The hunger hormone ghrelin in cachexia

Abstract

Cachexia is characterized by reduced food intake, muscle and adipose tissue loss associated with increased energy expenditure. Cachexia is highly prevalent and represents one of the main causes of increased morbidity, mortality and reduced quality of life in chronic diseases. Ghrelin plays an important role in stimulating and controlling hunger and maintaining energy homeostasis acting on central nervous system and on peripheral tissues. Most of the studies have been conducted in experimental settings and in cancer and uremic patients, showing interesting results in the treatment of cachexia. Further investigations are mandatory to obtain more definitive and conclusive results.

Keywords::

• anorexia
• cachexia
• cancer
• ghrelin
• uremia

1. Introduction

The loss of the desire to eat, which is defined as anorexia, is one of the most difficult symptoms to treat during chronic diseases. Alteration of taste, changes in smell, early satiety or nausea and vomiting may all contribute to the development of anorexia [1]. When signs and symptoms affecting nutritional status, such as increased metabolic rate, weight loss and muscle and adipose tissue wasting are also present, cachexia can be diagnosed [2]. The prevalence of cachexia is particularly high during cancer [3], end-stage renal disease and other acute and chronic conditions [1]. A relevant role in the pathogenesis of cachexia has been attributed to the dysregulation of hunger hormones [4]. Among the hypothalamic and peripheral mediators potentially involved in cachexia, that is, neuropeptide Y (NPY) [5], nesfatin-1, leptin and peptide YY (PYY) [4], a more specific role has been attributed to the peptide ghrelin. This peripheral hormone produced mainly by the enteroendocrine cells of gastric mucosa is able to link the growth hormone (GH) secretagogue receptor [6] and its physiological effects on the regulation of food intake and on body composition modification have been well identified and recently reviewed [7].

Other peptides, such as NPY and orexins, have been tested in cachexia, but their use was mainly limited to experimental models without providing definite results [8].

Most available studies of ghrelin in cachectic conditions, reported increased levels compared with healthy controls and documented its positive effects in the treatment of several catabolic conditions [9]. The potential of ghrelin in the treatment of cancer cachexia has been extensively reviewed in this Journal and is supported by its documented anti-inflammatory and pro-anabolic properties [10]. Such effects might prove beneficial even in other forms of muscle depletion such as age-related sarcopenia or sarcopenic obesity and warrant further investigation.

Acute and chronic administrations of ghrelin in rodent models of cachexia were associated with increased feeding and body weight consequently to increased expression of hypothalamic orexigenic peptides and decreased inflammatory markers [7]. This suggests that ghrelin and/or ghrelin agonists may be useful for treatment of anorexia–cachexia syndrome [10].

2. Cancer cachexia

Different experimental data on the use of ghrelin in cachexia showed significant increases in food intake and weight gain resulted from a reversal in the loss of lean body mass [8]. In particular, DeBoer et al. showed that ghrelin and a synthetic ghrelin receptor agonist in cachectic rats improved body weight and lean body mass retention via effects involving orexigenic neuropeptides and anti-inflammatory changes [11].

Clinical studies have evaluated the safety and efficacy of ghrelin in patients with cancer cachexia [12,13]. In particular, a randomized, placebo-controlled clinical study was conducted to evaluate ghrelin effects on appetite in a small sample of anorexic cancer patients. Ghrelin i.v. administration determined a significant increase in oral energy intake with respect to control subjects treated with saline [12]. In another randomized, double crossover study in advanced cancer patients, a low or high dose of ghrelin or placebo before lunch was infused daily [13]. Anorexia-related symptoms and energy and protein intake did not differ between the ghrelin and placebo groups. Although more patients preferred ghrelin to placebo at the middle and end of the study, this finding was not dose-dependent [13]. Considering these controversial results, more clinical evidences are mandatory. An important concern regarding the use of ghrelin in cancer anorexia–cachexia syndrome is determined by the fact that ghrelin may increase the circulating levels of growth factors, such as GH and insulin-like growth factor-1 (IGF-1) [6], which might stimulate and enhance tumor growth. As per the author's knowledge, no in vivo data are available evaluating the differences in tumor growth following ghrelin or GH-stimulating treatments. Long-term, large-scale clinical trials might provide insights on whether ghrelin treatment stimulates tumor growth in cancer patients.

3. Uremic cachexia

End-stage renal disease and uremia are frequently associated with cachexia. This condition is highly resistant to intervention and is a major predictor of morbidity and mortality for patients on either peritoneal dialysis or hemodialysis [14]. Based on the available data, renal failure is a clinical condition associated with GH resistance and with ghrelin resistance [14]. However, increased ghrelin levels could play a protective role to counteract the negative metabolic effects induced by the presence of inflammation, which is common feature in this condition [14]. In this regard, ghrelin exogenous administration may overcome ghrelin resistance at target organs, ameliorate metabolic alterations and result in clinical benefits [14]. In a small clinical study, aimed at evaluating the effects of subcutaneous administration of ghrelin in mild and moderate malnourished peritoneal dialysis patients, oral energy intake immediately doubled [15]. The same positive result has also been obtained in a 7-day trial, showing that in malnourished dialysis patients' daily subcutaneous ghrelin injection significantly improved appetite, with an increase in energy intake observed at the first study meal without side effects throughout the whole week of clinical observation [16]. Also, energy expenditure, evaluated with free-living pulse and motion monitors, was not influenced by ghrelin administration [16]. In an animal model of chronic renal failure, ghrelin infusion resulted in increased food intake and an improvement in body composition related in part to a decrease in muscle protein breakdown [17]. Moreover, ghrelin treatment significantly reduced inflammatory cytokines circulating levels in nephrectomized rats. Finally, ghrelin-treated animals showed a decrease in the expression of IL-1 receptor in the brainstem and a decrease in expression of the enzyme involved in the processing of proopiomelanocortin to the norexigenic peptide α-melanocyte-stimulating hormone (α-MSH) [17]. Ghrelin administration normalized low muscle mitochondrial enzyme activities in uremic rats [18]. This effect was associated with reduced muscle triglyceride content and higher AKT phosphorylation. Interestingly, the effects of ghrelin on mitochondria are independent of food intake modifications, while combined ghrelin administration and increased food intake were necessary to enhance AKT phosphorylation [18]. Therefore, it seems that ghrelin-induced muscle mitochondrial changes and lower tissue triglycerides could enhance insulin action and muscle anabolic response in the presence of improved anorexia. In this view, the use of ghrelin in renal patients with cachexia may induce clinical benefits especially related to its anticatabolic effects. Finally, ghrelin acting on central and peripheral pathways exerts different actions including orexigenic effects and influence on metabolic and neuroendocrine response in different tissues. In particular, the effect of ghrelin in improving food intake and modulating energy metabolism strongly suggests the possibility that ghrelin could be deeply involved in the pathophysiological and neurohormonal derangements commonly observed in cachexia associated with chronic diseases, such as cancer and uremia).

4. Other clinical conditions

The administration of ghrelin was also tested in cachectic patients affected by chronic heart failure. Ghrelin infusion determined improvement of food intake and body weight associated with reduction of muscle wasting and enhancement of patient exercise capacity and of left ventricular function [19]. Although interesting, this is neither a non-randomized nor a placebo-controlled trial, the results of which should be confirmed by future research.

In chronic obstructive pulmonary disease (COPD) patients, ghrelin administration significantly improved food intake, body composition and respiratory muscle strength apparently not through a modulation of the inflammatory status [20]. Instead, inflammation appears to be attenuated by ghrelin administration in a model of bleomycin-induced acute lung injury by protecting the alveolar epithelial cells and regulating lung inflammation [21].

Ghrelin infusion was also tested in post-gastrectomy cancer patients who often develop body weight loss and cachexia. In fact, appetite, food intake and body weight were improved after ghrelin administration compared with the placebo group [22]. Similar results were also obtained in patients undergoing esophagectomy who were able to preserve lean body mass in the postoperative period [23].

A summary of clinical studies of ghrelin administration in different forms of cachexia is reported in Table 1.

Table 1. A summary of clinical studies of ghrelin administration in different forms of cachexia.

Clinical setting	Dose	Side effects	Variables	Ref.
Cancer cachexia	5 pmol/kg/min i.v. for > 180 min	None	Energy intake, body weight, insulin, glucose, triglycerides	[12]
Cancer cachexia	2 or 8 µg/kg i.v. for 4 days, once a day	Increased bowel activity, abdominal pain, dry mouth, shortness of breath, sweating, asthenia, nausea, diarrhea, vomiting	Energy intake, appetite, inflammation	[13]
Uremic cachexia	3.6 nmol/kg s.c. once a week	None	Energy intake, blood pressure, appetite, insulin and glucose	[15]
Uremic cachexia	12 µg/kg s.c. for 1 week once a day	None	Energy intake, inflammation, blood pressure, glucose, insulin and lipid profile	[16]
Cardiac cachexia	2 µg/kg i.v. for 3 weeks twice a day	None	Food intake, body weight, lean body mass, GH, IGF-1, cardiac function and structure, exercise capacity, ventilator efficiency, inflammation, BNP, glucose, insulin, cortisol, renin, aldosterone, norepinephrine, epinephrine	[19]
COPD associated-cachexia	2 µg/kg i.v. for 3 weeks twice a day	None	Food intake, body weight, lean body mass, performance status, 6-min walk test, GH, IGF-1, muscle strength, functional capacity, inflammation, glucose, insulin, cortisol, norepinephrine, epinephrine	[20]
Total gastrectomy	3 µg/kg i.v. for 10 days twice a day	Profuse diaphoresis	Appetite, body weight, body composition, basal metabolic rate	[22]
Esophagectomy	3 µg/kg i.v. for 10 days twice a day	None	Energy intake, appetite, body weight, body composition	[23]

BNP: Brain natriuretic peptide; COPD: Chronic obstructive pulmonary disease; GH: Growth hormone; IGF-1: Insulin-like growth factor-1; i.v.: Intravenous; s.c.: Subcutaneous.

5. Conclusion

In conclusion, these ghrelin properties should foster future research aimed at developing novel and useful therapies against cachexia, which is yet an untreatable condition. Research on these aspects appears challenging, considering the different clinical settings in which ghrelin can be used. In fact, as discussed, cachexia can develop during several acute and chronic diseases, which are determined by different pathophysiological mechanisms. The most recent data suggest that ghrelin can represent a potentially rewarding avenue, but its optimal dosage, duration of the treatment and routes of administration need to be better investigated and clarified by larger clinical trials. More and better clinical evidence is needed before ghrelin use can be routinely recommended for the treatment of cancer anorexia. Future long-term, randomized placebo-controlled trials should focus on the safety of use and efficacy in improving appetite, body weight, lean body mass and quality of life in patients affected by anorexia and cachexia of chronic diseases, including cancer.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.