Associate editor: P. HolzerGhrelin signalling and obesity: At the interface of stress, mood and food reward
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.
References (223)
- et al.
Brain regulation of appetite and satiety
Endocrinol Metab Clin North Am
(2008) Central mechanisms involved in the orexigenic actions of ghrelin
Peptides
(2011)- et al.
Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin
Gastroenterology
(2001) - et al.
Sugar-dependent rats show enhanced responding for sugar after abstinence: evidence of a sugar deprivation effect
Physiol Behav
(2005) - et al.
Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake
Neurosci Biobehav Rev
(2008) - et al.
Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood–brain barrier
Peptides
(2008) - et al.
Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment
Clin Biochem
(2009) The plausibility of sugar addiction and its role in obesity and eating disorders
Clin Nutr
(2010)'Liking' and 'wanting' food rewards: brain substrates and roles in eating disorders
Physiol Behav
(2009)- et al.
Obesity and vulnerability of the CNS
Biochim Biophys Acta
(2009)
Ghrelin increases anxiety-like behavior and memory retention in rats
Biochem Biophys Res Commun
Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin
Biochem Biophys Res Commun
Ghrelin in the regulation of body weight and metabolism
Front Neuroendocrinol
Tackling of unhealthy diets, physical inactivity, and obesity: health effects and cost-effectiveness
Lancet
The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis
Neuron
Stress-induced obesity and the emotional nervous system
Trends Endocrinol Metab
Glucocorticoids, chronic stress, and obesity
Prog Brain Res
The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats
Gastroenterology
CCK in anxiety and cognitive processes
Neurosci Biobehav Rev
Compulsive overeating as an addiction disorder
A review of theory and evidence. Appetite
Role of dopamine receptor mechanisms in the amygdaloid modulation of fear and anxiety: Structural and functional analysis
Prog Neurobiol
Depression and obesity: a meta-analysis of community-based studies
Psychiatry Res
Targeting the ghrelin receptor to regulate food intake
Regul Pept
The role of the central ghrelin system in reward from food and chemical drugs
Mol Cell Endocrinol
Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons
Neuroscience
Systemic ghrelin and reward: effect of cholinergic blockade
Physiol Behav
Peripheral ghrelin enhances sweet taste food consumption and preference, regardless of its caloric content
Physiol Behav
High-fat diet selectively protects against the effects of chronic social stress in the mouse
Neuroscience
The temporal impact of chronic intermittent psychosocial stress on high-fat diet-induced alterations in body weight
Psychoneuroendocrinology
Investigation of the presence of ghrelin in the central nervous system of the rat and mouse
Neuroscience
Preliminary validation of the Yale Food Addiction Scale
Appetite
Introducing GOAT: a target for obesity and anti-diabetic drugs?
Trends Pharmacol Sci
Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues
Brain Res Mol Brain Res
Brain neurotransmitters in food and drug reward
Am J Clin Nutr
Dexamethasone stimulates the expression of ghrelin and its receptor in rat hypothalamic 4B cells
Regul Pept
Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats
Prog Neuropsychopharmacol Biol Psychiatry
Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward
Physiol Behav
Reward mechanisms in obesity: new insights and future directions
Neuron
Overweight and obesity affect treatment response in major depression
Biol Psychiatry
Effects of ghrelin on psychopathology, sleep and secretion of cortisol and growth hormone in patients with major depression
J Psychiatr Res
Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite
J Clin Invest
The MC4 receptor and control of appetite
Br J Pharmacol
UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals
Nature
Gut vagal afferents are not necessary for the eating-stimulatory effect of intraperitoneally injected ghrelin in the rat
J Neurosci
Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone
J Clin Endocrinol Metab
Antagonism of ghrelin receptor reduces food intake and body weight gain in mice
Gut
A role of ghrelin in neuroendocrine and behavioral responses to stress in mice
Neuroendocrinology
Modulation of feeding-induced activation of mesolimbic dopamine transmission by appetitive stimuli and its relation to motivational state
Eur J Neurosci
Homeostatic and non-homeostatic pathways involved in the control of food intake and energy balance
Obesity (Silver Spring)
Cited by (177)
Mining for the Next-Generation Microbiota Across the Gut–Brain Axis: A Case Study on the Translational Success of Bifidobacterium Longum APC1472
2024, The Gut-Brain Axis, Second EditionRelationship between psychological stress and ghrelin concentrations in pregnant women with overweight or obesity
2022, PsychoneuroendocrinologyObesity in Adolescents: Understanding the Combined Role of Food Security and Emotional and Behavioral Disorders
2022, Journal of Adolescent HealthCitation Excerpt :Biological markers related to stress, emotional and behavioral disorders, and obesity, individually and combined are being researched. The role of leptin, ghrelin, neuropeptide Y and the effect of dysregulation are being explored as potential mediators for causation as well as targets for treatment [12,36–38]. In addition, adolescents inflicted with very low food security, and emotional and behavioral disorders may not have the buffering effects of social support such as family resilience, family functioning, and neighborhood cohesion.