Elsevier

Pharmacology & Therapeutics

Volume 135, Issue 3, September 2012, Pages 316-326
Pharmacology & Therapeutics

Associate editor: P. Holzer
Ghrelin signalling and obesity: At the interface of stress, mood and food reward

https://doi.org/10.1016/j.pharmthera.2012.06.004Get rights and content

Abstract

The neuronal circuitry underlying the complex relationship between stress, mood and food intake are slowly being unravelled and several studies suggest a key role herein for the peripherally derived hormone, ghrelin. Evidence is accumulating linking obesity as an environmental risk factor to psychiatric disorders such as stress, anxiety and depression. Ghrelin is the only known orexigenic hormone from the periphery to stimulate food intake. Plasma ghrelin levels are enhanced under conditions of physiological stress and ghrelin has recently been suggested to play an important role in stress-induced food reward behaviour. In addition, chronic stress or atypical depression has often demonstrated to correlate with an increase in ingestion of caloric dense ‘comfort foods’ and have been implicated as one of the major contributor to the increased prevalence of obesity. Recent evidence suggests ghrelin as a critical factor at the interface of homeostatic control of appetite and reward circuitries, modulating the hedonic aspects of food intake. Therefore, the reward-related feeding of ghrelin may reveal itself as an important factor in the development of addiction to certain foods, similar to its involvement in the dependence to drugs of abuse, including alcohol. This review will highlight the accumulating evidence demonstrating the close interaction between food, mood and stress and the development of obesity. We consider the ghrelinergic system as an effective target for the development of successful anti-obesity pharmacotherapies, which not only affects appetite but also selectively modulates the rewarding properties of food and impact on psychological well-being in conditions of stress, anxiety and depression.

Introduction

Socrates famously said: “The rest of the world lives to eat, while I eat to live”. While this quote most likely refers to the fact that food fundamentally serves a nutritious purpose, within the current modern day society, in particular the Western world, food appears to be increasingly associated with aspects that exceed beyond nutrition, including behavioural reward and psychiatric disposition (i.e. mood). Likewise, it is becoming clear that associations exist between metabolic syndrome associated co-morbidities, in particular obesity, and affective psychiatric disorders, including anxiety and depression (McElroy et al., 2004, Goldbacher and Matthews, 2007, Kloiber et al., 2007, Gariepy et al., 2010, Marijnissen et al., 2011). Interestingly, obesity is associated with a 25% increased occurrence of anxiety and mood disorders (Simon et al., 2006). Reward signalling within the brain is mediated by the dopaminergic mesolimbic system and altered neurocircuitries within this system have been postulated to play a major role in both the development of obesity as well as depression and anxiety (Wang et al., 2001, Nash and Nutt, 2004, Nestler and Carlezon, 2006, Sullivan and Dufresne, 2006, de la Mora et al., 2010, Volkow et al., 2010). Moreover, hedonic eating behaviour and addiction display overlapping reward neurocircuitries and certain foods, in particular sugar, have been postulated to exhibit addictive properties (Avena et al., 2008, Kenny, 2011b). The pioneering work of Professor Bart Hoebel et al. on the neurocircuitry regulating brain reward and eating behaviour has lead to fundamental discoveries in the field of eating disorders and obesity, food addiction, alcohol consumption as well as depression (Hoebel, 1985, Konturek et al., 2004, Leibowitz, 2011, Parylak et al., 2011, Xu et al., 2011). A corticostriatal-hypothalamic circuitry has been described to mediate the motivation to obtain food rewards and to promote the overconsumption of palatable foods beyond acute homeostatic needs (Kelley et al., 2005). This results in hyperphagia which combined with decreased energy expenditure, following physical inactivity, leads to an excess accumulation of body fat or adiposity and often results in an obese phenotype (Marti et al., 2004, Chakrabarti, 2009). Obesity is defined by a body mass index (BMI) of greater than 30 kg/m2 (Eknoyan, 2008) and can originate following a variety of factors, both genetic and environmental (Bouchard, 2008, Rokholm et al., 2011). However, it is clear that whilst genetic predisposition can increase the likelihood for the development of obesity, genetic factors cannot account for all variation in BMI. Environmental factors such as altered lifestyle, the abundant availability as well as the low cost of highly caloric foods and the exposure to chronic psychological stressors in today's society, have equally contributed to the development of obesity (Marti et al., 2004, Swinburn et al., 2011). Both food intake and diet are closely intertwined with mood regulation and stress perception and response (Oliver and Wardle, 1999, Gibson, 2006, Morrison, 2009, Dallman, 2010). The overconsumption of calorie-dense foods extends far beyond the individual's nutritional needs and is mediated by a natural sensitivity to food stimuli and the associated pleasurable feelings associated with eating. This hedonic signalling in response to palatable food is increasingly being recognised as an important underlying cause for the increase in obesity worldwide (Berthoud, 2006). Thus, the link between obesity, appetite and food intake, which is already extensively described, is now extended towards the reward and motivation pathways as well as to the signalling pathways involved in stress and affective disorders such as anxiety and depression.

The ghrelinergic system mediates a plethora of biological activities, including the homeostatic regulation of appetite and food intake (for review see (Tschop et al., 2000, Nakazato et al., 2001, Cummings and Shannon, 2003, Korbonits et al., 2004, Kojima and Kangawa, 2005, Sun et al., 2007, Schellekens et al., 2009, Andrews, 2011)). In addition, it is now becoming clear that the orexigenic peptide, ghrelin and its receptor, the growth hormone secretagogue receptor (GHS-R1a), not only play a pivotal role in the homeostatic regulation of energy metabolism but also have an impact on the non-homeostatic regulation of food intake behaviours, such as the hedonic rewarding and motivational pathways (for review see (Dickson et al., 2011, Egecioglu et al., 2011, Skibicka and Dickson, 2011)). Furthermore, accumulating data suggest involvement of the ghrelin system in stress-induced food intake (Chuang et al., 2011, Diz-Chaves, 2011). This review will describe the recent advances in the understanding of ghrelin's role in the non-homeostatic rewarding aspect of feeding and the potential obligatory role for ghrelin in stress-induced eating behaviour. In addition, circulating ghrelin levels have been shown to be elevated following stress, which correlates with its anxiolytic as well as antidepressant‐like effects. Finally, a role for ghrelin in the concept of food addiction has been postulated to partly contribute to the obesity epidemic and will be discussed.

Section snippets

Ghrelin in food intake and obesity

Ghrelin is currently the only described orexigenic hormone from the periphery, which acts centrally to modulate the body's energy homeostasis and has therefore received attention from the pharmaceutical industry as an interesting target in obesity and other eating disorders (Horvath et al., 2003, Soares et al., 2008, Depoortere, 2009, Schellekens et al., 2009, Ogiso et al., 2011, Patterson et al., 2011, Yi et al., 2011, Costantino, 2012). The hormone ghrelin is a 28 amino acid peptide (Fig. 1),

The link between obesity, stress, anxiety and depression

The brain-gut axis mediates the communication between the gut and the CNS, which regulates appetite and satiety and maintains the body's energy homeostasis (Stanley et al., 2005, Ahima and Antwi, 2008, Simpson et al., 2008, Blevins and Baskin, 2010, Suzuki et al., 2010). Its dysregulation is linked to metabolic imbalances leading to obesity as well as to psychological conditions such as stress, anxiety and depression (McElroy et al., 2004, Simon et al., 2006, Goldbacher and Matthews, 2007,

Ghrelin in stress, anxiety and depression

Most neuropeptides regulating the homeostatic energy balance also play a key role in anxiety-like behaviour, further highlighting the importance of investigating the potential overlap in anxiety-related mechanisms and obesity. The neurobiological mechanisms between food intake and anxiety, as well as the neuronal circuitry of fear which underlies anxiety, are probably evolutionary selected as defensive survival mechanism involving neuropeptides, which regulate our response to environmental

Ghrelin in food reward behaviour

Appetite signalling functions to initiate food intake when nutrients are low. However, food also elicits pleasurable and rewarding signals, mediated via dopamine release in the mesolimbic circuitry system, which can override satiety and stimulate appetite independently of metabolic needs (Kenny, 2011b). The non-homeostatic motivational factors to obtain a food reward increase with food palatability and caloric content and the resulting over-consumption is being recognised as a key component in

Obesity and food addiction

Although the concept of food addiction is relatively recent, the term junk food has been around for decades. Recently, it has become clear that certain foods have strong addictive properties in certain individuals (Richardson et al., 2003, Parylak et al., 2011) and the behavioural impact of abused drugs and compulsive behaviours related to food intake are no longer studied independently. The concept of food addiction is increasingly being recognised to play a key role in the overconsumption of

Conclusion and future perspectives

The prevalence of obesity within the human population in today's society continues to grow. An altered lifestyle, changes in diet and a heightened stress exposure have been suggested to fundamentally contribute to the development of the obesity epidemic in modern day society (Cecchini et al., 2010, Swinburn et al., 2011).

Primarily due to the ghrelin-mediated central regulation of feeding behaviour, interference with the ghrelin system has been and still is considered an effective means to

Acknowledgments

The work was supported by Enterprise Ireland under grant number CC20080001. JFC and TGD are also supported in part by Science Foundation Ireland (SFI) in the form of a centre grant (Alimentary Pharmabiotic Centre) through the Irish Government's National Development Plan. The authors and their work were supported by SFI (grant numbers 02/CE/B124 and 07/CE/B1368). JFC is funded by European Community's Seventh Framework Programme; grant number: FP7/2007-2013, grant agreement 201714.

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