Obesity prevalence has been rising exponentially worldwide and is now a major burden for the healthcare systems. The main reason of obesity-related concern is the associated risk of developing common chronic diseases such as type 2 diabetes, hypertension, cardiovascular diseases and several cancers, which are significantly increased in the overweight and obese populations.1
Obesity results mainly from a positive balance between caloric intake and energy expenditure; thus the first step of any therapeutic intervention, involves lifestyle alterations with the aim of inverting the energy balance from positive to negative. This can be achieved by increasing physical activity and reducing caloric intake.2
Obesity is a chronic medical condition, as evidenced by the high likelihood of recurrence after weight loss. Therefore, as for any chronic disease, requires a long-term approach. The available weight loss treatments include combinations of diet, exercise, behavioral modification, pharmacotherapy and bariatric surgery.2
Drug therapy, aiming either to suppress appetite or alter nutrient absorption, is indicated for patients with body mass index (BMI) over 30kg/m2 or over 27kg/m2 associated with high-risk co-morbid conditions. Drug therapy typically induces only 5–10% weight loss, although enough to confer health benefits to the patient and improvement of obesity comorbidities.
Nevertheless, currently available drugs are rather limited and either cannot be used chronically or are prone to tolerance and secondary lack of effectiveness. Bariatric or obesity surgery is the only treatment that has proved to produce sustained weight loss in the long term. However, surgery is reserved for patients with BMI over 40kg/m2 or over 35kg/m2 associated with high-risk comorbid conditions, in whom medical weight loss treatments have failed and have not shown long-term effectiveness.3
In result of the self-evident limited treatment resources for obese patients, in particular for those with BMIs lower than 35kg/m2, alternative therapeutic targets would be most welcomed.
Energy homeostasis is critical for survival, therefore it is highly regulated in all living organisms. Energy homeostasis aims at promoting the stability of stored energy, which results from the balance between energy intake and energy expenditure.4
Energy homeostasis is regulated by brain centres, such as the hypothalamus, brainstem and the limbic system, which via neuropeptides, control food intake and energy expenditure. These centres are modulated by neural and hormonal signals coming from the periphery, arriving mostly from the adipose tissue and from the gastrointestinal tract.4
Ghrelin is a gastrointestinal peptide hormone that is predominantly produced by endocrine cells in the gastric fundus. Ghrelin acts in the arcuate nucleus of the basal hypothalamus on the central nervous system to stimulate food intake and decrease energy expenditure, by promoting the production and release of signals, such as neuropeptide Y and agouti-related peptide, and suppressing POMC, a precursor protein that through proteolytic cleavage originates α-MSH, which decreases appetite and increases energy expenditure.5
Ghrelin has also been shown to have a long-term effect on energy homeostasis by decreasing utilisation of fat as energy and shifting food preference towards high fat diet.6 Chronic ghrelin administration has been demonstrated to promote weight gain and adiposity, while ghrelin replacement partially reverses the weight and body fat loss after gastrectomy.6–8
In physiological conditions, ghrelin levels rise before meals and decrease with food intake.9 Furthermore, plasma ghrelin levels are usually inversely correlated with BMI; thus ghrelin is reduced in most obese patients when compared with normal weight individuals.10 Diet-induced weight loss has been shown to raise ghrelin levels that has been implicated in the weight regain phenomena.9
However, the increase of ghrelin levels associated with the weight loss induced by caloric deprivation seems to be prevented by some bariatric surgery procedures, which in addition to food intake restriction or malabsorption, may also contribute to the sustainability of weight loss attained trough surgical treatment.9
Ghrelin, being the only peripheral hormone known to stimulate food intake, is considered the most promising target for obesity treatment.
Blunting ghrelin activity
Thus, neutralisation of ghrelin biologic effects in energy homeostasis, using different experimental approaches has already been attempted in order to prove this concept.
Ghrelin or ghrelin receptor genetic deletion, ghrelin receptor antagonists and ghrelin O-acyltransferase (GOAT) inhibitors targeting the enzyme responsible for ghrelin acylation, are some of the different means that have been used to establish the consequences of blunting ghrelin activity. These approaches have demonstrated that by suppressing ghrelin activity, it is possible to decrease food intake, suppress re-feeding after food deprivation, increase the basal metabolic rate, decrease food efficiency, promote weight loss, prevent body weight gain, improve glucose tolerance and increase insulin secretion, thereby confirming the potential of ghrelin blockade for the treatment of obesity and type 2 diabetes.11
Anti-ghrelin vaccination strategies have aroused as an appealing therapeutic tool to treat obesity.12 Immunological approaches tested so far include passive polyclonal and monoclonal anti-acylated ghrelin antibody transfer, which were able to suppress ghrelin-mediated food intake, inhibit fast-induced feeding and reduce overall food intake upon re-feeding and increase energy expenditure during food deprivation.11
Although, representative as a proof-of-concept, passive immunisations are not likely to be transferable to the clinical setting as these have the limitation of lacking long-term effectiveness due to the reduced half-lives of the antibodies and the need for periodic administration. As an attractive alternative to induce a sustained immune response to suppress endogenous ghrelin bioactivity, active immunisation schemes have been pursued.
These have included the development of conjugates of ghrelin-bovine serum albumin (BSA), ghrelin-keyhole limpet haemocyanin (KLH) and ghrelin-virus-like particles (VLPs) conjugates.12–14 Among these immune-conjugates, those that rely on the use of adjuvants, such as BSA and KLH, in order to achieve an appropriate antibody response, carry the risk of exacerbated immune response or have restricted use in humans.12–14 In contrast to the immunisation using VLPs, viral proteins without genetic material hence with no pathogenic phenotype, represent the most recent advance towards a pharmacological blockade of ghrelin biological effects.15
Targeting ghrelin as a means of decreasing food intake and increasing energy expenditure has attracted the attention not only of pharmacological treatment approaches, but also in the surgical field. Sleeve gastrectomy is a restrictive bariatric surgery procedure that consists in the resection of the stomach along the greater gastric curvature and construction of a tubular gastric pouch, thus reducing the gastric volume. Sleeve gastrectomy results in an excess body weight loss that ranges from 33% to 90% depending on the series. The weight loss induced by sleeve gastrectomy has been attributed not only to the restriction of the stomach capacity, but also to the decrease of ghrelin levels, as the surgery involves resection of the majority of the gastric fundus, the main location where ghrelin is produced.16
More recently, embolisation of the left gastric artery, or bariatric gastric embolisation has been proposed as a potential minimally invasive approach when compared to bariatric surgery, offered by interventional radiologists to treat obesity. The aims of the gastric embolisation procedure are to induce an ischaemic depletion of ghrelin- secreting cells of the gastric fundus, thus suppressing ghrelin in order to modulate body weight. Preliminary studies in animal models have shown that bariatric embolisation resulted in a significant reduction in ghrelin-expressing cells in the gastric fundus and circulating ghrelin levels. In early clinical studies, bariatric gastric embolisation has also been shown to significantly affect weight.17
However, ghrelin suppression is not expected to be effective in the absence of high ghrelin levels, while with the sole exception of patients with Prader Willi Syndrome, most obese patients have low ghrelin levels. Furthermore, the role of ghrelin in food intake regulation seems to act predominantly in response to conditions of low energy intake, driving hunger, rather than regulating basal food intake or appetite.18
In addition, as food intake is the result of a highly regulated and redundant network, ghrelin inactivation procedures are likely to activate other compensatory pathways.
Therefore, is unlikely that any therapy based on ghrelin suppression alone will ever become broad anti-obesity agent.12
The patients who could probably benefit the most from the ghrelin suppressive approaches, such as pharmacological blockade or radiological interventions, are more likely to be individuals with BMIs ranging from 27 to 35kg/m2, enrolling on a diet and exercise programme, as adjuvant therapy for weight loss and for the prevention of weight regain.
Still, gastric embolisation should not be considered in bariatric surgery candidates, since the former can induce alterations in the microvasculature and fibrosis of the gastric wall that can hamper a future surgical procedure or increase the risk of surgical complications.
In conclusion, given the limited treatment resources available for obese patients, novel therapeutic approaches, such as bariatric embolisation, are most welcome. Nevertheless, as with any treatment, this will require careful patient selection in order to optimise the results.
Patients and physicians also need to be conscious that the single inhibition of the ghrelin pathway, as a means to interfere with body weight, is unlikely to be effective, and a multidisciplinary approach will still be required for obesity treatment.
- Kelly T et al. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond) 2008;32(9):1431–7.
- Fujioka K. Management of obesity as a chronic disease: nonpharmacologic, pharmacologic, and surgical options. Obes Res 2002;10(Suppl 2):116S–123S.
- Kushner R. Diets, drugs, exercise, and behavioral modification: Where these work and where they do not. Surg Obes Relat Dis 2005;1(2):120–2.
- Schwartz MW et al. Central nervous system control of food intake. Nature 2000;404(6778):661–71.
- Kojima M et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402(6762): 656–60.
- Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev 2005;85(2):495–522.
- Dornonville de la Cour C et al. Ghrelin treatment reverses the reduction in weight gain and body fat in gastrectomised mice. Gut 2005;54(7):907–13.
- Wren AM et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001;86(12): 5992.
- Cummings DE et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346(21):1623–30.
- Tschop M et al. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50(4):707–9.
- Monteiro MP. Obesity vaccines. Human Vaccines Immunotherapeutics 2014;10(4): 887–95.
- Monteiro M.P. Anti-ghrelin vaccine for obesity: a feasible alternative to dieting? Expert Rev Vaccines 2011;10(10):1363–5.
- Vizcarra JA et al. Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs. Domest Anim Endocrinol 2007;33(2):176–89.
- Zorrilla EP et al. Vaccination against weight gain. Proc Natl Acad Sci USA 2006;103(35):13226–31.
- Andrade S et al. Immunization against active ghrelin using virus-like particles for obesity treatment. Curr Pharm Des 2013;19(36):6551–8.
- Shi X et al. A review of laparoscopic sleeve gastrectomy for morbid obesity. Obes Surg 2010;20(8):1171–7.
- Weiss CR et al. Bariatric embolization of the gastric arteries for the treatment of obesity. J Vasc Interv Radiol 2015;26(5):613–24.
- Nakazato M et al. A role for ghrelin in the central regulation of feeding. Nature 2001;409(6817):194–8.