Search

With our aging society, more people hope for a long and healthy life. In recent years, researchers have focused on healthy longevity factors. In particular, calorie restriction delays aging, reduces mortality, and extends life. Ghrelin, which is secreted during fasting, is well known as an orexigenic peptide. Because ghrelin is increased by caloric restriction, ghrelin may play an important role in the mechanism of longevity mediated by calorie restriction. In this review, we will discuss the role of orexigenic peptides with a particular focus on ghrelin. We conclude that the ghrelin-growth hormone secretagogue-R signaling pathway may play an important role in the anti-aging mechanism., Competing Interests: No author has relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan., Competing Interests: AI has received grant support from Tsumura. The other authors declare no conflict of interest.

Cachexia is characterized by anorexia, weakness, weight loss, and muscle wasting. Anorexia and muscle wasting are the key features of cachexia and they affect mortality, morbidity, and quality of life. Consistent studies have found that feeding-regulating peptides such as melanocortin, ghrelin, and leptin are related to muscle metabolism, and the balance of catabolism and anabolism in muscle is regulated in the hypothalamus, which also regulates appetite and energy expenditure. In cachexia, proinflammatory cytokines, such as TNF-α, IL-1, IL-6 and Angiotensin II induce muscle atrophy. The mechanism is suggested via upregulation of MuRF1 and MAFbx. In contrast, the orexigenic peptide, AgRP and ghrelin have the effect to decrease proinflammatory cytokines and increase body weight, food intake, and muscle mass. The understandings of the pathological mechanism of anorexia and muscle metabolism in view of the crosstalk between brain and muscle will open the new way for the management of cachexia. In this review, we describe recent experimental and clinical studies that have examined the regulation of food intake and muscle wasting in cachexia. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Ghrelin is a growth hormone (GH) secretagogue and a potent orexigenic factor that stimulates feeding by interacting with hypothalamic feeding-regulatory nuclei. Its multifaceted effects are potentially beneficial as a treatment in human disease states. In both adult and pediatric chronic kidney disease (CKD) patients, decreased appetite plays a major role in wasting, which in turn is linked to morbidity and mortality; wasting has also been linked to high levels of leptin and proinflammatory cytokines. The beneficial effects of ghrelin treatment in CKD are potentially mediated by multiple concurrent actions, including the stimulation of appetite-regulating centers, anti-inflammatory effects, and direct kidney effects. Further evaluation of this appetite-regulating hormone in CKD is needed to confirm previous findings and to determine the underlying mechanisms.

Obese individuals often have increased appetite despite normal plasma levels of the main orexigenic hormone ghrelin. Here we show that ghrelin degradation in the plasma is inhibited by ghrelin-reactive IgG immunoglobulins, which display increased binding affinity to ghrelin in obese patients and mice. Co-administration of ghrelin together with IgG from obese individuals, but not with IgG from anorectic or control patients, increases food intake in rats. Similarly, chronic injections of ghrelin together with IgG from ob/ob mice increase food intake, meal frequency and total lean body mass of mice. These data reveal that in both obese humans and mice, IgG with increased affinity for ghrelin enhances ghrelin's orexigenic effect, which may contribute to increased appetite and overeating.

Eating disorders, including anorexia and bulimia nervosa, are potentially life-threatening syndromes characterized by severe disturbances in eating behavior. An effective treatment strategy for these conditions remains to be established, as patients with eating disorders tend to suffer from multiple relapses. Because ghrelin was originally discovered in the stomach mucosa, it has been widely studied over the past decade in an effort to uncover its potential roles; these studies have shed light on the mechanism by which ghrelin regulates food intake. Thus, studying ghrelin in the context of eating disorders could improve our understanding of the pathogenesis of eating disorders, possibly resulting in a promising new pharmacological treatment strategy for these patients. In addition, early detection and treatment of eating disorders are critical for ensuring recovery of young patients. Oral symptoms, including mucosal, dental, and saliva abnormalities, are typically observed in the early stages of eating disorders. Although oral care is not directly related to the treatment of eating disorders, knowledge of the oral manifestations of eating disorder patients may aid in early detection, resulting in earlier treatment; thus, oral care might contribute to overall patient management and prognosis. Moreover, ghrelin has also been found in saliva, which may be responsible for oral hygiene and digestion-related functions. This review discusses the pharmacological potential of ghrelin in regulating food-intake and the role of saliva and oral care in young patients with eating disorders.

Cachexia is characterized by decreased food intake, increased energy expenditure, and muscle wasting. It is observed in 80% of patients with advanced-stage cancer and is a major source of decreased quality of life and increased morbidity and mortality in cancer patients. Ghrelin plays an important role in stimulating hunger and maintaining energy homeostasis and is the first-line treatment option for cancer cachexia. Several studies in rodent models and clinical trials have demonstrated that ghrelin or ghrelin receptor (GHS-R) agonists are effective in the treatment of cancer cachexia; however, further large-scale long-term clinical trials are needed to confirm sustained effects. Recently, the traditional Japanese medicine rikkunshito has been shown to increase food intake in rats with cancer or administered chemotherapeutics. The orexigenic effect of rikkunshito is involved in the stimulation of endogenous ghrelin secretion by blocking the serotonin (5-HT) 2b/2c receptor pathway and the enhancement of GHS-R activity. A potentiator of ghrelin signaling such as rikkunshito may represent a novel approach for the treatment of cancer cachexia.

Ghrelin is a potent stimulant for gastric emptying and gastrointestinal (GI) movement. Clinically, it has been reported that the intravenous administration of ghrelin accelerates the rate of gastric emptying and induces gastric phase III contractions of the migrating motor complex in healthy volunteers. Recent technical advances in the measurement of GI motility in conscious small animals, including rats, mice, and the house musk shrew (Suncus murinus), have helped to elucidate the precise mechanism of action of ghrelin. Intravenous administration of ghrelin induces fasted motor activities with phase III-like contractions of the migrating motor complex in the antrum and duodenum in animals. These effects of ghrelin are mediated by activating the hypothalamic orexigenic neuropeptide Y neuron through ghrelin receptors located at the vagal afferent terminal. Stress hormone and anorexigenic peptides cause the disruption of fasted motor activity and induce fed-like motor activity. Ghrelin and the ghrelin signal potentiator rikkunshito successfully restore fed-like motor activities to fasted activities in fenfluramine-treated rats and in a cancer anorexia-cachexia animal model. These findings suggest that ghrelin can be expected to be a therapeutic target for GI disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Anorexia nervosa (AN) is a serious medical illness associated with gastrointestinal, metabolic, and psychological complications, and there are no effective pharmacologic treatments for the condition. Recent studies have suggested that the regulatory peptides, including ghrelin, are involved in the pathologic feeding behavior of AN. Previous studies have indicated that plasma total ghrelin and acyl ghrelin levels in patients with AN are higher than in controls, and the ratio of des-acyl ghrelin to acyl ghrelin in AN tend to be higher than in controls. In addition, ghrelin has been reported to stimulate appetite and food intake in various diseases, including chronic heart failure, chronic obstructive pulmonary disease, and cancer. Because it is speculated that difficulties in resolving the underlying psychological condition preclude reversal of the pathologic feeding behavior in AN, ghrelin is expected to be applied in a clinical setting as a new treatment. In this review, we describe the role of ghrelin in the pathophysiology and potential treatment of AN along the gut-brain axis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depressive disorders. These agents may cause upper gastrointestinal (GI) symptoms that lead to their discontinuation. We examined whether SSRIs modify physiologic GI motor activities in freely moving rats., Methods: The SSRIs fenfluramine, fluvoxamine, paroxetine, and fluoxetine were administered to 24-hour food-deprived rats, and then GI motility was measured in conscious, freely moving rats using a strain gauge force transducer method. Plasma acyl ghrelin levels were determined by enzyme immunoassay., Results: Plasma acyl ghrelin levels were analyzed in conjunction with fasted motor activities. Acyl ghrelin was increased in association with the occurrence of Phase III-like contractions of the migrating motor complex in the antrum and duodenum. SSRIs decreased acyl ghrelin and changed Phase III-like contractions to fed-like motor activities. Both effects were blocked by 5-HT2c, but not 5-HT1b, receptor antagonist. Neither melanocortin 4 nor the 3/4 receptor antagonists blocked this motor effect, although they restored the anorexia induced by SSRIs. The improving effect on GI motility by 5-HT2c receptor (5-HT2cR) antagonist disappeared after treatment with a growth-hormone secretagogue receptor antagonist, whereas ghrelin or ghrelin-releasing drug such as TJ-43 changed SSRI-induced fed-like motor activities to fasted activities., Conclusions: SSRIs have inhibitory effects on acyl ghrelin and GI motor activities through 5-HT2cR. Our study identifies the importance and divergence of central 5-HT2cR pathways that regulate GI motor activities through ghrelin and feeding/energy metabolism via melanocortin 4 receptor signaling.

Background: Obestatin is a recently identified ghrelin gene product that was reported to inhibit appetite and gastric motility in contrast to ghrelin. We investigated fasting obestatin and ghrelin levels in patients with obesity and anorexia nervosa., Methods: Fasting plasma obestatin, acyl-ghrelin, desacyl-ghrelin, leptin, glucose serum adiponectin, and insulin were measured in 10 obese subjects, 11 restricting-type anorexics, and 11 control subjects., Results: Obese group had significantly lower levels of obestatin (p < .01), while anorexic group had significantly higher levels (p < .01). Obestatin was negatively correlated with body mass index (BMI) (r = -.74), glucose (r = -.56), insulin (r = -.55), leptin (r = -.66), and also with the homeostasis model assessment of insulin resistance (HOMA-R) (r = -.49) and was positively correlated with acyl-ghrelin (r = .65) and desacyl-ghrelin (r = .60). No correlation was seen between obestatin and adiponectin, but the latter was negatively correlated with both acyl-ghrelin and desacyl-ghrelin. Desacyl-ghrelin to acyl-ghrelin ratio was significantly different between anorexic and control groups (p < .05), while no difference was seen between obese and control groups., Conclusions: Both obestatin and ghrelin are increased in anorexic and decreased in obesity. We suggest that obestatin is a nutritional marker reflecting body adiposity and insulin resistance.

Background: Obestatin is a recently identified peptide encoded by the same ghrelin gene. It has been reported that obestatin has anorexigenic and antigastroprokinetic activities as opposed to ghrelin. We investigated simultaneously obestatin, acyl ghrelin, and des-acyl ghrelin in the restricting type of anorexia nervosa (AN-R) patients., Methods: Three hormonal responses to the oral glucose tolerance test (OGTT) were measured in 10 AN-R patients and 10 healthy women., Results: Plasma obestatin, acyl ghrelin, and des-acyl ghrelin levels were significantly higher in AN-R patients than in control subjects throughout the OGTT. All of the three hormones decreased after the OGTT in both groups., Conclusions: We found that AN-R patients exhibited increased plasma levels of obestatin, acyl ghrelin, and des-acyl ghrelin throughout the OGTT compared with control subjects. The hormonal differences between groups are statistically most significant in obestatin, suggesting obestatin may serve as a marker reflecting both acute and chronic changes of the nutritional state in AN-R patients.