Abstract: The discovery of ghrelin and its role in human metabolism has promoted significant research and advances in the study of obesity and other weight-related disorders. Ghrelin is relevant to many disorders of metabolism and weight such as obesity, cachexia, Prader-Willi Syndrome (PWS), and Anorexia Nervosa (AN), and its role in the pathophysiology differs. The changes observed in ghrelin physiology in these disorders shed light on the overall role of ghrelin in human metabolism and growth. The purpose of this review is to summarize the existing literature on ghrelin and some disorders of metabolism and growth. The disorders that will be discussed include obesity, cachexia, PWS, and AN. Within each disorder we will review relevant ghrelin physiology, recent studies, and potential modes of intervention with ghrelin analogues.
Ghrelin is a 28-amino acid orexigenic peptide secreted mainly from the stomach and proximal small intestine that was discovered in 1999 (Kojima et al., 1999). It is currently the only known circulating hormone that stimulates appetite and promotes food intake (Ariyasu et al., 2001; Date et al., 2000; Kojima et al., 1999). Ghrelin is unique in that it is the only substance that is secreted in response to a reduction in gastrointestinal contents, and it is suppressed by eating (Williams and Cummings, 2005). Active (acyl ghrelin) and inactive (des-acyl ghrelin) isoforms of ghrelin have been identified. Once released, acyl ghrelin has a short half-life of about 30 minutes; subsequently it is converted to the inactive form, des-acyl ghrelin.
Activation of ghrelin is through the enzyme ghrelin O-acyltransferase (GOAT) which adds an N-octanoylated serine in position 3 to the proghrelin peptide (Gutierrez et al., 2008). This modification of ghrelin with acylation of a medium chain fatty acid is unique and is essential for ghrelin to bind to its receptor, the growth hormone secretagogue receptor (GHS-R) type 1a. The GHS-R is expressed in the hypothalamus, heart, lung, pancreas, intestine, and adipose tissue (Kojima et al., 1999). In human and animal studies, activation of the GHS-R receptor results in increased food intake (Nakazato et al., 2001; Wren et al., 2000), increased adiposity (Tschop et al., 2000), and growth hormone secretion. Peripheral and central administration of ghrelin increases feeding and promotes weight gain (Tschop et al., 2000; Wren et al., 2000).
Ghrelin exerts its action on appetite and food intake largely through central processes (Chen et al., 2004; Kamegai et al., 2001; Willesen et al., 1999). Signaling of circulating ghrelin is mediated by neurons of the arcuate nucleus of the hypothalamus. In particular, neurons expressing two potent orexigenic neuropeptides, neuropeptide Y (NPY) and agouti-related protein (AgRP), have been demonstrated to reduce the activity of proopiomelanocortin (POMC) neurons via ghrelin. Therefore, NPY and AgRP are mediators of the orexigenic effect of circulating ghrelin via inhibition of melanocortin signaling. It is important to note that there is also evidence that ghrelin signaling reaches the arcuate nucleus via vagal afferents. Date et al. (2002) demonstrated that subdiaphragmatic vagotomy or chemical vagal deafferentiation with capsaicin blocked the ability to peripherally administer ghrelin to stimulate food intake.
In the past decade, much has been learned about the actions of ghrelin. The ability to measure ghrelin isoforms (acyl and des-acyl ghrelin) has advanced the knowledge about ghrelin and its role in metabolism; however, it requires careful interpretation of studies that evaluate total versus active and inactive ghrelin. Des-acyl ghrelin does not bind to the GHS-R 1a, and its biological roles are uncertain in the absence of an identified equivalent receptor (Kojima et al., 1999). It is generally accepted that the acyl and des-acyl forms of ghrelin have differential effects in the tissues. Due to the vast nature of the tissues in which the GHS-R is expressed, the roles of ghrelin and ghrelin isoforms in maintenance of body weight and nutritional intake are many. Additionally, ghrelin is thought to play roles in memory, gastrointestinal motility, inflammation, apoptosis, and dopamine action. New hypotheses about ghrelin’s role in other aspects of metabolism and growth and related disorders continue to be evaluated.
The purpose of this review is to summarize the existing literature on ghrelin and disorders of metabolism and growth. The disorders that will be discussed include obesity, cachexia, Prader-Willi Syndrome (PWS), and Anorexia Nervosa (AN). Ghrelin physiology and potential intervention with ghrelin analogues have been carefully studied within each of these disorders. The changes observed in ghrelin physiology in these disorders shed light on the overall role of ghrelin in human metabolism and growth.
Ghrelin and Human Obesity
Circulating ghrelin levels are altered in obesity. Chronically low levels of circulating ghrelin are found in obese patients compared to normal subjects (Marchesini et al., 2004; Nagaya et al., 2001; Shimizu et al., 2003; Tschop et al., 2001b). Subjects with insulin resistance and therefore, high insulin levels, also experience chronically low ghrelin levels which are likely explained by a direct effect of insulin (Poykko et al., 2003). A recent study compared ghrelin concentrations in response to a meal between obese and normal-weight prepubertal children. Significant differences were found in ghrelin levels at 3 hours; ghrelin levels began recovery to baseline levels within 3 hours after food intake among obese compared to healthy children whose levels remained suppressed after 3 hours (Schellekens et al., 2010). Although low ghrelin levels are typical in obesity, visceral adipose tissue is more sensitive to these low levels compared to subcutaneous adipose tissue (Kola et al., 2005). This implies that lipid deposition will preferentially occur in visceral fat depots in obese individuals. Typically, ghrelin levels normalize with recovery to ideal body weight. However, the obese state becomes the homeostatic state, promoting weight gain after diet-induced weight loss. Another abnormality in ghrelin secretion in obesity is a blunting of the increase in nocturnal plasma ghrelin, further supporting aberrant ghrelin circulation in obesity.
Associations between obesity and ghrelin mutations have been identified in humans. Nucleotide changes in the preproghrelin locus have been identified (Hinney et al., 2002; Ukkola et al., 2001). Additionally, mutations in the GHS-R have been reported (Liu et al., 2007). These mutations are rare and not all mutations of the GHS-R result in obesity. For example, a mutation of the GHS-R selectively eliminated the constitutive activity without affecting the affinity, potency, and efficacy of endogenous ghrelin. Humans with this mutation have very short stature and may or may not have obesity (Pantel et al., 2006).
The role of ghrelin in appetite and food intake is well established. Interference of ghrelin signaling by use of pharmacologic agents can lead to decreased food intake and ultimately weight loss (Asakawa et al., 2003; Holdstock et al., 2003; Wortley et al., 2005). Another more drastic approach for interruption of ghrelin signaling is through bariatric surgery. Immediately (30 minutes) after Roux-en-Y gastric bypass, ghrelin levels are significantly decreased (Lin et al., 2004). Additionally, several studies have found that ghrelin levels are significantly decreased after weight loss with gastric bypass compared to baseline levels (Beckman et al., 2010). This is curious, since diet-induced weight loss does not result in decreased ghrelin levels. Decreased ghrelin concentrations after surgery may provide evidence of why gastric bypass is an effective means to achieve long-term weight loss. Although bariatric surgery is generally successful in reversing metabolic complications associated with morbid obesity, it is not widely available to the public as treatment for obesity. Therefore, medications that target ghrelin and the GHS-R (i.e., antagonists) have been suggested as attractive modalities to fight against obesity. Several GHS-R ligands are in development, and an anti-obesity vaccine which prevents ghrelin from reaching the central nervous system has been developed (Schellekens et al., 2010). Other pharmacologic approaches include antibodies against ghrelin, ghrelin enantiomers which can neutralize ghrelin (Becskei et al., 2008), and decreasing acyl ghrelin through inhibition of GOAT (Gualillo et al., 2008). While there exists great potential for pharmacologic intervention for obesity through ghrelin targets, there is currently no ghrelin anti-obesity drug on the market due to lack of efficacy, non-selectivity, poor bioavailability, and lack of sustained weight loss which is thought to be secondary to compensatory mechanisms.
Ghrelin and Cachexia
Cachexia or wasting is defined as unintentional weight loss in which both lean and fat mass are lost. Cachexia is often associated with increased energy expenditure and anorexia. A variety of diseases including chronic obstructive pulmonary disease (COPD), cancer, chronic renal insufficiency (CRI), and congestive heart failure (CHF) are associated with cachexia, and it significantly impacts morbidity and mortality (Nandi et al., 2002). Malnutrition in this setting is often very difficult to treat and is associated with worsening of the underlying disorder. The ability to alleviate cachexia would provide a significant increase in quality of life for patients with advanced cancer and the chronic medical conditions mentioned above.
Plasma ghrelin levels have been found to be higher in individuals with lower body mass index (BMI) compared to those with normal or higher BMIs (Huang et al., 2007; Shiiya et al., 2002; Soriano-Guillen et al., 2004). Some studies of patients with CHF, COPD, and cancer have demonstrated no significant difference in ghrelin concentrations between healthy individuals and patients when matching for BMI (Huang et al., 2007; Itoh et al., 2004; Nagaya et al., 2001). However, in other studies total ghrelin levels have been found to be elevated approximately 25% above normal in a variety of cancers causing cachexia, including lung, breast, colon, and prostate cancers (Garcia, 2005; Shimizu et al., 2003; Wolf et al., 2006). Garcia et al. (2005) demonstrated high levels of acyl ghrelin in patients with cancer and clinical cachexia. The cause of higher ghrelin levels in cancer cachexia may be multi-factorial, as these types of cancers have been reported to express ghrelin (Nikolopoulos et al., 2010). Due to the chronic elevation of active ghrelin in some cancers, concerns about saturation of the GHS-R and its therapeutic use and efficacy exist. Unlike cancer cachexia, cachexia associated with CRI is only associated with increases in total ghrelin levels (i.e., acyl ghrelin levels are not increased) (Yoshimoto et al., 2002). The elevation in total ghrelin is secondary to the fact that des-acyl ghrelin is cleared through the kidneys and accumulates with renal insufficiency. The lack of increase in active ghrelin in CRI suggests the potential use of ghrelin or ghrelin agonists in the treatment of renal cachexia.
Thus far, cancer cachexia has been among the best-studied application of ghrelin among the different settings of cachexia. The presence of anorexia in the face of elevated acyl ghrelin levels suggests either resistance to ghrelin’s orexigenic properties in the setting of cancer cachexia or overwhelming anorexic effects of other processes. Thus far, attempts at treating cancer cachexia with ghrelin have required supra-physiologic doses of ghrelin but have demonstrated nearly universally positive effects on appetite. This suggests that ghrelin’s effect on appetite-stimulating centers is not saturated in the setting of cancer cachexia (DeBoer, 2008). In a randomized, placebo-controlled study in cancer patients with cachexia, administration of ghrelin led to a significant increase in food intake and meal appreciation as compared to saline infusion (Neary et al., 2004). The short half-life of ghrelin and the route of delivery via injection limits the widespread use of ghrelin as a therapeutic agent. Recently, a novel oral ghrelin agonist and GH secretagogue (RC-1291) was developed to increase appetite and lean muscle mass in patients with cancer-related cachexia. This agent was evaluated in a study of healthy subjects and was shown to produce dose-related increases in body weight with no dose-limiting adverse effects (Garcia and Polvino, 2007).
In summary, most cachexia syndromes have been shown to have elevated levels of des-acyl ghrelin at baseline. It is not known whether these elevated levels of des-acyl ghrelin are causative of symptoms or a physiologic response to cachexia. Most disease states resulting in cachexia also demonstrate an elevation in acyl ghrelin that may be expected following loss of body mass. Early studies with ghrelin agonists (GHS-R 1a agonists) are promising and offer significant promise for the treatment of cachexia syndromes.
Ghrelin and Prader-Willi Syndrome (PWS)
Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency. Children with PWS present with rapid weight gain in childhood along with a voracious appetite. Other clinical findings include hypogonadism, aberrant body temperature control, and sleep disturbances. Although hypothalamic dysfunction is thought to be the basis for many of the features of PWS, the underlying mechanisms remain unknown. The discovery of ghrelin and its role in appetite regulation prompted researchers to investigate whether ghrelin is involved in the pathogenesis of obesity in the setting of PWS.
Elevated total ghrelin levels were first demonstrated among adults with PWS (Cummings et al., 2002; Delparigi, 2002). Subsequently Haqq and colleagues demonstrated that children with PWS compared to weight matched controls have 3- to 4-fold higher ghrelin levels (Haqq, 2003a). Additionally, this study included control groups of children with single gene mutations associated with morbid obesity (i.e., MC4R mutants and individuals with leptin deficiency), and fasting ghrelin was significantly greater in the PWS group compared to the morbidly obese control groups (Haqq, 2003a). The above studies and others that replicated these findings provide significant rationale that the hyperphagia observed in PWS may be secondary to elevated ghrelin levels. Of note, the negative correlation between ghrelin and adiposity is generally preserved among individuals with PWS (Delparigi, 2002), suggesting that although there is a shift in the relationship between ghrelin and adiposity, this condition does not represent complete ghrelin dysregulation. Additionally, the negative correlation between ghrelin and age remains intact as well such that as individuals with PWS age, their ghrelin levels decrease. This may be partly explained by the progressively increasing adiposity with age among individuals with PWS.
Intervention studies targeting elevated plasma ghrelin levels in PWS have been conducted. Octreotide, a somatostatin agonist, is used to treat acromegalic adults and children with hypothalamic obesity and has been shown to suppress ghrelin levels by 5-fold in healthy adults and 2-fold in people with acromegaly (Norrelund et al., 2002; Schaller et al., 2003). Haqq and colleagues demonstrated that short-term administration of moderate doses of octreotide suppressed ghrelin levels in children with PWS (Haqq, 2003b). Another 56-week prospective, randomized, cross-over study demonstrated that long-acting octreotide causes a decrease in acyl and des-acyl ghrelin concentrations (De Waele, 2008). However, these effects did not impact weight/BMI, appetite, or compulsive behavior towards food. It is unclear whether the lack of effects on weight and appetite are secondary to too small a reduction in ghrelin concentrations at the hypothalamic level, or if the above study lacked adequate power to detect changes in weight and appetite. Additionally, while octreotide decreases plasma ghrelin concentrations, it also decreases the concentrations of anorexigenic hormones, such as insulin and peptide YY (PYY). Octreotide has known side effects; the most significant is decreased insulin secretion which results in impaired glucose tolerance. Thus, at this time, there is little evidence to support the use of octreotide for the treatment of PWS. Agents that specifically target ghrelin secretion or its action on the GHS-R and do not interact with other appetite-regulating peptides are still potential options for the treatment of PWS.
Ghrelin and Anorexia Nervosa
Anorexia Nervosa (AN) is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. It is often coupled with a distorted self and body image which is maintained by various cognitive processes that alter how the individual evaluates and thinks about her or his body, food, and eating. Individuals with anorexia nervosa are thought to continue to feel hunger, but despite this they consume very small quantities of food. The etiology of AN is largely unknown, but is thought to be multi-factorial. Recent knowledge regarding hormones which regulate appetite (i.e., ghrelin, PYY) have prompted investigations into whether hormones such as ghrelin may be involved in the pathogenesis of AN.
Studies of ghrelin secretion in the setting of AN demonstrate a hypersecretory state, with increased basal total ghrelin concentrations (Misra et al., 2005; Prince et al., 2009). More recently, investigators have begun to measure active and inactive ghrelin isoforms in patients with eating disorders. Results have been somewhat inconsistent due to heterogeneous study samples (i.e., patients at varying stages of the disease) and differences in the ghrelin assays used (Harada et al., 2008; Hotta et al., 2004; Nakai et al., 2003). In general, studies have demonstrated that there are increased active and inactive forms of ghrelin in patients with restrictive eating disorders (Harada et al., 2008; Nakai et al., 2003). The reduced food intake that is a hallmark of AN despite chronically increased ghrelin levels has led to speculation that this condition represents a state of “ghrelin insensitivity or resistance” (Broglio et al., 2004; Miljic et al., 2006). This theory was tested by researchers who showed that AN patients did not respond to ghrelin administration by increasing appetite and food intake as did the healthy controls (Broglio et al., 2004; Miljic et al., 2006). Furthermore, the elevation of ghrelin level in AN tends to normalize when patients regain their body weight with intensive treatment aimed at weight restoration (Nakahara et al., 2007; Otto et al., 2001; Soriano-Guillen et al., 2004; Tanaka et al., 2004). This observation is consistent with previously reported findings that ghrelin levels increase in the setting of active weight loss or caloric deficit such as cachexia caused by chronic illness (Corbetta et al., 2003; Nagaya et al., 2001), and decrease in the presence of hyperinsulinemia and obesity (McLaughlin et al., 2004; Tschop et al., 2001b). It has been suggested that the increased circulating ghrelin levels in AN may be largely due to the energy deficit.
Dynamic studies of patients with AN may shed some light on how the disorder is maintained. In healthy individuals, ghrelin secretion is suppressed after macronutrient ingestion (Cummings et al., 2001; Tschop et al., 2001a) and, both acyl and total ghrelin levels are significantly reduced following macronutrient ingestion by carbohydrates and protein and less potently by lipids (Foster-Schubert et al., 2008). The magnitude of suppression is positively associated with caloric content and macronutrient admixture (Erdmann et al., 2004; Marzullo et al., 2006). Alteration in the dynamic ghrelin response to meal ingestion has been described in patients with AN. Significantly blunted suppression of ghrelin following meal ingestion or oral glucose administration has been described in underweight AN patients (Nedvidkova et al., 2003; Tanaka et al., 2003), while suppression to a similar degree as seen in normal subjects has also been observed in other studies (Misra et al., 2004; Nakahara et al., 2007; Stock et al., 2005). The latter, suppression of ghrelin to a comparable degree to that of healthy, normal weight individuals is a potential mechanism by which the disorder is maintained. In other words, re-feeding of patients with AN, even at early stages with sub-optimal levels of nutrition might adequately suppress ghrelin levels such that ongoing repletion of nutrition is not promoted through ghrelin. Studies of patients early in the course of treatment are indicated. Another relevant study was completed by Kowalska and colleagues who reported that fasting ghrelin levels were higher in AN women, and that the fall in ghrelin was greater than in control and obese subjects after the euglycemic hyperinsulinemic clamp. The authors speculated that the greater suppression of ghrelin by insulin among women with AN may lead to more rapid feeling of satiety in AN (Karczewska-Kupczewska et al., 2010). This study highlights the idea that hormones such as ghrelin and insulin and potentially others may interact in AN to promote and maintain the disorder.
To develop effective ghrelin targeted treatment to increase food intake and restore energy balance in people with AN requires a better understanding of the mechanism of the state of “ghrelin resistance.” Terashi and colleagues recently explored whether decreased levels of ghrelin reactive autoantibodies could explain elevated plasma ghrelin in AN and provide an explanation for ghrelin resistance in the setting of AN (Terashi et al., 2011). Autoantibodies to ghrelin are naturally occurring and it is thought that physiologic ghrelin autoantibodies help regulate its plasma levels. Researchers found that patients with AN had significantly lower plasma levels of acyl ghrelin IgG, IgM, and IgA autoantibodies. These low levels persisted even after one month of refeeding in the AN patients (Terashi et al., 2011). These data provide one theory about the ghrelin resistance observed in patients with AN. Further research is needed to understand why people with AN do not respond appropriately to ghrelin, a potent stimulator of food intake.
Ghrelin causes an increase in food intake, down-regulation of energy expenditure, and conservation of body fat, all of which promote weight gain and obesity. There are weight-related disorders that are characterized by elevated ghrelin levels such as cachexia, AN, and PWS. The difference in these disorders is the response of the individual to ghrelin. Individuals with AN and cachexia fail to increase their food intake and appear to have some degree of ghrelin resistance, while individuals with PWS are more sensitive to ghrelin and have a voracious appetite.
Weight-related disorders that demonstrate differences in ghrelin secretion offer opportunities for interventions that target ghrelin. However, this has proven challenging due to many factors. First, the regulation of appetite, energy expenditure, and maintenance of weight is highly integrated and redundant with feedback mechanisms. In other words, while ghrelin may play a significant role in these functions, there are other substances that compensate when ghrelin signaling is interrupted. Second, it is unlikely that GHS-R type 1a is the only receptor responsible for ghrelin’s activity and other GHS-R subtypes have been suggested. Finally, ghrelin has other functions in addition to regulation of appetite such as gastrointestinal motility, glucose metabolism, memory, and cardiac output. Interruption of ghrelin signaling may negatively impact these other important functions and body systems.
The authors have no conflicts of interest to report.
Jennifer B. Hillman, M.D., Division of Adolescent Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, 3333 Burnet Avenue, MLC 4000, Cincinnati, Ohio 45229, USA.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(61):521-528, June 2011.]