Elsevier

Neuropharmacology

Volume 58, Issue 1, January 2010, Pages 2-16
Neuropharmacology

Review
Lean mean fat reducing “ghrelin” machine: Hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity

https://doi.org/10.1016/j.neuropharm.2009.06.024Get rights and content

Abstract

Obesity has reached epidemic proportions not only in Western societies but also in the developing world. Current pharmacological treatments for obesity are either lacking in efficacy and/or are burdened with adverse side effects. Thus, novel strategies are required. A better understanding of the intricate molecular pathways controlling energy homeostasis may lead to novel therapeutic intervention. The circulating hormone, ghrelin represents a major target in the molecular signalling regulating food intake, appetite and energy expenditure and its circulating levels often display aberrant signalling in obesity. Ghrelin exerts its central orexigenic action mainly in the hypothalamus and in particular in the arcuate nucleus via activation of specific G-protein coupled receptors (GHS-R). In this review we describe current pharmacological models of how ghrelin regulates food intake and how manipulating ghrelin signalling may give novel insight into developing better and more selective anti-obesity drugs. Accumulating data suggests multiple ghrelin variants and additional receptors exist to play a role in energy metabolism and these may well play an important role in obesity. In addition, the recent findings of hypothalamic GHS-R crosstalk and heterodimerisation may add to the understanding of the complexity of bodyweight regulation.

Introduction

The prevalence of obesity is rapidly increasing in both developed and developing countries and is a worldwide burden upon health care systems (Bloom et al., 2008). Obesity and its associated morbidities can be viewed as the effects of imbalance between energy intake and expenditure (Chakrabarti, 2009). Genetic predisposition within individuals increases the likelihood of the development of obesity (Bouchard, 2008, Dahlman and Arner, 2007, Loos and Bouchard, 2003). Indeed, 40–70% of the population variation in body mass index (BMI) is accounted for by genetic factors (Willer et al., 2009). This includes variants of the fat mass and obesity associated gene (FTO) and the melanocortin 4 receptor (MC4R) (Li and Loos, 2008, Loos et al., 2008, Willer et al., 2009). However, the current increase of the obesity epidemic seems largely the result of the current lifestyle of dietary habits and physical activity patterns (Marti et al., 2004). The high rate of obesity has led to increases in complications associated with obesity, notably the Metabolic Syndrome (Reaven's Syndrome X; the Insulin Resistance Syndrome), which describes a constellation of cardiovascular risk factors, specifically insulin resistance (type 2 diabetes), glucose intolerance, dyslipidemia and hypertension. The co-occurrence of adiposity within the Metabolic Syndrome increases the relative morbidity risk (Cheng and Leiter, 2006, Mikhail, 2009). Therefore, it is not surprising that the obesity epidemic has focussed the attention and effort of the pharmaceutical industry to the development of anti-obesity drugs (Bloom et al., 2008). Current strategies for obesity aim either to 1) decrease appetite through central action, 2) modulate metabolism through peripheral actions 3) alter fat absorbtion or 4) to modulate gut peptide receptors (Chakrabarti, 2009) (Hughes, 2009, Naslund and Hellstrom, 2007). Understanding the regulatory pathways involved in energy intake and storage (i.e. fat accumulation) versus energy expenditure (i.e. fat oxidation) is needed to understand and counter the current obesity crisis. It is becoming clear that various elements are involved in energy balance and a critical regulatory role has been identified for the hypothalamic peptide system in the central regulation of appetite and energy metabolism. Within this hypothalamic peptide system, ghrelin is the first and only known peripheral hormone identified exerting an orexigenic effect (Nakazato et al., 2001). The major hypothalamic site controlling appetite is taken by the neurons in the arcuate nucleus (ARC) and considerable evidence supports the role for ghrelin in mealtime hunger and meal initiation, increasing food intake and body weight (Cummings et al., 2001, Tschop et al., 2000). The aim of this review is to evaluate the role and the effects of ghrelin in the ARC of the hypothalamus on energy homeostasis and energy balance, and the dysregulation of this pathway in obesity. Moreover, we will explore the possibility that modulating ghrelin signalling via receptor heterodimerisation with additional GPCRs could be implicated in weight regulation and as a potential novel therapeutic strategy for obesity.

Section snippets

Ghrelin and ghrelin receptor

The discovery of ghrelin was reported by Kojima and colleagues in 1999 through the process of reverse pharmacology. Ghrelin was shown to be the endogenous ligand for the orphan growth hormone secretagogue receptor (GHS-R), which in turn had been shown to be specific for synthetic GHS (Bednarek et al., 2000, Ghigo et al., 2001, Kojima et al., 1999, Muccioli et al., 2001). The name ghrelin is based on its role as a growth hormone-releasing peptide, and is derived from the word ‘ghre’ in

Ghrelin signalling in obesity

One of the most important established biological actions of ghrelin is the regulation of food intake and energy homeostasis and it has aptly been termed the hunger hormone (Kojima et al., 2004, Nakazato et al., 2001, Tschop et al., 2000). Peripheral ghrelin translates information about nutrients and gut to the brain to determine meal initiation, meal frequency and long term regulation of body weight (Cummings and Shannon, 2003, Kojima et al., 1999). Ghrelin plasma concentrations increase before

Additional receptor subtypes

The accumulation of data over the last few years points to the existence of multiple ghrelin variants and additional ghrelin receptors suggesting ghrelin or ghrelin variant-mediated regulation of appetite and food intake by receptor subtypes other then GHS-R1a (Baldanzi et al., 2002, Camina, 2006). Initial data claimed the GHS-R1b receptor to be neither responsive to ghrelin nor to GHSs while at the same time GHS-R1a negative but GHS-R-1b positive cell lines did show a response to ghrelin (De

Modulation of GPCR signalling via oligomerisation

Receptor oligomerisation, in which receptors of the same and different families combine to generate homo- or heterodimers or other multimeric complexes with unique biochemical and functional characteristics, is becoming increasingly accepted as a fundamental process in receptor signalling (George et al., 2002, Hebert and Bouvier, 1998). Recently, Ferre and colleagues outlined clear definitions describing receptor heteromers including GPCRs (Ferre et al., 2009). Oligomerisation has long been

Ghrelin receptor heterodimerisation

In addition to the existence of additional (GHS-R) receptor types, ghrelin variants and the ligand promiscuity on the GHS-R1a, recently data has been emerging that receptor homo- and heterodimerisation with other GPCRs can explain the differential ghrelin signalling. The promiscuous binding of GHRH to GHS-R1a (described above) and the observed synergistic interaction of GHRH and ghrelin on the GHS-R-1a has been explained by a homodimeric model for the ghrelin receptor (Fig. 4a), in which

Therapeutic implications

The increasing prevalence of obesity over the past several decades is reaching epidemic proportions and is becoming an increasing health burden because of the accompanying serious medical conditions, such as cardiovascular disease and type-2 diabetes, which increase morbidity and mortality (Bloom et al., 2008). Elucidating the complex biological mechanisms regulating feeding behaviour and energy balance may lead to more effective treatments. Biomedical research of the past years has been

Conclusion

Targeting ghrelin and its receptor in the fight against obesity remains very complex due to the highly integrated and redundant feedback mechanisms which activate compensatory changes in appetite, energy expenditure and weight maintanance. Data is accumulating suggesting and demonstrating that GHS-R1a is not solely responsible for ghrelin's activity. The plethora of functions associated with ghrelin's activation outside the hypothalamus-gut axis reinforces the complexity of ghrelin signalling.

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    Food for Health Ireland is an industry-led research centre, funded by Enterprise Ireland (EI) through the Irish Government’s National Development Plan (NDP). The authors, and the work herein, were supported by EI, NDP.

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