Decreased plasma nesfatin-1 levels in patients with acute myocardial infarction

Nesfatin-1 is a novel anorexigenic hormone which has close relationship with diabetes, obese, anorexia nervosa, psychiatric disorders and neurogenic diseases. The aim of our study was to evaluate levels of plasma nesfatin-1 among patients presenting with coronary artery disease and the correlation between nesfatin-1 levels and other clinical parameters. Fasting plasma levels of nesfatin-1 were tested in 48 acute myocardial infarction (AMI) patients, 74 stable angina pectoris (SAP) patients and 34 control subjects. All of them were examined by coronary angiography. The severity of coronary atherosclerosis was assessed using the Gensini score. Plasma nesfatin-1 levels were significantly lower in AMI group than SAP group or control group (0.91 ± 0.08 ng/mL vs. 0.98 ± 0.19 ng/mL and 1.09 ± 0.39 ng/mL, respectively, P < 0.05). In AMI patients, plasma nesfatin-1 levels were negatively correlated with high-sensitivity C-reactive protein, neutrophil% or Gensini scores. Such information implies that lower nesfatin-1 concentration may play a very important role in the development of AMI.     

Association between nesfatin-1 levels and metabolic improvements in severely obese patients who underwent biliopancreatic derivation with duodenal switch

ContextNesfatin-1 is a neuroendocrine peptide with potent anorexigenic activity in rodents. The potential role of nesfatin-1 on the regulation of energy balance, metabolic functions and inflammation is currently debated in obese humans. In the present study, nesfatin-1 fluctuations and their associations with metabolic factors were investigated in severely obese patients who underwent biliopancreatic diversion with duodenal switch (BPD/DS) and severely obese controls (SOC).Basic proceduresSixty severely obese patients who underwent BPD/DS and 15 SOC (matched for BMI and age) were included in the study. Associations between nesfatin-1 levels and body composition, glucose metabolism, lipid profile as well as inflammatory markers were evaluated at baseline and over a post-surgery12-month (12 M) period.Main findingsBody weight was reduced at 6 M and at 12 M in BPD/DS patients (P < 0.001). Nesfatin-1 levels were reduced at 6 M (women: P < 0.05) and at 12 M (men and women; P < 0.001) in BPD/DS patients. At baseline, nesfatin-1 levels negatively correlated with weight, fat (FM) and fat-free mass (FFM) in the whole population (combined BPD/DS and SOC patients). At 12 M, nesfatin-1 concentrations positively correlated with weight, FM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, triglyceride and apoB values. At 12 M, % changes in nesfatin-1 were positively associated with% changes in weight, FM, FFM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, apoB and C-reactive protein.ConclusionNesfatin-1 levels decrease following BPD/DS-induced weight loss and are significantly associated with parameters of metabolic health.     

Obestatin对血浆ghrelin和nesfatin-1水平及胃排空的影响

目的:探讨侧脑室注射obestatin对大鼠血浆酰基化ghrelin、去酰基化ghrelin、nesfatin-1水平的影响以及对胃排空的调控。方法:侧脑室注射obestatin,采用酶免疫测定(EIA)法检测血浆酰基化ghrelin、去酰基化ghrelin、nesfatin-1水平以及胃排空率的变化。结果:侧脑室分别注射0.1、0.3或1.0 nmol obestatin,大鼠血浆酰基化ghrelin、去酰基化ghrelin以及nesfatin-1水平无显著改变(P0.05),且酰基化ghrelin与去酰基化ghrelin比率无显著改变(P0.05);侧脑室注射obestatin,大鼠摄食量无显著改变,但胃排空率明显增加(P0.05);胃排空率明显延迟(P0.05)。与侧脑室注射1.0 nmol Obestatin组相比,注射1.0 nmol Obestatin+CRF,大鼠摄食量无显著改变,胃排空率明显延迟(P0.05)。各组摄食量及进入十二指肠内食物量无明显差异(P0.05)。结论:中枢obestatin促进大鼠的胃排空,可能与h/r CRF通路有关。     

The anti-inflammatory and anti-apoptotic effects of nesfatin-1 in the traumatic rat brain

Nesfatin-1 has been demonstrated to possess anti-inflammatory and anti-apoptotic effects in the rat brain with subarachnoid hemorrhage. The study was designed to investigate the influence of nesfatin-1 on inflammatory responses and neuronal cell apoptosis after traumatic brain injury. Wistar rats were subjected to 5, 10 or 20 μg/kg of nesfatin-1 at designed time points (0.5, 2, 4 or 8h after head trauma) intraperitoneally. Rats were sacrificed at hours 2, 6 and 12, as well as day 1, 2, 3 and 5 after head trauma. The administration of 10 or 20 μg/kg of nesfatin-1 at hour 0.5 after head trauma could significantly suppress gene expressions of nuclear factor kappa-B, lessen concentrations of tumor necrosis factor-alpha, interleukin-1beta and interleukin-6, diminish caspase-3 activity as well as reduce number of apoptotic neuronal cells in traumatic rat brain tissues (P<0.05), but the administration of 5 μg/kg of nesfatin-1 not (P>0.05). Moreover, 20 μg/kg nesfatin-1 also significantly suppressed the inflammation and neuronal cell apoptosis when applied 2, 4 or 8h after head trauma. However, a clear concentration-response or time-response relationship was not found. These findings suggest that nesfatin-1 may inhibit nuclear factor kappa-B-dependent inflammatory responses, and lessen caspase-3-mediated neuronal cell apoptosis after traumatic brain injury in rats.     

Permeability of the blood-brain barrier to a novel satiety molecule nesfatin-1

Nesfatin-1 has recently been identified as a hypothalamic and brain stem peptide that regulates feeding behavior. Here, we determined the ability of nesfatin-1 to cross the blood–brain barrier (BBB) of mice. We used multiple-regression analysis to determine that radioactively labeled nesfatin-1 injected intravenously entered the brain. The entry rate (K_i) of ¹³¹I-nesfatin-1 from blood-to-brain was 0.20 ± 0.02 μl/g min. This modest rate of entry was not inhibited by the administration of nonradioactive nesfatin-1, suggesting that BBB transport of nesfatin-1 into the brain is by a nonsaturable mechanism. High performance liquid chromatography (HPLC) and acid precipitation showed that most of the injected radiolabeled nesfatin-1 reached the brain as intact peptide, and capillary depletion with vascular washout revealed that 67% of ¹³¹I-nesfatin-1 crossed the BBB to reach the brain parenchyma. Efflux of labeled nesfatin-1 from brain back into blood was by way of bulk flow. These findings demonstrate that nesfatin-1 crosses the BBB in both the blood-to-brain and brain-to-blood directions by nonsaturable mechanisms.     

Ginkgo biloba extract enhances male copulatory behavior and reduces serum prolactin levels in rats

The aim of this study was to investigate the effects of Ginkgo biloba extract (EGb 761) on male copulatory behavior in rats. EGb 761 (1 mg/ml) induced significant production of testosterone (T) in rat Leydig cells in vitro. Its effects on sexual behavior were then tested in Long-Evans male rats after 7, 14, 21, or 28 days of oral gavage of vehicle (distilled water) or EGb 761 at doses of 10, 50, or 100 mg/kg. Administration of 50 mg/kg of EGb 761 for 28 days and of 100 mg/kg for 14 or 21 days significantly increased intromission frequency compared to controls on the same day. An increase in ejaculation frequency was seen after treatment with 50 mg/kg of EGb 761 for 14, 21, or 28 days when compared to either the control group on the same day or the same group on day 0. A reduction in ejaculation latency was only seen after administration of 50 mg/kg of EGb 761 for 14 days compared to the vehicle-treated group. After treatment for 28 days, no significant difference was seen in mount latency, intromission latency, serum T levels, reproductive organ weight, sperm number, or levels of the metabolite of dopamine, 3,4-dihydroxyphenylacetic acid in the brain with any dose of EGb 761, but significantly reduced serum prolactin levels and increased dopamine levels in the medial preoptic area and arcuate nucleus were seen at the dose of 50 mg/kg. These findings show that EGb 761 (especially at the dose of 50 mg/kg) enhances the copulatory behavior of male rats and suggest that the dopaminergic system, which regulates prolactin secretion, may be involved in the facilitatory effect of EGb 761.     

Nesfatin-1 and ghrelin levels in serum and saliva of epileptic patients: hormonal changes can have a major effect on seizure disorders

Nesfatin-1 and ghrelin are the two recently discovered peptide hormones involved in the control of appetite. Besides its main appetite-control function, ghrelin also has anticonvulsant effects, while nesfatin-1 causes depolarization in the paraventricular nucleus (PVN). The aims of this study, therefore, were to investigate: (i) whether there are differences in the concentrations of nesfatin-1 and ghrelin in saliva and serum samples between eplilepsy patients and normal controls and (ii) whether salivary glands produce nesfatin-1. The study included a total of 73 subjects: 8 patients who were newly diagnosed with primary generalized seizures and had recently started antiepileptic drug therapy; 21 who had primary generalized seizures and were continuing with established antiepileptic drug therapy; 24 who had partial seizures (simple: n = 12 or complex: n = 12) and were continuing with established antiepileptic drug therapy; and 20 controls. Salivary gland tissue samples were analyzed for nesfatin-1 expression by immunochemistry and ELISA. Saliva and serum ghrelin levels were measured by ELISA and RIA, and nesfatin-1 levels by ELISA. Nesfatin-1 immunoreactivity was detected in the striated and interlobular parts of the salivary glands and the ducts. The nesfatin-1 level in the brain was around 12 times higher than in the salivary gland. Before antiepileptic treatment, both saliva and serum nesfatin-1 levels were around 160-fold higher in patients who are newly diagnosed with primary generalized epilepsy (PGE) than in controls; these levels decreased with treatment but remained about 10 times higher than the control values. Saliva and serum nesfatin-1 levels from patients with PGE and partial epilepsies who were continuing antiepileptic drugs were also 10-fold higher than control values. Serum and saliva ghrelin levels were significantly (twofold) lower in epileptic patients before treatment than in controls; they recovered somewhat with treatment but remained below the control values. These results suggest that the low ghrelin and especially the dramatically elevated nesfatin-1 levels might contribute to the pathophyisology of epilepsy. Therefore, serum and saliva ghrelin and especially the remarkably increased nesfatin-1 might be candidate biomarkers for the diagnosis of epilepsy and for monitoring the response to anti-epileptic treatment.     

NUCB2/nesfatin-1对小鼠摄食行为的调控及机制

目的:探讨NUCB2/nesfatin-1对小鼠摄食行为的调控及机制。方法:利用侧脑室埋管,免疫组化染色等方法,探讨侧脑室和外周注射nesfatin-1对小鼠摄食行为的影响。结果:侧脑室注射不同剂量nesfatin-1(0.3μg,1μg,3μg),注药后4 h夜间进食量明显减少,且呈显著剂量依赖关系(t=2.61~4.78,P0.05~0.01),侧脑室注射3μg nesfatin-1,小鼠前3小时累积摄食量明显降低(t=8.69~10.73,P0.01),且持续降低12小时(t=2.64,P0.05),同时餐间间隔时间明显延长(t=2.66,P0.05),每分钟/1-4 h进食量明显降低(t=2.63,P0.05),且进食每克食物所用时间明显增加(t=3.02,P0.05)。在下丘脑弓状核,外侧区和背内侧核均有NUCB2/nesfatin-1免疫阳性神经元表达。皮下或腹腔注射nesfatin-1,小鼠进食量和进食行为均无显著改变(P0.05)。结论:中枢nesfatin-1可抑制小鼠摄食行为。     

糖尿病大鼠ghrelin和nesfatin-1表达动力学及其调控

目的:探讨STZ诱导糖尿病大鼠ghrelin和nesfatin-1动力学及分泌调节变化。方法:STZ诱导糖尿病大鼠模型;采用葡糖糖脱氢酶分析法测量血浆葡萄糖水平;免疫放射分析检测血浆ghrelin、nesfatin-1、胰岛素、胰岛素样生长因子1(IGF-1)、生长激素(GH)含量;采用real-time PCR检测ghrelin m RNA水平变化;免疫组化观察ghrelin和nesfatin-1免疫活性细胞数量。结果:糖尿病大鼠体重显著降低(t=23.16,P<0.01),血糖水平显著升高(t=22.55,P<0.01),血浆胰岛素和IGF-1水平显著降低(t=6.50,t=24.13,P<0.01),但GH水平显著升高(t=3.30,P<0.05)。糖尿病大鼠血浆总ghrelin(t=7.03,P<0.01)和活性ghrelin(t=3.33,P<0.05)水平均显著升高,血浆nesfatin-1水平则显著降低(t=6.24,P<0.01);糖尿病大鼠血浆总ghrelin与GH(r=0.81,P<0.01)和IGF-1水平(r=-0.58,P<0.01)呈显著相关性;与对照组大鼠相比,糖尿病大鼠胃总ghrelin(t=16.86,P<0.01)和活性ghrelin(t=3.30,P<0.05)水平均显著降低;而胃nesfatin-1(t=7.93,P<0.01)水平则显著升高。胃总ghrelin水平与血浆IGF-1水平呈明显相关性(r=0.65,P<0.01);与对照组大鼠相比,糖尿病大鼠胃ghrelin m RNA表达水平显著升高(t=16.8,P<0.01),胃底ghrelin免疫活性细胞数量显著减少(t=3.98,P<0.01);实验中给予大鼠自由饮食,糖尿病大鼠血浆总ghrelin水平显著增加(t=7.53,P<0.01),nesfatin-1水平显著降低(t=5.46,P<0.01)。糖尿病大鼠注射胰岛素后,可使增加的ghrelin水平(t=1.76,P=0.11)和降低的nesfatin-1水平接近正常(t=1.96,P=0.06);且胰岛素可显著反转糖尿病大鼠胃总ghrelin(t=8.54,P<0.01)和nesfatin-1水平(t=2.42,P<0.05);以及注射胰岛素后,糖尿病大鼠胃底ghrelin细胞显著增加,nesfatin-1细胞明显减少(t=3.21,t=2.59,P<0.05)。结论:Ghrelin或nesfatin-1参与糖尿病大鼠能量平衡调控。     

Individual plasma ghrelin changes in the same patients in hyperthyroid,hypothyroid and euthyroid state

Ghrelin is a multifunctional peptide of widespread expression. Since it has been shown to influence energy homeostatis, its potential role in thyroid dysfunction may have clinical significance. In this study, plasma ghrelin changes have been analyzed in the same patients in three different thyroid states for the first time. The study group consisted of 16 patients who had been diagnosed with hyperthyroidism, were treated with radioiodine, developed hypothyroidism after treatment, and finally became euthyroid on l-thyroxine substitution. In the initial state of hyperthyroidism plasma ghrelin levels correlated negatively with fT₃ and fT₄. In hypothyroidism ghrelin concentration increased significantly (p < 0.05). Although the mean value of plasma ghrelin tended to decrease in the euthyroid state, the individual difference between hypothyroidism and euthyroidism was not significant. Plasma ghrelin in euthyroidism was still significantly higher than in hyperthyroidism (p < 0.05), and correlated positively with ghrelin levels in hyperthyroidism and hypothyroidism. In our opinion, plasma ghrelin fluctuations may reflect metabolic changes in patients with thyroid dysfunction. Moreover, it cannot be excluded that in thyroid disorders ghrelin acts as a compensatory factor, helping to balance metabolic disturbances.     

Nesfatin-1(30-59) but not the N- and C-terminal fragments, nesfatin-1(1-29) and nesfatin-1(60-82) injected intracerebroventricularly decreases dark phase food intake by increasing inter-meal intervals in mice

Nesfatin-1 is an 82 amino acid N-terminal fragment of nucleobindin2 that was consistently shown to reduce dark phase food intake upon brain injection in rodents. We recently reported that nesfatin-1(1-82) injected intracerebroventricularly (icv) reduces dark phase feeding in mice. Moreover, intraperitoneal injection of mid-fragment nesfatin-1 (nesfatin-1(30-59)) mimics the food intake-reducing effects of nesfatin-1(1-82), whereas N-terminal (nesfatin-1(1-29)) and C-terminal fragments (nesfatin-1(60-82)) did not. We therefore characterized the structure-activity relationship of nesfatin-1 injected icv to influence the dark phase meal pattern in mice. Mouse nesfatin-1(1-29), nesfatin-1(30-59), nesfatin-1(60-82) or vehicle was injected icv in freely fed C57Bl/6 mice immediately before the dark phase and food intake was monitored using an automated episodic feeding monitoring system. Nesfatin-1(30-59) (0.1, 0.3, 0.9 nmol/mouse) induced a dose-related reduction of 4-h food intake by 28%, 49% and 49% respectively resulting in a 23% decreased cumulative 24-h food intake compared to vehicle at the 0.3 nmol/mouse dose (p<0.05). The peak reduction occurred during the 3rd (-96%) and 4th hour (-91%) post injection and was associated with a reduced meal frequency (0-4h: -47%) and prolonged inter-meal intervals (3.1-times) compared to vehicle (p<0.05), whereas meal size was not altered. In contrast, neither nesfatin-1(1-29) nor nesfatin-1(60-82) reduced dark phase food intake at equimolar doses although nesfatin-1(60-82) prolonged inter-meal intervals (1.7-times, p<0.05). Nesfatin-1(30-59) is the active core of nesfatin-1(1-82) to induce satiety indicated by a reduced meal number during the first 4h post injection. The delayed onset may be indicative of time required to modulate other hypothalamic and medullary networks regulating nocturnal feeding as established for nesfatin-1.     

24-hour changes in circulating prolactin, follicle-stimulating hormone, luteinizing hormone, and testosterone in young male rats subjected to calorie restriction

This work analyzes the effect of calorie restriction on the 24 h variation of pituitary-testicular function in young male Wistar rats by measuring the circulating levels of prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Control animals were provided an equilibrium calorie diet and the experimental animals a calorie-restriction diet equivalent to 66% of food restriction for four weeks starting on day 35 of life. Different groups of control and experimental rats were killed at 6 h intervals around the clock, beginning 1 h after light on (HALO). Compared to the control animals, the mean secretion of prolactin was augmented and that of LH and testosterone decreased in calorie-restricted rats, whereas FSH release remained unchanged. Significant changes in the 24 h secretory pattern of circulating prolactin, LH, and testosterone occurred in the calorie-restricted rats. These include the appearance of a second maximum of plasma prolactin at 21 HALO, blunting of the LH peak seen at 13 HALO, and phase-shift of the testosterone peak from 13 HALO in controls to 17 HALO in calorie-restricted rats. The significant positive correlation between individual LH and testosterone levels found in controls was no longer observed in calorie-restricted rats. Availability of nutrients presumably affects the mechanisms that modulate the circadian variation of the pituitary-gonadal axis in growing male rats.     

CCK-8S activates c-Fos in a dose-dependent manner in nesfatin-1 immunoreactive neurons in the paraventricular nucleus of the hypothalamus and in the nucleus of the solitary tract of the brainstem

Recently, a new neuropeptide, named nesfatin-1, was discovered. It has been reported that nesfatin-1 inhibits food intake after injection into the third ventricle as well as intraperitoneal (ip) injection. Cholecystokinin (CCK) is well established to play a role in the regulation of food intake. The aim of the study was to examine whether CCK-8S injected ip modulates neuronal activity in nesfatin-1 immunoreactive (ir) neurons localized in the PVN and in the nucleus of the solitary tract (NTS). Additionally, tyrosine hydroxylase-immunoreactivity (TH-ir) in the PVN was determined to assess the distribution of TH-ir fibers in relation to nesfatin-1-ir. Non-fasted male Sprague-Dawley rats received 6 or 10 µg CCK-8S/kg or vehicle solution (0.15 M NaCl; n = 4 all groups) ip. The number of c-Fos-ir neurons was determined in the PVN, arcuate nucleus (ARC), and NTS. Double staining procedure for nesfatin-1 and c-Fos revealed that CCK-8S increased significantly and in a dose-dependent manner the number of c-Fos positive nesfatin-1-ir neurons in the PVN ( 4-fold and 7-fold) and NTS ( 9-fold and 26-fold). Triple staining in the PVN showed a dose-dependent neuronal activation of nesfatin-1 neurons that were colocalized with CRF and oxytocin. Double labeling against nesfatin-1 and TH revealed that nefatin-1-ir neurons were encircled in a network of TH-ir fibers in the PVN. No effect on the number of c-Fos-ir neurons was observed in the ARC. These results suggest that the effects of CCK on the HPA axis and on food intake may, at least in part, be mediated by nesfatin-1-ir neurons in the PVN.     

Ghrelin, des-acyl ghrelin and obestatin: three pieces of the same puzzle

The major active product of ghrelin gene is a 28-amino acid peptide acylated at the serine 3 position with an octanoyl group, called simply ghrelin. Ghrelin has a multiplicity of physiological functions, affecting GH release, food intake, energy and glucose homeostasis, gastrointestinal, cardiovascular, pulmonary and immune function, cell proliferation and differentiation and bone physiology. Nevertheless, recent developments have shown that ghrelin gene can generate various bioactive molecules besides ghrelin, mainly des-acyl ghrelin and obestatin, obtained from alternative splicing or from extensive post-translational modification. Although their receptors have not yet been identified, they have already proven to be active, having intriguingly subtle but opposite physiological actions to ghrelin. This suggests the existence of a novel endocrine system with multiple effector elements which not only may have opposite actions but may regulate the action of each other. In this review, we summarize the steps which lead to the production of the different ghrelin gene products and examine the most significant differences between them in terms of structure and actions.     

Diethylstilbestrol increases the density of prolactin cells in male mouse pituitary by inducing proliferation of prolactin cells and transdifferentiation of gonadotropic cells

Diethylstilbestrol (DES) has been implicated in mammalian abnormalities. We examined the effects of DES on follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) cells in the pituitaries of male mice treated with various doses of DES for 20 days. DES reduced the density of FSH and LH cells in a dose-dependent manner, but increased that of PRL cells. When the expression of estrogen receptor (ER) α and β was assessed, an induction of ERβ by DES was found predominantly in PRL cells. However, since these effects were abolished in ERα knockout mice, DES appears to act primarily through ERα. When the expression of Ki-67 and Pit-1 in PRL cells was examined at various time-points after DES treatment, some PRL cells became Ki-67 positive at 10–15 days, and Pit-1-positive cells were increased at 5–15 days. Furthermore, some FSH and LH cells became Pit-1 positive, and co-localized with PRL at 5–10 days. Our results indicate that DES increases PRL cells by inducing proliferation of PRL cells and transdifferentiation of FSH/LH cells to PRL cells.     

Central nesfatin-1 reduces the nocturnal food intake in mice by reducing meal size and increasing inter-meal intervals

Nesfatin-1 is well established to reduce food intake upon brain injection in rats, while in mice its anorexigenic action and brain expression are largely unexplored. We characterized the influence of intracerebroventricular (icv) and peripheral (intraperitoneal, ip, subcutaneous, sc) injection of nesfatin-1 on dark phase ingestive behavior using an automated feeding monitoring system and co-localized NUCB2/nesfatin-1 immunoreactivity in the associated brain areas. Nesfatin-1 (0.3, 1 or 3 μg/mouse, icv) caused a dose-related reduction of 4-h dark phase food intake by 13%, 27%, and 46% respectively. Nesfatin-1 (3 μg/mouse, icv) action had a 2-h delayed onset, 82% peak inhibition occurring at 3-4 h post-injection and was long lasting (30% reduction for 12 h period post-injection). Nesfatin-1 (3 μg/mouse, icv)-treated mice had a 46% lower meal frequency associated with 2-times longer inter-meal intervals and a 35% reduction in meal size compared to vehicle during the 1-4 h post-injection (p < 0.05). NUCB2/nesfatin-1-immunopositive neurons were found in hypothalamic (supraoptic, paraventricular, arcuate, dorsomedial, lateral) and brainstem (dorsal vagal complex) feeding regulatory nuclei. When injected peripherally, neither food intake nor feeding microstructure parameters were altered. These results demonstrate that NUCB2/nesfatin-1 is prominently expressed in mouse hypothalamus and medulla and acts in the brain to curtail the dark phase feeding by inducing satiation and satiety indicated by reduced meal size and prolonged inter-meal intervals respectively. The lack of nesfatin-1 effect when injected peripherally at a 23-times higher dose indicates a primarily central site of the anorexigenic action for nesfatin-1 in mice.     

Endogenous GLP-1 acts on paraventricular nucleus to suppress feeding: Projection from nucleus tractus solitarius and activation of corticotropin-releasing hormone,nesfatin-1 and oxytocin neurons

Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetic patients and shown to reduce food intake and body weight. The anorexigenic effects of GLP-1 and GLP-1 receptor agonists are thought to be mediated primarily via the hypothalamic paraventricular nucleus (PVN). GLP-1, an intestinal hormone, is also localized in the nucleus tractus solitarius (NTS) of the brain stem. However, the role of endogenous GLP-1, particularly that in the NTS neurons, in feeding regulation remains to be established. The present study examined whether the NTS GLP-1 neurons project to PVN and whether the endogenous GLP-1 acts on PVN to restrict feeding. Intra-PVN injection of GLP-1 receptor antagonist exendin (9–39) increased food intake. Injection of retrograde tracer into PVN combined with immunohistochemistry for GLP-1 in NTS revealed direct projection of NTS GLP-1 neurons to PVN. Moreover, GLP-1 evoked Ca²⁺ signaling in single neurons isolated from PVN. The majority of GLP-1-responsive neurons were immunoreactive predominantly to corticotropin-releasing hormone (CRH) and nesfatin-1, and less frequently to oxytocin. These results indicate that endogenous GLP-1 targets PVN to restrict feeding behavior, in which the projection from NTS GLP-1 neurons and activation of CRH and nesfatin-1 neurons might be implicated. This study reveals a neuronal basis for the anorexigenic effect of endogenous GLP-1 in the brain.     

Plasma levels of nesfatin-1 as a new biomarker in depression in Asians: evidence from meta-analysis

Abstract

Objective: This study aims to review the alteration of plasma nesfatin-1 levels in patients with depression.

Methods: Under the guidance of the latest PRISMA checklist, a systematic review and meta-analysis were conducted by searching English database (PubMed, Web of Science, EMDASE) and Chinese database for relevant studies up to August, 2019. Pooled standardised mean difference (SMD) with 95% confidence intervals (CI) was calculated with the random effects model.

Results: Nine studies that reported the association between plasma levels of nesfatin-1 and the risk of depression with 567 patients and 447 control participants were included in the meta-analysis. Compared with the healthy controls, depressive patients had a higher plasma level of nesfatin-1 [SMD (95% CI):1.58(0.75, 2.41), Z?=?3.74, p for Z?<?0.001; I² = 96.8%, p for I² < 0.001]. The subgroup analyses and meta-regression failed to find the source of the heterogeneity. No evidence of publication bias was found either in Begg’s test (p?=?0.348) or the Egger’s test (p?=?0.523).

Conclusion: The present meta-analysis indicated that a higher plasma level of nesfatin-1 was associated with an increased risk of depression.     

CRH receptor type 1 mediates continual hypoxia-induced changes of immunoreactive prolactin and prolactin mRNA expression in rat pituitary

We have reported that, in rats, hypoxia (10.8% O2) stimulates prolactin (PRL) release from the pituitary. This study is designed to compare the response of pituitary PRL to acute hypoxia (AH), continual hypoxia (CH), intermittent hypoxia (IH), cold, and restraint, individually and combined with hypoxia. This study also investigates the involvement of the corticotropin-releasing hormone receptor 1 (CRH R1) in the hypoxia-induced PRL response. Hypoxia was induced by exposing the rats to high altitudes of 2 km (16.0% O2) or 5 km (10.8% O2). The PRL levels in the pituitary (iPRL) and in plasma (pPRL) were measured by immunocytochemistry and RIA assay, respectively. The acute hypoxia of 5 km for 2-24 h caused a biphasic change (early decrease and late increase) of PRL. Both CH and IH at 2 or 5 km for 1-5 days markedly increased pPRL but decreased iPRL. Continual severe hypoxia (10.8% O2) for periods of 10, 15, and 25 days significantly enhanced pPRL but this effect was less marked at the lower altitude (16.0% O2) and did not occur during intermittent hypoxia (at both altitudes). The increased pPRL was significantly enhanced by restraint, restraint + hypoxia, hypoxia, and cold + hypoxia exposure. Treatment with a CRH R1 antagonist (CP-154,526) reversed hypoxia-decreased immunoreactive PRL and upregulated PRLmRNA in the pituitary. The data suggest that both CH and IH can stimulate rat PRL release in a time-course- and intensity-dependent manner. However, compared to the relatively low CH-induced response, restraint induced a more powerful response than either cold or hypoxia alone. CRH R1 mediates PRL secretion and PRL mRNA expression in the pituitary under hypoxic exposure. Hypoxia-enhanced PRL response over the lifespan may play a significant role in adaptation to an extreme environment.     

Correlation between suckling-induced changes in the ultrastructure of mammotrophs and prolactin release

Effects of suckling on the structure of mammotrophs and the release of prolactin, were studied in rats on the 10th day of lactation with the use of electron microscopy and radioimmunoassay techniques. Nursing animals were separated from their young for 8 hr and subsequently united and permitted to nurse for 1, 5, 15, 30 min; or 1, 2 and 4 hr. Blood samples were obtained prior to and throughout the suckling interval and pituitary glands were processed for electron microscopy. Control animals consisted of normal lactating females and animals separated from their young for 8 hr. Normally lactating controls had high prolactin serum levels (501 +/- 95 ng/ml) and synthetically active appearing mammotrophs. An 8 hr separation from the pups induced a dramatic lowering of serum prolactin (32 +/- 5 ng/ml), an increase in secretory granule storage, and a great dilation of rough endoplasmic reticulum (RER) cisternae. Five min of renewed suckling resulted in a rise of plasma prolactin levels (605 +/- 183 ng/ml) which remained high thereafter. The major ultrastructural changes observed during the first 30 min of suckling were as follows: 1) at 1 min, the RER became cmone?); 2) AT 5 MIN, AND MUCH MORE OBVIOUSLY AT 15 AND 30 MIn, a massive discharge of secretory granules was observed; and 3) at 15 min, the collapsed RER underwent transformation for 1,2 and 4 hr) induced new hormone synthesis as suggested by the presence of hypertrophied Golgi elements and numerous immature granules. This was accompanied by a new transformation of the RER from the vesicular into a lamellar form now consisting of very slender cisternae lined with numerous ribosomes, presumably involved in the renewal of the synthetic process. The morphologic findings described correlate well with the time table of prolactin release. In addition, the dramatic early changes in the structure of the RER suggest a possible involvement of this organelle in the storage and release of a proposed rapidly releasable pool of prolactin.