Nesfatin-1的研究新进展

Nesfatin-1是一种厌食调节肽,在中枢和外周广泛表达。近年研究显示nesfatin-1在消化、内分泌、精神等多系统中发挥重要作用,但其作用机制尚未完全明确。本文就nesfatin-1的研究进展作一综述。     

膈下迷走神经切断对大鼠中枢nesfatin-1抑酸作用的影响

目的:探讨双侧膈下迷走神经切断对侧脑室注射nesfatin-1的抑酸作用的影响.方法:♂SD大鼠,侧脑室置管后,每只大鼠分别给予侧脑室注射1、5和50 pmol的nesfatin-1及等体积的灭菌水(5μL/rat),于2 h后处死大鼠,收集胃液,测定其胃酸的变化,用实时定量PCR检测(real-time quantitative PCR,qRT-PCR)检测胃黏膜中H~+/K~+-ATPase mRNA的表达、测定酶的活性.另外,将侧脑室成功置管的♂SD大鼠分成迷走神经切断组和假手术组,每组分别给予nesfatin-1(50pmol)及等体积的灭菌水(5μL/rat),于2 h后处死大鼠,观察迷走神经切断术对nesfatin-1引起的胃酸变化的影响.结果:大鼠侧脑室注射浓度为5 pmol和50pmol的nesfatin-1后2 h,大鼠胃酸分泌减少,其中50 pmol作用最强(P0.05).同时大鼠胃黏膜中H~+/K~+-ATPase mRNA的表达和活性受到抑制(P0.05).另外,对大鼠行膈下迷走神经切断术,侧脑室注射nesfatin-1引起的胃酸分泌的减少以及H~+/K~+-ATPase mRNA的表达和活性的下降等效应也消失,与对照组相比差异无统计学意义(P0.05).结论:侧脑室注射nesfatin-1可呈剂量依赖性地抑制大鼠胃酸的分泌,这一效应可能是通过激活迷走神经途径实现的.     

糖调节受损和2型糖尿病患者血浆nesfatin-1水平的变化

采用酶联免疫法测定了初诊2型糖尿病患者、糖调节受损(IGR)患者、正常糖耐量(NGT)者血浆nesfatin-1水平.结果显示,2型糖尿病和IGR组血浆nesfatin-1水平明显高于NGT组[(1.91±0.79和1.80±0.80对1.41±0.58)μg/L,P＜0.01].血浆nesfatin-1水平与体重指数(BMI)、空腹血糖、空腹胰岛素、HbA1C、稳态模型评估的胰岛素抵抗指数(HOMA-IR)呈明显正相关(P＜0.05或P＜O.01).多元回归分析结果表明HOMA-IR和BMI分别是影响血浆nesfatin-1水平的独立相关因素(均P＜0.01).提示血浆nesfatin-1可能参与了胰岛素抵抗和2型糖尿病的发生和发展.     

Nesfatin-1的研究进展

Nesfatin-1是一种来源于核组蛋白2(NUCB2)的新厌食肽,广泛存在于下丘脑和脑干中众多参与摄食调节的核团,亦大量存在于外周消化系统。目前,nesfatin-1抑制摄食的作用机制尚未完全阐明。本文对近年国内外nesfatin-1的相关研究进展作一综述。     

不同糖耐量人群血清nesfatin-1水平及相关因素分析

目的 研究不同糖耐量人群血清nesfatin-1水平变化,及其与体重指数(BMI)、血糖、胰岛素敏感性等的关系.方法 115例研究对象分为正常糖耐量组(NGT组,33例)、糖耐量减低组(IGT组,30例)和新诊2型糖尿病组(T2DM组,52例)3组.根据BMI将T2DM组分为糖尿病肥胖组(T2DM-OB组,22例)和糖尿病正常体重组(T2DM-NW组,30例).采用ELISA法检测血清nesfatin-1水平.同时测定空腹血糖(FPG)、餐后2h血糖(2 h PG)、白细胞介素-6(IL-6)、胰岛素、糖化血红蛋白A1c(HbA1c)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白-胆固醇(LDL-C)、高密度脂蛋白-胆固醇(HDL-C).T2DM-OB组给予吡格列酮治疗,使仅BMI高于T2DM-NW组(P＜0.05)后再次检测血清nesfatin-1水平.计算稳态模型评估-胰岛素抵抗指数(HOMA-IR)、BMI、腰臀比(WHR)等.结果(1)T2DM组和IGT组血清nesfatin-1水平显著高于NGT组[(1 780±660) ng/L,(1 620±590) ng/Lvs.(1 390±610) ng/L,P＜0.05].(2)T2DM-OB组血清nesfatin-1水平显著高于T2DM-NW组[(1 897±670) ng/L vs.(1 690±650)ng/L,P＜0.05],经吡格列酮治疗后T2DM-OB组nesfatin-1水平仍高于T2DM-NW组[(1 791±634) ng/L vs.(1 690 ±650)ng/L,P＜0.05].(3)Nesfatin-1水平与TG、FPG、2hPG、HbA1c、IL-6、HOMA-IR、BMI呈正相关(r=0.582,0.568,0.587,0.552,0.546,0.523,0.562).多元逐步回归分析显示,HOMA-IR、FPG、BMI与血清nesfatin-1水平独立相关.结论 随着糖耐量受损程度的加重及肥胖的发生,nesfatin-1水平逐渐升高,nesfatin-1可能在肥胖及糖耐量受损中发挥重要作用.     

血清nesfatin-1与非酒精性脂肪性肝病的相关性研究

目的探讨血清nesfatin-1与非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的关系。方法选取NAFLD患者及正常对照者各60例,测定BMI、WHR、TG、TC、LDL、HDL、FBG、FIN、nesfatin-1水平,计算HOMA-IR。结果 (1)NAFLD患者的BMI、WHR、LDL、TC、TG、FBG、FIN、HOMA-IR均高于正常对照组(P0.05),而HDL、nesfatin-1低于正常对照组(P0.05);(2)协方差分析显示,校正年龄、BMI、WHR、TG、TC、FBG、HDL、LDL、FIN、HOMA-IR等后,两组间nesfatin-1水平的差异具有统计学意义(P0.05);(3)多元逐步回归分析显示,nesfatin-1水平是患NAFLD的危险因素(OR=1.426,P0.01)。结论 NAFLD患者nesfatin-1水平明显下降,nesfatin-1可能通过影响摄食行为参与了胰岛素抵抗(IR)的发生、发展,进而导致NAFLD。     

母婴分离大鼠血浆nesfatin-1与内脏敏感性的关系

目的:探讨新生期母婴分离对成年大鼠血浆nesfatin-1的影响及其与大鼠内脏敏感性的关系.方法:新生♂SD大鼠随机分为母婴分离组和正常组.母婴分离组大鼠自出生后第2-15天,每天上午8:00-11:00将幼鼠与母鼠分开,其余时间与母鼠共笼饲养,正常组幼鼠不做处理.第8周时,大鼠接受结直肠扩张(colorectal distension,CRD),检测腹壁撤退反射(abdominal withdrawal reflex,AWR)和腹外斜肌放电活动(electromyographic,EMG),ELISA法检测血浆nesfatin-1和糖皮质激素(glucocorticoid,GC)水平.结果:第8周时,母婴分离大鼠的体质量明显低于正常对照组.母婴分离大鼠血浆nesfatin-1、GC水平均明显高于正常大鼠,且血浆nesfatin-1水平与GC水平呈正相关.当CRD压力为40、60和80 mmHg时,母婴分离大鼠的AWR评分和EMG曲线下面积均明显高于正常对照.并且母婴分离大鼠的AWR评分和EMG曲线下面积均与血浆nesfatin-1水平呈正相关关系.结论:新生期母婴分离诱导成年大鼠的内脏高敏感性和血浆nesfatin-1水平的升高.内脏高敏感性可能与血浆nesfatin-1水平的升高有关.     

妊娠合并糖尿病患者血清 nesfatin-1与胰岛素抵抗的关系研究

目的：探讨妊娠合并糖尿病患者血清nesfatin-1水平与胰岛素抵抗（insulin resistance ,IR）的关系。方法选取妊娠合并糖尿病患者28例（观察组）,OGTT正常孕妇26例（NGT组）,健康的非妊娠妇女29例（NC组）,用酶联免疫吸附法检测血清nesfatin-1的水平,并检测BMI ,糖脂代谢指标和HOMA-IR ,并作相关分析。结果观察组血清nesfatin-1水平均显著高于NGT组和NC组,差异有统计学意义（均 P＜0.05）。观察组患者血清nesfatin-1均与FBG、FINS和HOMA-IR呈正相关（ r＝0.31、0.59、0.69,均 P＜0.05）,TG和HOMA-IR还是nesfatin-1水平的独立相关因素（ B＝0.51、0.47,均 P＜0.05）。结论血清nesfatin-1与妊娠合并糖尿病和IR的发生发展有一定联系。     

nesfatin-1在胰岛素抵抗骨骼肌细胞中对PI3K/AKT信号通路的影响

目的探讨过表达新型饱食分子蛋白(nesfatin-1)对L6骨骼肌胰岛素抵抗及磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/AKT)信号通路和下游糖原合成酶激酶(GSK)-3β、葡萄糖转运蛋白(GLUT)-4表达的影响。方法建立L6细胞胰岛素抵抗模型后,用过表达nesfatin-1的腺相关病毒(AAV)和空载对照腺相关病毒(PC)感染L6细胞,将细胞分为四组,分别为空载对照腺相关病毒组(PC组),PC+棕榈酸(PA)组,过表达nesfatin-1组,nesfatin-1+PA组,四组均加入100 nmol/L重组人胰岛素(Insulin),PC+PA组和nesfatin-1+PA组再加入250μmol/L PA处理24 h后收集培养基上清,用葡萄糖过氧化物酶方法测定上清液中葡萄糖含量,用Western印迹检测PI3K、AKT及其下游信号分子GSK-3β、GLUT-4的蛋白表达变化。结果与PC组比较,过表达nesfatin-1组p-AKT、GSK-3β、GLUT-4蛋白表达水平明显增高(P<0.05);与PC+PA组相比,nesfatin-1+PA组p-AKT、GSK-3β、GLUT-4蛋白表达水平明显增高(P<0.05);与nesfatin-1组相比,nesfatin-1+PA组p-AKT、GSK-3β、GLUT-4蛋白表达水平明显下降(P<0.05)。结论过表达nesfatin-1可显著增加骨骼肌细胞对葡萄糖的摄取,减轻胰岛素抵抗,并经PI3K-AKT通路上调下游GSK-3β、GLUT-4的表达。     

NUCB2/nesfatin-1在肥胖大鼠胃肠道组织中的表达

目的:研究肥胖与正常大鼠胃肠组织NUCB2 mRNA及NUCB2/nesfatin-1蛋白的表达.方法:30只健康♂Wistar大鼠随机均分为高脂高营养性肥胖组和正常对照组,8wk后取其胃、十二指肠、小肠、结肠组织,分别采用实时荧光定量RT-PCR及免疫组织化学的方法检测NUCB2 mRNA及NUCB2/nesfatin-1蛋白的表达.结果:(1)肥胖组大鼠胃、十二指肠、小肠NUCB2 mRNA表达量分别是对照组的2.02、1.49、1.23倍(t=4.256,P=0.000;t=3.455,P=0.002;t=2.402,P=0.026),且NUCB2 mRNA表达量与大鼠Lee’s指数均呈正相关(r=0.677,P=0.006;r=0.561,P=0.030;r=0.538,P=0.039);两组大鼠结肠组织NUCB2 mRNA表达差异无统计学意义(t=1.835,P=0.077);(2)两组大鼠胃黏膜中下2/3、十二指肠布氏腺及潘氏细胞、小肠潘氏细胞中均检测到NUCB2/nesfatin-1蛋白的表达;肥胖组大鼠胃NUCB2/nesfatin-1蛋白表达较对照组增多(Z=-2.955,P=0.003),表达量与大鼠Lee’s指数呈正相关(r=0.677,P=0.008);肥胖组大鼠十二指肠及小肠潘氏细胞中NUCB2/nesfatin-1蛋白表达较对照组减少(Z=-2.026,P=0.043;Z=-2.648,P=0.008),表达量与大鼠Lee’s指数均呈负相关(r=-0.557,P=0.031;r=-0.617,P=0.014).结论:NUCB2/nesfatin-1在大鼠胃肠道中分布广泛,肥胖大鼠胃组织NUCB2 mRNA及NUCB2/nesfatin-1蛋白表达上调、潘氏细胞NUCB2/nesfatin-1蛋白表达下调.     

Nesfatin-1 regulates the lateral hypothalamic area melanin-concentrating hormone-responsive gastric distension-sensitive neurons and gastric function via arcuate nucleus innervation

Nesfatin-1, a recently discovered neuropeptide involved in satiety. Recent studies have revealed that central nesfatin-1 inhibits gastric emptying and gastric acid secretion, though the mechanisms involved in these processes are not known. We aim to explore the effects of nesfatin-1 on a population of gastric distension (GD)-sensitive neurons in the lateral hypothalamus (LHA), gastric motility, and gastric secretion and the role for an arcuate nucleus (Arc)-LHA neural pathway in these processes. Single unit extracellular discharge recordings were made in of LHA. Further, gastric motility and gastric secretion in rats were monitored. Retrograde tracing and fluorescent immunohistochemical staining were used to explore nesfatin-1 neuron projection. The results revealed that administration of nesfatin-1 to the LHA or electric stimulation of the Arc could alter the neuronal activity of melanin-concentrating hormone (MCH)-responsive, GD-responsive neurons in LHA, which could be blocked by pretreatment with MCH receptor-1 antagonist PMC-3881-PI or weakened by pretreatment of a nesfatin-1 antibody in LHA. Administration of nesfatin-1 into LHA could inhibit gastric motility and gastric secretion, and these effects could be enhanced by administration of PMC-3881-PI. Electrical stimulation of Arc promoted the gastric motility and gastric secretion. Nesfatin-1 antibody or PMC-3881-PI pretreatment to LHA had no effect on Arc stimulation-induced gastric motility, but these pretreatments did alter Arc stimulation-induced effects on gastric secretion. Our findings suggest that nesfatin-1 signaling in LHA participates in the regulation of efferent information from the gastrointestinal tract and gastric secretion which also involve MCH signaling. Further, they show that a nesfatin-1-positive Arc to LHA pathway is critical for these effects.     

Minireview: nesfatin-1--an emerging new player in the brain-gut, endocrine, and metabolic axis

Nesfatin-1 is a recently identified 82-amino-acid peptide derived from the precursor protein, nucleobindin2 (NUCB2). The brain distribution of NUCB2/nesfatin-1 at the mRNA and protein level along with functional studies in rodents support a role for NUCB2/nesfatin-1 as a novel satiety molecule acting through leptin-independent mechanisms. In addition, nesfatin-1 induces a wide spectrum of central actions to stimulate the pituitary-adrenal axis and sympathetic nervous system and influences visceral functions and emotion. These central actions combined with the activation of NUCB2/nesfatin-1 neurons in the brain by various stressors are indicative of a role in the adaptive response under stressful conditions. In the periphery, evidence is mounting that nesfatin-1 exerts a direct glucose-dependent insulinotropic action on β-cells of the pancreatic islets. However, the cellular mechanisms of nesfatin-1's action remain poorly understood, partly because the receptor through which nesfatin-1 exerts its pleiotropic actions is yet to be identified.     

Nesfatin-1 neurons in paraventricular and supraoptic nuclei of the rat hypothalamus coexpress oxytocin and vasopressin and are activated by refeeding

Nesfatin-1, a newly discovered satiety molecule, is located in the hypothalamic nuclei, including the paraventricular nucleus (PVN) and supraoptic nucleus (SON). In this study, fine localization and regulation of nesfatin-1 neurons in the PVN and SON were investigated by immunohistochemistry of neuropeptides and c-Fos. In the PVN, 24% of nesfatin-1 neurons overlapped with oxytocin, 18% with vasopressin, 13% with CRH, and 12% with TRH neurons. In the SON, 35% of nesfatin-1 neurons overlapped with oxytocin and 28% with vasopressin. After a 48-h fast, refeeding for 2 h dramatically increased the number of nesfatin-1 neurons expressing c-Fos immunoreactivity by approximately 10 times in the PVN and 30 times in the SON, compared with the fasting controls. In the SON, refeeding also significantly increased the number of nesfatin-1-immunoreactive neurons and NUCB2 mRNA expression, compared with fasting. These results indicate that nesfatin-1 neurons in the PVN and SON highly overlap with oxytocin and vasopressin neurons and that they are activated markedly by refeeding. Feeding-activated nesfatin-1 neurons in the PVN and SON could play a role in the postprandial regulation of feeding behavior and energy homeostasis.     

Association of serum nesfatin-1 concentrations with atrial fibrillation

Nesfatin-1, 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 nesfatin-1 concentrations and AF. A population of 200 patients with AF and 108 patients without AF were enrolled in this study. These patients were divided into three subgroups of paroxysmal AF, persistent AF, and permanent AF. Serum nesfatin-1 concentrations were lower in AF patients than in controls. Logistic regression analysis showed that serum nesfatin-1 concentrations were inversely associated with AF. Serum nesfatin-1 concentrations in permanent AF patients decreased compared with those in persistent and paroxysmal AF groups. In addition, persistent AF patients showed reduced serum nesfatin-1 concentrations compared with paroxysmal AF subjects. Serum nesfatin-1 concentrations were negatively correlated with left atrial diameter. In conclusion, serum nesfatin-1 concentrations were inversely correlated with AF development.     

Nutrient responsive nesfatin-1 regulates energy balance and induces glucose-stimulated insulin secretion in rats

Nesfatin-1 is a recently discovered anorexigen, and we first reported nesfatin-like immunoreactivity in the pancreatic β-cells. The aim of this study was to characterize the effects of nesfatin-1 on whole-body energy homeostasis, insulin secretion, and glycemia. The in vivo effects of continuous peripheral delivery of nesfatin-1 using osmotic minipumps on food intake and substrate partitioning were examined in ad libitum-fed male Fischer 344 rats. The effects of nesfatin-1 on glucose-stimulated insulin secretion (GSIS) were examined in isolated pancreatic islets. L6 skeletal muscle cells and isolated rat adipocytes were used to assess the effects of nesfatin-1 on basal and insulin-mediated glucose uptake as well as on major steps of insulin signaling in these cells. Nesfatin-1 reduced cumulative food intake and increased spontaneous physical activity, whole-body fat oxidation, and carnitine palmitoyltransferase I mRNA expression in brown adipose tissue but did not affect uncoupling protein 1 mRNA in the brown adipose tissue. Nesfatin-1 significantly enhanced GSIS in vivo during an oral glucose tolerance test and improved insulin sensitivity. Although insulin-stimulated glucose uptake in L6 muscle cells was inhibited by nesfatin-1 pretreatment, basal and insulin-induced glucose uptake in adipocytes from nesfatin-1-treated rats was significantly increased. In agreement with our in vivo results, nesfatin-1 enhanced GSIS from isolated pancreatic islets at both normal (5.6 mM) and high (16.7 mM), but not at low (2 mM), glucose concentrations. Furthermore, nesfatin-1/nucleobindin 2 release from rat pancreatic islets was stimulated by glucose. Collectively, our data indicate that glucose-responsive nesfatin-1 regulates insulin secretion, glucose homeostasis, and whole-body energy balance in rats.     

Identification and characterization of nesfatin-1 immunoreactivity in endocrine cell types of the rat gastric oxyntic mucosa

Hypothalamic nesfatin-1, derived from the nucleobindin2 (NUCB2) precursor, inhibits nocturnal food intake and body weight gain in rats. Nesfatin-1 is able to cross the blood-brain barrier, suggesting a peripheral source of nesfatin-1. Many centrally acting food intake regulatory neuropeptides are also produced in the periphery, especially in the gastrointestinal tract. Therefore, we investigated the gene expression of NUCB2 and distribution of nesfatin-1-immunoreactive cells in the stomach. Microarray mRNA expression profiles in purified small endocrine cells of the gastric mucosa substantiated by quantitative RT-PCR showed significantly higher NUCB2 mRNA expression compared with brain and heart. Western blot confirmed the expression of NUCB2 protein and its transport into a secretory soluble fraction of gastric mucosal endocrine cell homogenates. Immunohistochemical colabeling for nesfatin-1 and ghrelin, histidine decarboxylase, or somatostatin revealed two subtypes of nesfatin-1-positive endocrine cells. Cells in the midportion of the glands coexpressed nesfatin-1 and ghrelin, whereas few cells in the glandular base coexpressed nesfatin-1 and somatostatin or histidine decarboxylase. High-resolution three-dimensional volume imaging revealed two separate populations of intracytoplasmic vesicles in these cells, one containing nesfatin-1 and the other ghrelin immunoreactivity. Microarray rat genome expression data of NUCB2 in small gastric endocrine cells confirmed by quantitative RT-PCR showed significant down-regulation of NUCB2 after 24 h fasting. In summary, NUCB2 mRNA expression as well as protein content is present in a specific subset of gastric endocrine cells, most of which coexpress ghrelin. NUCB2 gene expression is significantly regulated by nutritional status, suggesting a regulatory role of peripheral nesfatin-1 in energy homeostasis.     

Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis

A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses.     

Correlation of Brain Neuropeptide (Nesfatin-1 and Orexin-A) Concentrations with Anthropometric and Biochemical Parameters in Malnourished Children

Objective:Malnutrition continues to be a leading cause of stunted growth in many countries. This study aimed to investigate serum nesfatin-1 and orexin-A levels in underweight children and the potential correlations of these levels with anthropometric and nutritional parameters.Methods:The study enrolled 44 prepubertal children (between 2 and 12 years of age) with thinness grades of 1-3 and 41 healthy age- and gender-matched children. The demographic, clinical and laboratory parameters including nesfatin-1 and orexin-A concentrations were compared between the two groups. The correlations of nesfatin-1 and orexin-A with biochemical and anthropometric parameters were investigated. The receiver operating characteristic (ROC) analysis were also performed for evaluating nesfatin-1 and orexin-A in distinguishing children with malnutrition from healthy controls.Results:Thyroid-stimulating hormone, vitamin B12 and insulin levels were significantly lower in the study group than controls (p=0.001, p=0.049 and p=0.033, respectively). Mean nesfatin-1 levels in the malnourished group was also significantly lower compared to the healthy controls (3871.2±1608.8 vs. 5515.0±3816.4 pg/mL, p=0.012). No significant difference was observed in the orexin-A levels between the two groups (malnourished vs. control groups: 1135.7±306.0 vs. 1025.7±361.6 pg/mL, p=0.141). Correlation analyses revealed a positive correlation of nesfatin-1 and a negative correlation of orexin-A with body mass index (BMI) z-score. ROC analysis demonstrated that nesfatin-1 and orexin-A cannot be used to distinguish children with malnutrition from healthy controls (AUC: 0.620, p=0.061 for nesfatin-1 and AUC: 0.584, p=0.190 for orexin-A).Conclusion:The positive correlation of nesfatin-1 and the negative correlation of orexin-A with BMI suggest that these neuropeptides may be a part of a protective mechanism in the maintenance of nutritional status and that they may have a role in regulating food intake in undernourished children.     

Cellular distribution, regulated expression, and functional role of the anorexigenic peptide, NUCB2/nesfatin-1, in the testis

Nesfatin-1, product of the precursor NEFA/nucleobindin2 (NUCB2), was initially identified as anorectic hypothalamic neuropeptide, acting in a leptin-independent manner. In addition to its central role in the control of energy homeostasis, evidence has mounted recently that nesfatin-1 is also produced in peripheral metabolic tissues, such as pancreas, adipose, and gut. Moreover, nesfatin-1 has been shown to participate in the control of body functions gated by whole-body energy homeostasis, including puberty onset. Yet, whether, as is the case for other metabolic neuropeptides, NUCB2/nesfatin-1 participates in the direct control of gonadal function remains unexplored. We document here for the first time the expression of NUCB2 mRNA in rat, mouse, and human testes, where NUCB2/nesfatin-1 protein was identified in interstitial mature Leydig cells. Yet in rats, NUCB2/nesfatin-1 became expressed in Sertoli cells upon Leydig cell elimination and was also detected in Leydig cell progenitors. Although NUCB2 mRNA levels did not overtly change in rat testis during pubertal maturation and after short-term fasting, NUCB2/nesfatin-1 content significantly increased along the puberty-to-adult transition and was markedly suppressed after fasting. In addition, testicular NUCB2/nesfatin-1 expression was up-regulated by pituitary LH, because hypophysectomy decreased, whereas human choriogonadotropin (super-agonist of LH receptors) replacement enhanced, NUCB2/nesfatin-1 mRNA and peptide levels. Finally, nesfatin-1 increased human choriogonadotropin-stimulated testosterone secretion by rat testicular explants ex vivo. Our data are the first to disclose the presence and functional role of NUCB2/nesfatin-1 in the testis, where its expression is regulated by developmental, metabolic, and hormonal cues as well as by Leydig cell-derived factors. Our observations expand the reproductive dimension of nesfatin-1, which may operate directly at the testicular level to link energy homeostasis, puberty onset, and gonadal function.