiano et al . , 2012 ) .
goebel - stengel and wang ( 2012 ) showed that nucb2/ nesfatin-1 immunoreactivity is distributed in mouse brain areas involved in the regulation of stress response and visceral functions activated by an acute psychological stressor suggesting that nesfatin-1 might play a role in the efferent component of the stress response .
peptides regulating food intake often act in concert or in series with other neurotransmitters to exert their actions ( perry and wang , 2012 ) .
nesfatin-1/nucb-2 is co - localized with a number of hypothalamic peptides regulating food intake ( fort et al . , 2008 ; shimizu et al . , 2009 ; maejima et al
, 2009 ; yoshida et al . , 2010 ; tan et al . , 2011 ; kerbel and unniappan , 2012 ; goebel - stengel and wang , 2013 ) .
several interactions have been described to underlie the central anorexic effect of nesfatin-1 ( shimizu et al . , 2009 ) .
it has also been shown to play important roles in the control of cardiovascular function ( mimee et al . , 2012 ) .
in situ hybridization and immunohistochemical researches have evidentiated the expression of nesfatin-1 throughout the brain and , particularly , in the medullary autonomic gateway known as the nucleus of the solitary tract ( nts ) ( mimee et al . , 2012 ) .
( 2012 ) showed that provide critical insight into the circuitry and physiology involved in the profound effects of nesfatin-1 and highlight the nts as a key structure mediating these autonomic actions .
two proteins have been localized in the arcuate nucleus ( arc ) and implicated in the regulation of food intake : the serine - threonine - kinase mammalian target of rapamycin ( mtor ) as part of the tor signaling complex 1 ( torc1 ) , and nesfatin-1 derived from the precursor protein nucleobindin2 , as reported by inhoff et al .
in fact , nesfatin-1 is not only intracellularly co - localized with cocaine- and amphetamine - regulated transcript ( cart ) peptide as reported before , but also with phospho - mtor ( pmtor ) and neuropeptide y ( npy ) in arc neurons ( inhoff et al . , 2010 ) .
this data could also confirm results from previous studies , showing that the majority of nesfatin-1 neurons are also positive for cart peptide , whereas most of the pmtor is co - localized with npy and only to a lesser extent with cart ( inhoff et al . ,
a study , described by maejima et al . ( 2009 ) , provided a strong evidence for the involvement of oxytocin pathway in nesfatin-1 's inhibitory effect on food intake .
first of all , oxytocin injected into the 3v reduces food intake via a leptin - independent mechanism ( maejima et al . ,
2009 ) . at the same time nesfatin-1 injected into the 3v activates oxytocin - positive neurons in the magnocellular part of the pvn as assessed by double labelling for fos / oxytocin immunoreactivity and in vitro it stimulates the release of oxytocin from pvn neurons ( maejima et al . , 2009 ) .
in addition there is pharmacologic and anatomical support for oxytocinergic projections from the pvn to the nucleus of the solitary tract to be involved in the anorexigenic signalling of nesfatin-1 ( maejima et al . , 2009 ) .
an oxytocin receptor antagonist injected into the hindbrain at the level of the 4v blocked the food intake reducing effect of nesfatin-1 injected into the pvn and tracing studies showed synaptic contacts between oxytocinergic nerve terminals and pro - opiomelanocortin ( pomc ) neurons in the nucleus of the solitary tract .
yosten and samson ( 2010 ) also showed that an oxytocin antagonist injected intracerebroventricular blocks the food intake suppressing effects of intracerebroventricular nesfatin-1 and -melanocyte - stimulating hormone ( -msh ) .
therefore , nesfatin-1 acts through a serial neuronal circuit , in which nesfatin-1 activates the central melanocortin system , which , in turn , acts through the central oxytocin system , leading to an inhibition of food and water intake and an increase in mean arterial pressure ( yosten and samson , 2010 ) .
future research should seek to clarify whether the hypothalamic / nesfatin-1-oxytocin - brainstem / pomc signalling is the predominant pathway or an intrahypothalamic nesfatin-1-pomc / oxytocin network exists .
some studies showed that based on the observation of a delayed and long lasting anorexigenic effect , following intracerebroventricular injection of nesfatin-1 which mimics the characteristics of the food intake reducing effect of crf2 receptor agonists , urocortins ( chen et al .
the possible involvement of the crf2 receptors in the mediation of nesfatin-1 's effect was investigated .
the crf2 antagonist , astressin2-b ( wang et al . , 2013 ) , injected intracerebroventricular completely abolished the dark phase food intake reduction induced by intracerebroventricular nesfatin-1 ( stengel et al . , 2009 ) .
by contrast , a control peptide of similar structure as astressin2-b but without affinity to the crf2 receptor did not influence intracerebroventricular nesfatin-1 's action ( stengel et al . , 2009 ) .
( 2009 ) , astressin2-b injected intracerebroventricular did not modulate the rapid onset reduction of food intake observed after intracerebroventricular injection of nesfatin-1 .
in contrast to the effect on food intake , the crf2 antagonist , astressin2-b injected intracerebroventricular did not alter the intracerebroventricular nesfatin-1 induced delayed gastric emptying ( stengel et al . ,
2009 ) giving rise to different downstream signalling pathways mediating intracerebroventricular nesfatin-1 's inhibitory effects on food intake and gastric transit . finally ,
as reported by yosten and samson ( 2010 ) , the melanocortin 3/4 receptor antagonist , shu9119 injected intracerebroventricular diminished , and into the 3v abolished ( oh - i et al . , 2006 ) ,
the anorexigenic effect of nesfatin-1 . nesfatin-1 probably act in series through the recruitment of the central melanocortin and crf2 's pathways to reduce food intake .
another , intracerebroventricular administration of nesfatin-1 induced c - fos expression in crf neurons , and nesfatin-1 increased cytosolic ca2 + concentrations in single crf neurons in the pvn ( jia et al . , 2013 ) . it is now well established that the brain crf / crf1 signaling system modulates pain responses ( jia et al . , 2013 ) .
these observations suggest that nesfatin-1 may be involved in the autonomic regulation of visceral sensation ( jia et al . , 2013 ) .
jia et al . ( 2013 ) suggested that nesfatin-1 may be associated with the visceral hypersensitivity state of irritable bowel syndrome , and this may be mediated , at least in part , by brain crf / crf1 signaling pathways .
it has also been postulated that nesfatin-1/nucb-2 may be produced by the hypothalamus ( goebel - stengel and wang , 2013 ) ; the relatively high cerebrospinalfluid ( csf)/plasma nesfatin-1/nucb-2 ratios suggest that a substantial amount of csf nesfatin-1/nucb-2 may originate from central neurons . the possible discrepancy in the production of nesfatin-1/nucb-2 , by these central neurons may account for the differences in csf / plasma nesfatin-1/nucb-2 ratio between obese and lean subjects observed by tan et al .
furthermore , it is probable that nesfatin-1/nucb-2 has protein binding , and that differences in protein binding in obese and lean subjects may also explain these findings .
finally , it is possible that the efficiency of nesfatin-1/nucb-2 uptake into csf is reduced in obese individuals , possibly due to saturation of transporters ( tan et al . , 2011 ) .
some data demonstrated that nesfatin-1/nucb-2 is a novel depot - specific adipokine preferentially expressed in subcutaneous adipose tissue / adipocytes .
adipose tissue nesfatin-1/nucb-2 expression increases with obesity and is altered in states of feeding and malnutrition ( ramanjaneya et al . , 2010 ) .
reduced leptin sensitivity or leptin resistance is a common phenomenon in obesity ( ramanjaneya et al . , 2010 ) . in the light of this and the pre - clinical findings that central and peripheral injection of nesfatin-1 exerts its food reducing effects via a leptin - independent mechanism ( oh - i et al . , 2006
; shimizu et al . , 2009 ) , targeting nesfatin-1 may be a promising approach in the drug treatment of obesity and its complications .
ongoing pre - clinical data suggest the possible use of subcutaneous and intranasal routes of nesfatin-1 administration ( shimizu et al . , 2009 ) , which needs to be further explored .
another important aspect to be unraveled is the weight loss upon chronic administration of nesfatin-1 ( li et al . , 2010 ;
gonzalez et al . , 2012 ; li et al . , 2013 ; dong et al . , 2013 ) and possible related changes in energy balance and/or basal metabolic rate ( foo et al
, 2008 ; garca - galiano et al . , 2010 ; gonzales et al . , 2011 ; paasz et al . , 2012 ; kerbel and unniappan , 2012 ; garca - galiano et al . , 2012 ; ghanbari niaki et al . , 2013 ; vas et al . ,
in fact , nesfatin-1 has a remarkably prolonged effect on food intake and body temperature ( knczl et al . , 2012 ) .
time course of nesfatin-1 's effects may be varied depending on the time applied ( knczl et al . , 2012 ) .
many of the nesfatin-1/nucb2 neurones are cold sensitive , and are positioned in key centres of thermoregulation ( knczl et al . , 2012 ) .
nesfatin-1 regulates energy expenditure a far more potent way than it was recognised before making it a preferable candidate anti - obesity drug ( knczl et al . , 2012 ) .  
future research should seek to clarify whether nesfatin-1/nucb-2 would be beneficial in the management of obesity .
another , bariatric surgery produces differential influences with regards to circulating nesfatin-1 and in particular the receptor involved in the peptide 's actions , and the processing of nucb2 to nesfatin-1 in hypotalamic or gut tissues still remain elusive ( finelli et al . , 2014 ) .
the data obtained in basic experiments of nesfatin-1 should be useful for the development of a new anti - obesity treatment .
however , the mechanisms of endocrine and metabolic effects of nesfatin-1 have not been known well by now , and the influences of nesfatin-1 administered peripherally should be much more clarified in vivo before starting controlled clinical trials in the future .
in fact , the details of nesfatin-1 physiology ought to be clarified , and it may be considered suitable in the future , as a potential drug in the pharmacotherapy of obesity .
on the other hand , some putative nesfatin-1 antagonists may improve eating disorders ( paasz et al . , 2012 ) .
 in this article , we review on the current concepts about nesfatin-1 as a new anti - obesity treatment and evaluate the existing issues in the context of this knowledge and the available literature . 
 the intent is to enable clinicians to know nesfatin-1 as a new anti - obesity treatment and make rational decisions based on this perspective as possible clinical application . 
 future research should seek to clarify whether nesfatin-1 would be beneficial in the management of obesity . 
Introduction
Nesfatin-1/NUCB-2 and anorexigenic effect
Nesfatin-1 and anti-obesity treatment
Conclusive remarks
Disclosure statement