Ghrelin与生长激素关系的研究进展

Ghrelin是最近发现的一种脑—肠肽,具有强烈的促生长激素(GH)释放的作用,此外还能调节能量代谢、食欲、睡眠等。目前认为,ghrelin可同时作用于人体腺垂体和下丘脑,与促生长激素释放激素协同促进GH分泌。Ghrelin的分泌具有性别差异,可被生长抑素抑制,但外周GH水平对ghrelin的分泌无明显影响。另外,胰岛素样生长因子1可通过下调ghrelin受体的表达而影响其作用。     

Ghrelin在消化系统的作用

Ghrelin是一种生长激素释放激素受体的内源性配体,具有调节生长激素和其他激素的分泌、促进摄食、调节能量代谢和胃肠功能等多种生物学作用。Ghrelin及其受体在下丘脑、垂体、胃、胰腺、肾脏、唾液腺等脏器中都有表达,可能是脑与胃肠道之间调节内分泌的一种介质,有望在诊断和治疗某些消化系统疾病中发挥一定的作用。此文就ghrelin对消化系统功能的调节作用作一简要综述。     

Ghrelin和糖尿病

Ghrelin是近年来发现的一种内源性生长激素促分泌剂受体的配体。大量研究已证实,ghrelin不仅能促进生长激素的分泌,而且还具有增加体重及调节能量代谢的作用。新近研究发现,ghrelin与胰岛素及糖脂代谢密切相关,低ghrelin水平可以作为2型糖尿病和糖耐量减低的一个危险因子,并且ghrelin还参与炎症及免疫应答的调节。     

Ghrelin与心力衰竭

Ghrelin是一种由28个氨基酸组成的多肽,是生长激素促分泌素受体的内源性配体.近年来研究显示心力衰竭时ghrelin及其受体的表达及功能发生变化;Ghrelin除具有促进生长激素分泌的作用外,还具有抑制心肌细胞凋亡、抑制心室重构、增强心肌收缩力、直接保护心肌、改善心肌能量代谢、改善心功能、延缓心源性恶病质的生物学效应.这就提示ghrelin可能从上述多方面发挥抗心力衰竭的作用,具有治疗心力衰竭的潜在功效.     

Ghrelin与生长激素关系的研究进展

Ghrelin是最近发现的一种脑-肠肽,具有强烈的促生长激素（GH）释放的作用,此外还能调节能量代谢、食欲、睡眠等.目前认为,ghrelin可同时作用于人体腺垂体和下丘脑,与促生长激素释放激素协同促进GH分泌.Ghrelin的分泌具有性别差异,可被生长抑素抑制,但外周GH水平对ghrelin的分泌无明显影响.另外,胰岛素样生长因子1可通过下调ghrelin受体的表达而影响其作用.     

Ghrelin和糖尿病

Ghrelin是近年来发现的一种内源性生长激素促分泌剂受体的配体.大量研究已证实,ghrelin不仅能促进生长激素的分泌,而且还具有增加体重及调节能量代谢的作用.新近研究发现,ghrelin与胰岛素及糖脂代谢密切相关,低ghrelin水平可以作为2型糖尿病和糖耐量减低的一个危险因子,并且ghrelin还参与炎症及免疫应答的调节.     

Ghrelin与胎儿及新生儿生长发育和能量代谢的关系

Ghrelin是生长激素释放激素受体的内源性配体,在胎儿及新生儿生长发育和能量代谢过程中发挥重要作用.胎儿期血循环中ghrelin来源于自身分泌(主要是胰腺,胃分泌较少)和胎盘,既有辛酰基化又有去酰基化ghrelin存在,可直接刺激细胞增殖、骨生长,诱导神经管发生.脐血ghrelin水平明显高于母血,并与胎盘重量、胰岛素样生长因子-1、出生体重及身长呈负相关.新生儿期ghrelin主要由胃黏膜细胞分泌,新生儿肠内营养物质的摄入促进胃肠ghrelin分泌细胞的成熟和分泌.新生儿血清总ghrelin水平高于脐血,并与出生体重、身长呈负相关,小于胎龄儿血ghrelin水平高于正常胎龄儿和大于胎龄儿.     

Ghrelin的心血管效应及作用机制

Ghrelin是一种体内生长激素促分泌素受体的内源性配体,其除了能促进生长激素分泌外,在体内许多器官系统还发挥着重要作用。Ghrelin在心血管系统中的作用,包括:改善内皮细胞功能失调、抗心肌细胞凋亡、增加射血分数、扩张外周血管和减轻心脏缺血/再灌注损伤等。现重点阐述ghrelin的心血管效应及其作用机制。     

Ghrelin与能量平衡及糖代谢的关系

Ghrelin是生长激素促分泌物受体的第一个内源性配体,具有促进生长激素分泌、促进摄食、减少脂肪利用等作用,并与胰岛素、瘦素等相互作用,影响能量平衡及糖代谢,因而与肥胖、胰岛素抵抗及2型糖尿病密切相关。进一步研究ghrelin的作用对研究肥胖、胰岛素抵抗、2型糖尿病的发生、发展过程具有指导意义。     

Obestatin对胰腺分泌和增殖的作用

Obestatin是由ghrelin基因编码的含有23个氨基酸的脑肠肽,其在体内多种器官组织中均有表达且具有多种功能,对于其受体问题的研究多集中在G蛋白耦联受体39(GPR39)与胰高血糖素样肽(GLP)-1受体.Obestatin不仅对胰腺的内分泌与外分泌功能产生重要的影响,而且在抑制胰岛β细胞凋亡和促进其存活方面表现出积极的作用.研究obestatin在保护胰岛细胞及影响胰腺分泌中的作用和机制,将为糖尿病的治疗提供新的理念.     

Antagonism of ghrelin receptor reduces food intake and body weight gain in mice

BACKGROUND AND AIMS: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is an appetite stimulatory signal from the stomach with structural resemblance to motilin. We examined the effects of the gastric peptide ghrelin and GHS-R antagonists on energy balance and glycaemic control in mice. MATERIALS AND METHODS: Body weight, fat mass, glucose, insulin, and gene expression of leptin, adiponectin, and resistin in white adipose tissue (WAT) were measured after repeated administrations of ghrelin under a high fat diet. Gastric ghrelin gene expression was assessed by northern blot analysis. Energy intake and gastric emptying were measured after administration of GHS-R antagonists. Repeated administration of GHS-R antagonist was continued for six days in ob/ob obese mice. RESULTS: Ghrelin induced remarkable adiposity and worsened glycaemic control under a high fat diet. Pair feeding inhibited this effect. Ghrelin elevated leptin mRNA expression and reduced resistin mRNA expression. Gastric ghrelin mRNA expression during fasting was increased by a high fat diet. GHS-R antagonists decreased energy intake in lean mice, in mice with diet induced obesity, and in ob/ob obese mice; it also reduced the rate of gastric emptying. Repeated administration of GHS-R antagonist decreased body weight gain and improved glycaemic control in ob/ob obese mice. CONCLUSIONS: Ghrelin appears to be closely related to excess weight gain, adiposity, and insulin resistance, particularly under a high fat diet and in the dynamic stage. Gastric peptide ghrelin and GHS-R may be promising therapeutic targets not only for anorexia-cachexia but also for obesity and type 2 diabetes, which are becoming increasingly prevalent worldwide.     

Ghrelin in gastroenteric pathophysiology

Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor 1a (GHS-R1a). It is localized in distinct cells of the gastric mucosa, mainly distributed in the mid portion of the oxyntic gland characterized by P/D1 granules in man and X/A-like granules in rodents. The ghrelin cell represents the second most frequent endocrine cell type after the enterochromaffin-like cells in gastric oxyntic mucosa, pointing to a potentially relevant role in the physiology of the stomach. Ghrelin has no relevant homology with any known gastrointestinal peptide and displays strong GH-releasing activity both in animals and in humans. However, in addition to stimulating GH secretion, ghrelin possesses several other endocrine and extraendocrine biological activities that are explained by the widespread distribution of ghrelin and GHS-R1a expression. In the rat, ghrelin exerts a control in gastric acid secretion and motility: the gastric acid secretion is stimulated by peripheral administration of high doses of ghrelin, but inhibited by very low doses of ghrelin delivered into the central nervous system. Moreover, ghrelin provides a potent and dose-related gastroprotective action against ethanol- and stress-induced gastric ulcers. The integrity of both nitric oxide (NO) system and capsaicin afferent nerves are required for the gastroprotective effect of ghrelin, whereas the vagus nerve might be involved in conveying ghrelinergic signal from periphery to the brain. In addition, prostaglandins derived by the constitutive cyclooxygenase (COX) activity are essential for the protective activity of ghrelin in ethanol and stress-induced gastric lesions. Given its prevailing role in physiological and pathophysiological gastric function, the discovery of ghrelin will open new perspectives and potential clinical implications in the gastroenteric field.     

Endocrine impact of Helicobacter pylori: focus on ghrelin and ghrelin o-acyltransferase

Ghrelin is predominantly produced by the gastric enteroendocrine cell compartment and is octanoylated by the recently discovered ghrelin o-acyltransferase (GOAT) before secretion into the bloodstream. This octanoylation is essential for many of the biological properties of ghrelin including appetite stimulation and anti-inflammatory properties as only the acylated form of ghrelin binds to the ghrelin receptor, the growth hormone secretagogue receptor (GHS-R). Given the gastric location of ghrelin production...     

The ghrelin axis in disease: potential therapeutic indications

Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood actions of acylated ghrelin administration are its orexigenic effects, and the stimulation of GH secretion. Ghrelin also seems to play a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease.     

Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors

Ghrelin is a novel gastrointestinal hormone produced by rat and human gastric X-like neuroendocrine cells, which strongly stimulates GH secretion and influences energy balance, gastric motility, and acid secretion. Ghrelin is expressed in pituitary and gastrointestinal endocrine tumors. It binds to the GH secretagogue receptor (GHS-R), which is present in a wide variety of central and peripheral human tissues. The aim of the present study was 2-fold: 1) to determine, by immunohistochemistry and mRNA analysis, whether pancreatic islet cells produce ghrelin and express GHS-R; and 2) to investigate ghrelin and GHS-R expression in pancreatic endocrine tumors. Seven cases of nonneoplastic pancreatic tissue and 28 endocrine tumors were studied. In pancreatic islets, ghrelin immunoreactivity was present in all cases and confined to beta-cells. Eleven of the 28 (39%) endocrine tumors were immunoreactive for ghrelin. In situ hybridization and RT-PCR confirmed the immunohistochemical data for both tumors and islets but also revealed ghrelin mRNA in 8 and 11 additional tumors, respectively. GHS-R 1a and 1b mRNAs were present in 7 of 28 and 14 of 28 tumors, respectively, studied by RT-PCR. These findings demonstrate that ghrelin production is not restricted to the stomach but is also present in pancreatic beta-cells and endocrine tumors (regardless of the type of pancreatic hormone produced, if any). Expression of GHS-R in some of the endocrine tumors studied indicates that autocrine/paracrine circuits may be active in neoplastic conditions.     

Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes

OBJECTIVE: Ghrelin, the endogenous ligand of growth hormone secretagogue receptor (GHS-R), acts on the pituitary and the hypothalamus to stimulate the release of growth hormone (GH) and promotes appetite and adiposity. It has also been reported to increase myocardial contractility, induce vasodilation, and protect against myocardial-infarction-induced heart failure. Though principally gastric in origin, it is also produced by other tissues. This work investigated whether cardiomyocytes synthesize and secrete ghrelin, and how its production in these cells responds to stress and exogenous apoptotic agents. METHODS: Ghrelin and its receptor expression was studied by RT-PCR, immunohistochemistry, and competitive binding studies in mouse adult cardiomyocyte cell line HL-1, and primary cultured human cardiomyocytes. Ghrelin accumulation in cardiomyocyte culture medium was measured by radioimmunoassay. Viability and apoptosis assays were carried on by MTT and Hoechst dye vital staining, respectively. RESULTS: RT-PCR showed that HL-1 cells produce mRNAs for both ghrelin and GHS-R, and that GHS-R1a is expressed in human cardiomyocytes; and competitive binding studies using (125)I-labelled ghrelin showed efficient constitutive expression of GHS-R at the surface of HL-1 cells. Immunohistochemistry confirmed the presence of ghrelin in the cytoplasm of HL-1 cells and of isolated human cardiomyocytes in primary culture. Radioimmunoassay showed that ghrelin was secreted by HL-1 cells and human cardiomyocytes into the culture medium. Ghrelin did not modify the viability of HL-1 cells subjected to 12-h starvation, but did protect against the apoptosis inducer cytosine arabinoside (AraC). Finally, production of ghrelin mRNA in HL-1 cardiomyocytes was reduced by AraC but increased if exposure to AraC was preceded by GH treatment. CONCLUSIONS: Ghrelin is synthesized and secreted by isolated murine and human cardiomyocytes, probably with paracrine/autocrine effects, and may be involved in protecting these cells from apoptosis.     

Effects of ghrelin on gastric distension sensitive neurons and gastric motility in the lateral septum and arcuate nucleus regulation

Background

Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) and a peptide hormone that promotes food intake and gastric motility. Our aims are to explore the effects of ghrelin on gastric distension (GD) sensitive neurons in the lateral septum, and the possible regulation of gastric motility by ghrelin through the hypothalamic arcuate nucleus (ARC).

Methods

Single-unit discharges were recorded, extracellularly, and the gastric motility was monitored by the administration of ghrelin in the lateral septum. The projection of nerve fiber and expression of ghrelin were observed by retrograde tracer and fluo-immunohistochemistry staining. The expression of GHS-R and ghrelin was determined by real-time polymerase chain reaction and western blotting analysis.

Results

There were GD neurons in the lateral septum. The administration of ghrelin could excite both GD-excitatory (GD-E) and GD-inhibitory (GD-I) neurons in the lateral septum. Gastric motility was significantly enhanced by the administration of ghrelin in the lateral septum in a dose-dependent manner. Pretreatment with [d-Lys-3]-GHRP-6, however, could completely abolish the ghrelin-induced effects. Electrical stimulation of the ARC could significantly excite the response of GD neurons to ghrelin, increase ghrelin protein expression in the lateral septum and promote gastric motility. Nevertheless, these effects could be mitigated by pretreatment of [d-Lys-3]-GHRP-6. Electrical lesion of the lateral septum resulted in decreased gastric motility. The GHS-R and Ghrelin/FG-double labeled neurons were observed in the lateral septum and ARC, respectively.

Conclusions

It is suggested that the lateral septum may receive afferent information from the gastrointestinal tract and promote gastric motility. Ghrelin plays an important role in promoting gastric motility in the lateral septum. The ARC may be involved in the regulation of the lateral septum’s influence on gastric motility.     

Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines

BACKGROUND: Ghrelin, a natural growth hormone secretagogue (GHS), has been identified in prostate carcinoma cell lines. OBJECTIVES: To investigate the presence of ghrelin and its receptors in human prostate tumours and in DU-145, PC-3 and LNCaP prostate carcinoma cell lines, and to assess the effects of ghrelin and its more abundant circulating form, des-octanoyl ghrelin, on cell proliferation. METHODS: Ghrelin and types 1a and 1b GHS receptor (GHS-R) were determined at the mRNA and protein levels by RT-PCR, in situ hybridization, immunohistochemistry and enzyme immunoassay in tissues, cell lines and culture medium. Ghrelin binding was determined by radioreceptor assay. The effects on cell proliferation were evaluated by growth curves. RESULTS: Ghrelin mRNA was found in prostatic carcinomas and benign hyperplasias, but immunohistochemistry was negative. GHS-R1a and 1b mRNAs were absent from carcinomas, but GHS-R1b mRNA was present in 50% of hyperplasias. Ghrelin peptide and mRNA were present in PC-3 cells exclusively, whereas GHS-R1a and 1b mRNAs were expressed in DU-145 cells only. Specific [125I]Tyr4-ghrelin binding was detected in prostate tumour, DU-145 and PC-3 cell membranes and the binding was displaced by ghrelin, synthetic GHS and des-octanoyl ghrelin, which is devoid of GHS-R1a binding affinity and GH-releasing activity. Ghrelin and des-acyl ghrelin inhibited DU-145 cell proliferation, displayed a biphasic effect in PC-3 cells and were ineffective in LNCaP cells. CONCLUSIONS: Specific GHS binding sites, other than GHS-R1a and 1b, are present in human prostatic neoplasms. Ghrelin, in addition to des-acyl ghrelin, exerts different effects on cell proliferation in prostate carcinoma cell lines.     

Ghrelin and the endocrine pancreas

Ghrelin is a 28-amino-acid peptide predominantly produced by the stomach, while substantially lower amounts derive from other tissues including the pancreas. It is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R1a) and strongly stimulates GH secretion, but acylation in serine 3 is needed for its activity. Ghrelin also possesses other endocrine and nonendocrine actions reflecting central and peripheral GHS-R distribution including the pancreas. The wide spectrum of ghrelin activities includes orexigenic effect, control of energy expenditure, and peripheral gastroenteropancreatic actions. Circulating ghrelin levels mostly reflect gastric secretion as indicated by evidence that they are reduced by 80% after gastrectomy and even after gastric by-pass surgery. Ghrelin secretion is increased in anorexia and cachexia but reduced in obesity, a notable exception being Prader-Willi syndrome. The negative association between ghrelin secretion and body weight is emphasized by evidence that weight increase and decrease reduces and augments circulating ghrelin levels in anorexia and obesity, respectively, and agrees with the clear negative association between ghrelin and insulin levels. In fact, ghrelin secretion is increased by fasting whereas it is decreased by glucose load as well as during euglycemic clamp but not after arginine or free fatty acid load in normal subjects; in physiological conditions, however, the most remarkable inhibitory input on ghrelin secretion is represented by somatostatin as well as by its natural analog cortistatin that concomitantly reduce beta-cell secretion. This evidence indicates that the endocrine pancreas plays a role in directly or indirectly modulating ghrelin secretion.