国际精神病学杂志 JOURNAL OF INTERNATIONAL PSYCHIATRY 2017 年第 44 卷第 1 期 - - Advances in Research of Nesfatin-1 Mediated Stress and Stress-Related Anxiety and D

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1 Advances in Research of Nesfatin-1 Mediated Stress and Stress-Related Anxiety and Depressive Disorder WANG Gaohua 1 WU Shengjuan 1 WANG Huiling 1 WEI Yanyan 1 LI Jiangbo 2 ABSTRACT Nesfatin-1 is a novel appetite inhibitory factor. The studies in recent years show that Nesfatin-1 is also involved in the process of stress response. The studies on pathogenesis of Nesfatin-1 mediated stress response and stress-related anxiety and depressive disorder were reviewed in this paper. Key Words Nesfatin-1 Stress Anxiety Depression CLC R74. Document Code A Paper NO Nesfatin-1 is a polypeptide composed of N-terminal 82 amino acids formed by nucleobindin 2 NUCB2 under the action of hormone lyase. Nesfatin-1 was found to be a novel feeding inhibitory factor and widely expressed in the also been found in other stress-related nuclei in the main center and co-expressed with the stress-related neuropeptide and meanwhile it has played an important role in mediating the stress response while the stress response is associated closely with the pathogenesis of anxiety and depressive disorders. More and more studies show that Nesfatin-1 has been disorder is still unclear. Therefore the review of Nesfatin-1 and its studies will be of an important significance in the clinical diagnosis and treatment of the anxiety and depressive disorder. 1. Distribution of Nesfatin-1 in Central Nervous System In the animal studies Nesfatin-1 was found to be distributed in stress regulation-associated nuclei in the central nervous system and co-expressed with stress-related neuropeptide. For example in the hypothalamus Nesfatin-1 was mainly expressed in the paraventricular nucleus PVN arcuate nucleus ARC supraoptic nucleus SON perifornical nucleus PEF dorsal nucleus lateral hypothalamus area and zone-shaped area meanwhile coexpressed with corticotropin releasing hormone CRH growth somatostatin vasopressin oxytocin melanophorecontracting hormone MCH and cocaine-amphetamine-regulated transcript CART in the hypothalamus. Nesfatin-1 was also expressed in the pituitary and its expression in the pituitary was greater than that in the hypothalamus a large number of Nesfatin-1 expressions were also found in oculomotor nucleus EW dorsal raphe nucleus DR raphe pallidus nucleus RPa locus coeruleus LC and nucleus tractus solitarius NTS and they were co-expressed in CART urothelin norepinephrine and 5- hydroxytryptamine HT in the stress-sensitive marginal areas of the central nervous system a large number of Nesfatin-1 positive neurons were also distributed such as central amygdaloid nucleus CeA and Oval bed nucleus of stria terminalis BSTov. The distribution of Nesfatin-1 in the central nervous system and its co-expression with the associated neuropeptides suggest that it may be involved in the regulation of stress response. Funding: this paper was supported by the National Science Foundation of China ( ) and Natural Science Foundation of Hubei Province of China (201 CFA02 ). Institutions of Authors: 1 Mental Health Center of Renmin Hospital of Wuhan University (Wuhan ); 2 Department of Clinical Psychology of the Second People s Hospital of Wuhu City, Jiangsu. First Author: WANG Gaohua ( ), male, born in Tianmen, Hubei; M.D and chief physician; Research interests: Biology and psychopharmacology of depression. Corresponding Author: LI Jiangbo, lijiangbo involved in the pathogenesis of anxiety and depressive disorder. However the pathogenesis of anxiety and depressive hypothalamus. The hypothalamus is the main neural center of stress response regulation. In recent years Nesfatin-1 has

2 2. Nesfatin-1 and Stress 2.1 Nesfatin-1 and Acute Stress Proto-oncogene C-Fos is one of the immediate early genes IEG and it can be quickly expressed via the induction of many stimuli drugs and normal nerve impulses and its expressed product - Fos protein appeared in the activated neuron nucleus which can used as the marker of neuronal activation. The studies show that after the acute restraint stress reaction of 30 min Fos protein expression of Nesfatin-1 positive neurons in SON PVN ventrolateralmedulla VLM LC caudal NTS and RPa in rat was up-regulated for different degrees but there was no change of plasma Nesfatin-1 level which indicates that the acute restraint stress reaction can excite the Nesfatin-1 positive neurons in the central nervous system thus regulating the autonomic nervous system and stressrelated behaviors. Nesfatin-1 neurons in EW nucleus of mice can be excited by the acute restraint stress to increase the levels of NUCB2 mrna 1. However it was found in the studies of rats that Nesfatin-1 neurons in EW nucleus of rats can also be excited by the acute stress but the level of NUCB2 mrna did not change 2 which indicates that the difference of species may be existed for the Nesfatin-1 mediated stress response. Furthermore the water avoidance stress WAS model can excite to different extent the Nesfatin-1 positive neurons in PVN LC RPa VLM and NTS. Xu et al. found that the WAS induced the increase of plasma Nesfatin-1 concentration and hypothalamus NUCB2 mrna expression and it was positively correlated with the increase of cortisol 3 which indicates that Nesfatin-1 mediated acute stress reaction is associated with the HPA axis. The intraperitoneal injection of lipopolysacchharide LPS namely an inflammatory stress model also excited or stimulated the Nesfatin-1 positive neurons of different percentages in central nuclei such as PVN 34 NTS 20 SON 52 and ARC 5 and simultaneously the highest level of plasma Nesfatin-1 was reached 5h after injection of the LPS. Rats were subject to abdominal surgery and the findings show that the excitability of Nesfatin-1 positive neurons in the central nervous system and stress-related nuclei increased. Konczol et al. reported that adrenalectomy could increase the expression of NUCB2 mrna in PVN while the intravenous injection of Nesfatin-1 could significantly increase the concentration of serum adrencocorticotropic hormone ACTH and serum corticosterone 4 which indicates that there is a certain feedback relationship between Nesfatin-1 and adrenal corticosterone. This proves that the restraint stress water avoidance stress inflammatory stress and surgical stress can excite to different extent the Nesfatin-1 positive neurons in the central nervous system. However any attempt to elucidate the stress response mechanism mediated by Nesfatin-1 positive neurons in different brain regions shall be further researched. 2.2 Nesfatin-1 and Chronic Stress At present there are few studies on the Nesfatin-1 mediated chronic stress. By establishing the chronic unpredictable mild stress CUMS model Xu et al. found that the excitability of Nesfatin-1 positive neurons in EW nuclei increased but the level of NUCB2 mrna did not change 2 and the acute stress could however increase the level of NUCB2 mrna 1. This shows that Nesfatin-1 mediated acute and chronic stress mechanisms may be different. Moreover in the EW nuclei only 35 of Nesfatin-1 positive neurons were activated by the CUMS 2 and also no change of expression level of NUCB2 mrna of hypothalamus and plasma Nesfatin-1 level in rats with the CUMS model was reported in some studies which shows that the Nesfatin-1 neurons are still not sensitive to the chronic stress. 2.3 Central Nervous Intervention of Exogenous Nesfatin-1 The injection of Nesfatin-1 in the lateral ventricles and the third ventricle could increase the plasma ACTH and corticosterone concentration 4 5 which suggests that Nesfatin-1 can activate the HPA axis. The concentration of plasma ACTH began to rise 10 min after the injection of Nesfatin-1 in the third ventricle and the corticosterone concentration began to rise 30min after the injection but the ACTH and corticosterone concentrations were both returned to the baseline value 30min and 60min respectively after the injection 5. In contrast the rising and recovery time of plasma ACTH and corticosterone concentrations for intracerebroventricular injection of Nesfatin-1 was longer 4. The effect

3 of Nesfatin-1 on plasma ACTH and corticosterone was not directly acted on the pituitary and in vitro co-culture of pituitary cells and Nesfatin-1 did not change the concentration of both plasma ACTH and corticosterone 4. The studies showed that the change of their concentrations was caused by Nesfatin-1 by affecting the CRH positive neurons in PVN. Nesfatin-1 could achieve the depolarization or hyper-polarization by changing the Ca2+ concentration in CRH positive neurons in PVN. Thus Nesfatin-1 can act on the PVN by way of autocrine or paracrine to regulate the stress-related HPA axis. Furthermore the intracerebroventricular injection of Nesfatin-1 can activate the stress-related neurons in the central nervous system e. g. oxytocine positive neurons in PVN which releases the oxytocin to excite the neurons in NTS. Yoshida et al. found that the injection of Nesfatin-1 in the central nervous system could excite the CRH positive neurons in PVN the norepinephrine neurons in SON NTS and LC and the 5-HT neurons in DR while these brain regions were all associated with the stress 5. The summary of the studies on Nesfatin-1 mediated stress shows that the exogenous Nesfatin-1 can excite the stress sensitive neurons in the central nervous system and meanwhile the stress can also excite the Nesfatin-1 positive neurons in the hypothalamus brain stem and other brain regions so as to participate in the stress-related activities of endocrine and autonomic nervous systems. This suggests that Nesfatin-1 a novel neuropeptide is closely associated rats and the stressful life event is closely related to the anxiety and depression which suggests that Nesfatin-1 may also be involved in the pathogenesis of stress-related anxiety and depressive disorder. 3. Nesfatin-1 and Anxiety & Depression it has a greater impact on the feeding behavior of the body. The injection of Nesfatin-1 in the third ventricle can induce the anxiety and fear-related behaviors of rats in a dose-dependent manner. It was found later that the intraperitoneal injection of Nesfatin-1 could inhibit the exploring behavior of rats from inducing their anxious behaviors and its mechanism might be associated with hypothalamus and prefrontal ERK/CREB/BDNF signaling pathways 6. The clinical studies showed that the plasma Nesfatin-1 level in patients with anorexia nervosa was positively correlated with the anxiety scores and Nesfatin-1 was firstly involved in regulating the anxious behaviors of the patients with anorexia nervosa and then regulating their feeding behavior and body mass index 7. Some researchers even believed that Nesfatin-1 could be used as the target of drug action for stress-related anxiety disorder 8. However the plasma Nesfatin-1 level has been reported to be lower in male patients with generalized anxiety disorder GAD. Some recent studies also showed that Nesfatin-1 was not significantly associated with the GAD 9 which seems to be contrary to the findings of previous studies. However there are relatively few similar studies and the consistency of the samples is lower so it is necessary to increase the quantity of samples for further study. The effect of central and peripheral Nesfatin-1 on the anxiety disorder is not parallel. The peripheral tissues can produce and secrete Nesfatin-1 and simultaneously Nesfatin-1 can also pass through the blood-brain barrier freely. Therefore central and peripheral Nesfatin-1 can regulate the anxiety disorder and other psychopathological changes via the body s circulation. Similar to anxiety disorder depressive disorder is a mental disorder most closely associated with the stress. The morbidity of depressive disorder in female patients is twice as much as that of male patients. The clinical studies of Ari et al. reported that the plasma Nesfatin-1 level in patients with depressive disorder was increased but there was no significant difference between male patients and female patients and it was positively correlated with the 10 Hamilton Depression Rating Scale HAMD which suggests that Nesfatin-1 is associated with the depressive disorder. Bloem et al. found that similar to the rodents Nesfatin-1 was expressed in EW nuclei of mankind and there was no significant difference of NUCB2 mrna levels in men and women. The studies on the patients with depressive disorder who committed suicide without the medical treatment showed that NUCB2 mrna in EW nuclei of male patients was twice higher than that in normal human and NUCB2 mrna in EW nuclei of female patients was three Anxiety disorder is a kind of stress-related mental disorder with a higher morbidity in crowds and meanwhile with the regulation of stress response. However a persistent chronic stress can lead to the depression-like behaviors in

4 times lower than that in normal human 11. Hofmann found that the plasma Nesfatin-1 level in obese female patients was positively correlated with the anxiety and depression scores and the plasma Nesfatin-1 level in obese male patients was negatively correlated with the anxiety and depression scores 12. Hence the gender difference existed in Nesfatin-1 mediated depressive pathogenesis change mechanism. This might be associated with the different dietary habits of men and women and meanwhile it has also provided the clue for researching the gender difference of the morbidity of depressive disorder. Wang Gaohua et al. reported a significant increase of plasma Nesfatin-1 concentration in the patients with diabetes and depressive disorder and the Nesfatin-1 was associated with the incidence of diabetes and depressive disorder and the severity of depression 13. Nesfatin-1 could induce the depression-like behaviors in rats and was associated with immuno-inflammatory response and hypothalamic synaptic vesicle protein mrna expression imbalance 14 which further proves that Nesfatin-1 plays an important role in the pathogenesis of depressive disorder. Some researchers even believed that Nesfatin-1 could become the target of anti-depressant effects 8. There are more and more studies on the relationship between Nesfatin-1 and anxiety and depression but the number is still relatively small. It is still difficult to elucidate the mechanism. Through concluding the existing studies the possible mechanisms are as follows 1 Nesfatin-1 can hyperpolarize the NPY positive neurons to inhibit the activity of NPY positive neurons while NPY has the anxiolytic and antidepressant effects 2 stress can activate Nesfatin-1 positive neurons in LC and DR while LC and DR are the gathering locations of norepinephrine neurons and 5-HT neurons and meanwhile exogenous Nesfatin-1 can also activate the norepinephrine neurons and 5-HT neurons in LC while 5-HT and NE dysfunction are associated closely with the morbidity of anxiety and depressive disorder 3 Nesfatin-1 can regulate the HPA axis to affect the change of anxiety and depressive behaviors via the interaction of CRH positive neurons in PVN 5 4 Nesfatin-1 can activate the melanocortin pathway in the central nervous system while melanocortin can inhibit the neurons in hypothalamic gamma aminobutyric acid GABA to cause the anxiety and depression response. In summary Nesfatin-1 has the function of abnormal regulation in the pathogenesis of anxiety and depressive disorder and the action mechanism and possible difference in gender regulation are still needed for further studies. 4. Conclusion The conclusion of the existing studies shows that Nesfatin-1 has been increasingly reported to be involved in the regulation of stress response and stress-related anxiety and depressive disorder. Through the autoradiography Nesfatin-1 specific receptor has been initially found by researchers in cerebral cortex hypothalamic paraventricular nucleus dorsal vagal nucleus and cerebellum etc. 15 but its specific receptor is still unknown. So there is no available specific receptor antagonist. This makes it difficult for future studies. The researchers shall still make unremitting endeavor to reveal the action mechanism of Nesfatin-1 in stress disorder affective disorder feeding disorder co-morbidity affective disorder of somatic disease and other diseases and reveal whether Nesfatin-1 can become the action target of effective anti-anxiety and antidepressants in the future. References 1. OkereB Xu L RoubosEW et al. Restraint stress alters the secretory activity of neurons co-expressing urocortin-1 cocaine-and amphetamine-regulated transcript peptide and nesfatin-1 in the mouse Edinger-Westphalnucleus J. Brain Res p Xu L Bloem B Gaszner B et al. Stress-related changes in the activity of cocaine- and amphetamine-regulatedtranscript and nesfatin neurons in the midbrain non-preganglionic Edinger-Westphal nucleus in therat J. Neuroscience p Xu Y Y Ge J F Qin G et al. Acute but not chronic stress increased the plasma concentration and hypothalamicmrnaexpression of NUCB2/nesfatin-1inrats J. Neuropeptides p Konczol K Bodnar I ZelenaD et al. Nesfatin-1/NUCB2 may participate in the activation of the hypothalamic-pituitary-adrenal axis in rats J. NeurochemInt p Yoshida N Maejima Y Sedbazar U et al. Stressor-responsive central nesfatin-1 activates corticotropin-releasinghormone nor-

5 adrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis J. Aging AlbanyNY p Ge J F Xu Y Y Qin G et al. Nesfatin-1 a potent anorexic agent decreases exploration and induces anxiety-like behavior in rats without altering learning or memory J. Brain Res p Hofmann T Ahnis A Elbelt U et al. NUCB2/nesfatin-1 Is Associated with Elevated Levels of Anxiety in Anorexia Nervosa J. PLoS One p. e BaliA SinghN Jaggi AS. Neuropeptides as therapeutic targets to combat stress-associated behavioral and neuroendocrinological effects J. CNS Neurol Disord Drug Targets p Bahceci B Bagcioglu E Dilek A et al. Is There any Association Between Nesfatin-1 and Generalized Anxiety Disorder? klinik psikofarmakoloji bulteni-bulletin of clinical psychopharmacology p Ari M Ozturk OH Bez Y et al. High plasma nesfatin-1 level in patients with major depressive disorder J. ProgNeuropsychopharmacol Biol Psychiatry p Bloem B Xu L MoravaE et al. Sex-specific differences in the dynamics of cocaine- and amphetamine-regulated transcript and nesfatin-1 expressions in the midbrain of depressed suicide victims vscontrols J. Neuropharmacology p Hofmann T Elbelt U Ahnis A et al. Sex-specific regulation of NUCB2/nesfatin-1 Differential implication inanxiety in obese men andwomen J. Psychoneuroendocrinology p Wang G H Wei Y Y Wang H L et al. The correlation study of Nesfatin-1 and type-2 diabetes mellitus complicated with depres- tion and Imbalance of Synaptic Vesicle Proteins J. Front Neurosci p Prinz P Goebel-Stengel M Teuffel P et al. Peripheral and central localization of the nesfatin-1 receptor using autoradiography in rats J. Biochem Biophys ResCommun p 收稿日期 2016 年 4 月 5 日 sion J. Journal of International Psychiatry p Ge J F Xu Y Y Qin G et al. Depression-like Behavior Induced by Nesfatin-1 in Rats Involvement of Increased Immune Activa-

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