Ghrelin mediates stress-induced food-reward behavior in mice

Abstract

The popular media and personal anecdotes are rich with examples of stress-induced eating of calorically dense "comfort foods." Such behavioral reactions likely contribute to the increased prevalence of obesity in humans experiencing chronic stress or atypical depression. However, the molecular substrates and neurocircuits controlling the complex behaviors responsible for stress-based eating remain mostly unknown, and few animal models have been described for probing the mechanisms orchestrating this response. Here, we describe a system in which food-reward behavior, assessed using a conditioned place preference (CPP) task, is monitored in mice after exposure to chronic social defeat stress (CSDS), a model of prolonged psychosocial stress, featuring aspects of major depression and posttraumatic stress disorder. Under this regime, CSDS increased both CPP for and intake of high-fat diet, and stress-induced food-reward behavior was dependent on signaling by the peptide hormone ghrelin. Also, signaling specifically in catecholaminergic neurons mediated not only ghrelin's orexigenic, antidepressant-like, and food-reward behavioral effects, but also was sufficient to mediate stress-induced food-reward behavior. Thus, this mouse model has allowed us to ascribe a role for ghrelin-engaged catecholaminergic neurons in stress-induced eating. IntroductionMost humans experience altered feeding behaviors upon stress, with approximately 40% eating more and 40% eating less than usual (1). Furthermore, upon stress, most people report an increase in the intake of highly palatable foods, independent of hyperphagia or hypophagia (2, 3). Altered eating is also a frequent finding in individuals with major depressive disorder, with the "atypical" subtype even containing hyperphagia as a possible distinguishing characteristic (4). In one study, 46% of study subjects who met DSM-IV criteria for major depressive disorder with atypical features reported increased appetite (5). Of the remaining depressed patients without atypical features, 18% reported increased appetite, while 50% reported decreased appetite (5). The complex eating behaviors that are associated with and/or stimulated by stress and major depression undoubtedly contribute to the increased number of overweight and obese individuals who experience or have experienced stress and depression. For example, a longitudinal study from New Zealand showed that major depression in late-adolescent girls was associated with a 2.3-fold increased risk of obesity in adulthood and, furthermore, that the prevalence of obesity in adulthood was positively correlated with the number of major depressive episodes during adolescence in these girls (6). In another study, 47% of a large cohort of subjects with atypical depression reported increased body weight (5). Also, the combined overweight and obesity prevalence in a sample of US veterans with posttraumatic stress disorder was found in a chart review study to exceed that within the US general population by 20% (7).

Palatability Can Drive Feeding Independent of AgRP Neurons

“…This result is reminiscent of a recent study showing that ghrelin action on dopaminergic neurons is sufficient to drive food-reward in a context of chronic stress, referred to as 'comfort feeding' (Chuang et al, 2011). Our observations are also in line with a study showing that loss of AgRP neuron function promotes greater excitability of VTA dopamine neurons (Dietrich et al, 2012).…”

“…When access to palatable liquid diet was provided, the body weight of the AgRP-ablated mice was rapidly regained ( Figure 6C); furthermore, while control animals maintained caloric intake, the AgRP-ablated mice consumed more calories ( Figure 6D). Our finding that AgRP-ablated mice exhibit exaggerated hyperphagia on a palatable diet and greater anorexia during stress is consistent with the hypothesis that, in the absence of AgRP neurons, feeding is less motivated by energy demand and more sensitive to changes in stress and reward value (Chuang et al, 2011).…”

Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling

“…The VTA dopamine neurons express GHSR and respond to ghrelin by increasing the action potential frequency and the Acb dopamine release (Abizaid et al, 2006;Jerlhag et al, 2007). Also, rewarding foods-induced Acb dopamine release is reduced in GHSR knockout mice (Egecioglu et al, 2010), and selective GHSR expression in catecholaminergic cells, including the VTA dopamine neurons, is sufficient to mediate ghrelin-induced conditioned place preference for HFD (Chuang et al, 2011). The possibility that ghrelin signaling could involve a form of central sensitization that affects the intake of palatable foods may be clinically relevant and deserves future studies as alterations in ghrelin signaling seem to contribute to the magnitude of binge eating episodes in some, but not all, patients with binge eating disorder (Geliebter et al, 2008).…”

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

“…However, it is also possible that this interaction extends beyond the homeostatic hypothalamic regulation of food intake and may involve hedonic feeding behaviour. Indeed, recent studies have identified the ghrelinergic system as a key player in hedonic food intake behaviours, including the motivational drive to eat, the rewarding aspects of food intake and the stress-induced ingestion of palatable foods [84][85][86][87][88][89][90][91][92] . Interestingly, the 5-HT2C receptor has also been implicated in reward-related behaviours 93,94 , which may explain some overlapping functionalities with the GHS-R1a receptor including involvement in the hedonic regulation of food intake.…”