Ghrelin, obesity and diabetes

The high prevalence of obesity and diabetes will lead to higher rates of morbidity and mortality. The search for drugs to treat these metabolic disorders has, therefore, intensified. The stomach-derived peptide ghrelin regulates food intake and body weight. Recent work suggests that ghrelin also controls glucose metabolism. In addition, current evidence suggests that most of the actions of ghrelin could contribute to the metabolic syndrome. The ghrelin signaling system is, therefore, a promising target for the development of new drugs for the treatment of obesity and diabetes. Agents that block the ghrelin signaling system might be especially useful targets. This Review summarizes the potential and the limitations of ghrelin as a tool to better understand, prevent and treat obesity and diabetes.     

瘦素,Ghrelin与非酒精性脂肪肝

非酒精性脂肪肝病（nonalcoholic fatty liver disease，NAFLD）是一种肝组织病理学改变与酒精性肝病相类似但无过量饮酒史的临床综合征。NAFLD疾病谱包括单纯性脂肪肝、脂肪性肝炎、脂肪性肝硬化三种主要类型。随着社会经济的发展，生活水平提高及生活方式的转变，患病率迅猛增高，已成为危害人类健康的三大肝病之一。NAFLD是代谢综合征的一个重要特征，其发病机制与肥胖，脂质代谢，胰岛素抵抗密切相关。     

Ghrelin, a novel placental-derived hormone

Ghrelin, a GH-releasing acylated peptide, has been recently identified from the rat stomach. The purified peptide consists of 28 amino acids in which the serine 3 residue is n-octanoylated. Here we show that ghrelin messenger RNA and ghrelin peptide are present in the human as well as in rat placentae. In human placenta, ghrelin was detected by PCR at both first trimester and after delivery. While ghrelin was not detected by immunohistochemistry in human placenta at term, it was easily identified by immunohistochemistry at first trimester being mainly expressed in cytotrophoblast cells and scarcely in syncytiotrophoblast ones. Ghrelin was also identified in a human choriocarcinoma cell line, the BeWo cells. Ghrelin was found, by immunohistochemistry, in the cytoplasm of labyrinth trophoblast of rat placenta, whereas other placental cell types seems to be negative for ghrelin immunostaining. Moreover, placental ghrelin messenger RNA, in pregnant rats, showed a characteristic profile of expression being practically undetectable during early pregnancy, with a sharp peak of expression at day 16 and decreasing in the latest stages of gestation. In conclusion, ghrelin has been detected in human and rat placenta showing a pregnancy-related time course of expression. Whether placenta-derived ghrelin is involved in the modulation of GH release, or placental cell growth and differentiation remains to be established.     

Ghrelin in mental health, sleep, memory

Ghrelin acts as a neuropeptide. It participates in sleep-wake regulation. After systemic ghrelin treatment nonREM sleep is promoted in male humans and mice. This effect is influenced by gender, time of administration and depression. Ghrelin does not modulate sleep in healthy women and during the early morning in male subjects. In depressed women REM sleep is diminished after ghrelin. In elderly men and depressed men sleep promotion by ghrelin was preserved. In rats after central ghrelin feeding and wakefulness increased. The nocturnal secretion pattern of cortisol, GH, LH, FSH and hypothalamo-pituitary-thyroid hormones are influenced by ghrelin. Furthermore ghrelin appears to be related to memory and to be involved in the pathophysiology of CNS disorders, particularly depression.     

Ghrelin in obesity

Ghrelin was discovered for its ability to bind the growth hormone secretagogue receptor (GHSR1a) and stimulate growth hormone release. However, much research conducted with this novel stomach hormone is focused on proposed roles for it to participate in regulating energy balance. Exogenous administration of ghrelin stimulates food consumption in experimental animals and humans, presenting the hormone as the first to stimulate appetite after peripheral administration and implicates it for an etiology of obesity. The hormone also presents other exceptional characteristics that solicit need for future study. The peptide is modified by acylation with a mediumchain fatty acid on its third residue, and it is that ghrelin peptide that binds GHS-R1a. Enzymes or transfer proteins responsible for such acylation and de-acylation remain unknown. Specific assays for both acyl- and des-acyl ghrelin are not available nor are methods to prevent de-acylation in blood samples. Such knowledge is important because des-acyl ghrelin is reported to bestow biology distinct from that of ghrelin and that signal may actually oppose those prescribed for its acylated parent. This review of ghrelin data relating to obesity recognizes the complexity of ghrelin endocrinology and attempts to be cautious when discussing studies that measured ghrelin during different physiological states. Although much more exploration is needed, we placed more emphasis on reviewing studies during different physiological states when conclusions are less dependent on measurement of ghrelin. Despite these shortcomings, we conclude that there is ample evidence indicating ghrelin participates in regulating energy balance.     

Ghrelin与动脉粥样硬化

Ghrelin是近年来发现的一种促进生长激素分泌的多肽,是生长激素促分泌物受体的内源性配体。研究发现,ghrelin除了具有增加摄食及调节能量代谢的作用外,还具有降低血压、对抗炎症反应、保护血管内皮细胞等多种生物学效应,提示其在心血管疾病尤其是在动脉粥样硬化方面具有潜在的治疗效应。     

Ghrelin and cancer

Ghrelin is a peptide hormone that was originally isolated from the stomach as the endogenous ligand for the growth hormone secretagogue receptor (GHSR). Ghrelin has many functions, including the regulation of appetite and gut motility, growth hormone release from the anterior pituitary and roles in the cardiovascular and immune systems. Ghrelin and its receptor are expressed in a number of cancers and cancer cell lines and may play a role in processes associated with cancer progression, including cell proliferation, apoptosis, and cell invasion and migration.     

Ghrelin and GH secretion

Ghrelin is an acylated peptide recently isolated from rat and human stomach that potently stimulates GH release in vivo and in vitro in rats and humans. Ghrelin specifically activates the receptor for the growth hormone secretagogues (GHS) and it has been proposed that it may be the endogenous ligand mimicked by these synthetic compounds. Ghrelin is primarily produced in endocrine cells of the stomach, and to a lesser extent, in other peripheral tissues, including the pituitary. Although ghrelin is the most potent GH-secretagogue so far identified, its circulating levels do not correlate with those of GH either in physiological and pathological conditions. Because of these and many other observations, it may be postulated that ghrelin is not physiologically involved in the regulation of growth hormone secretion. Nonetheless, ghrelin may serve as a very useful model for the development of more potent synthetic GHS, which may be therapeutically useful for the treatment of human GH deficiency.     

Ghrelin in pathological conditions

The recently identified gastric hormone ghrelin was initially described as a natural Growth Hormone Secretagogue Receptor ligand. Apart from ghrelin's first discovered action, which was the stimulation of Growth Hormone release, implications for many other functions have been reported. It seems that ghrelin exhibits an important role in conditions related to processes regulating nutrition, body composition and growth, as well as heart, liver, thyroid or kidney dysfunction. In this review, current available knowledge about ghrelin's role in various pathological conditions is presented.