Ghrelin and food reward
Introduction
Throughout history, physicians and thinkers realized the importance of a proper diet for the maintenance of good health. In support of it, recent medical literature often cites the sentence, āLet food be thy medicine and medicine be thy foodā, wrongly attributed to Hippocrates (Cardenas, 2013). Ludwig Andreas Feuerbach āyou are what you eatā is also often quoted in this context (Feuerbach, 1863/4). The success of these citations reflects the concern about food in today's world in which overabundance of calories coupled to sedentary life style gives rise to the current obesity epidemic (Hill and Peters, 1998). Indeed, recent evidence shows a marked increase in obesity from 1975 to 2016 (NCD-RisC, 2017). This condition relates to a state of fat excess arising from high energy intake and low physical expenditure (Hill and Peters, 1998). Obesity, however, is a complex and multifactorial pathology involving genetic, biological, environmental, and behavioral factors. Contrasting with obesity, undernutrition or malnutrition in spite of food availability is a common problem in the context of cancer- or aging-related cachexia (Favaro-Moreira et al., 2016). It is also a condition in which feeding control is altered. Since the discovery of the orexigenic hormone ghrelin in 1999, there has been much focus on elucidating the pathways through which it operates, with the expectation that this knowledge could help the discovery of novel targets of therapeutic value for these conditions.
In this review we focus on ghrelin, which is one of the most potent orexigenic signal, and we critically assess its central effects and their relevance in the regulation of food reward-associated behaviors and energy balance.
Section snippets
Interaction between homeostatic and reward mechanisms in food intake
It is well known that homeostatic neuronal circuits in the hypothalamus integrate peripheral information, such as metabolites and hormones, to modulate food intake and energy balance [reviews in (Al Massadi et al., 2017, Belgardt and Bruning, 2010)]. However feeding control is also regulated by brain structures pertaining to the reward system (Berthoud, 2011). The reward system was serendipitously discovered in rats by Olds and Milner who used its self-stimulation for operant training (Olds and
Ghrelin
Ghrelin was purified from rat stomach about twenty years ago as a 28-amino acid octanoylated peptide and shown to be the endogenous ligand of the growth hormone (GH) secretagogue receptor (now termed GHSR1a, Howard et al., 1996, Kojima et al., 1999). GHSR1a is a 7-transmembrane receptor coupled to GĪ±q/11, which activates phospholipase CĪ³ and Ca2+ release from internal stores [see (Camina, 2006) for a review]. Beyond the initial results in relation with GH releasing effects (Kojima et al., 1999,
Role of ghrelin in reward and addiction
In addition to its well-known effects on energy homeostasis regulation at the hypothalamic level [reviews in (Al Massadi et al., 2017, Muller et al., 2015)], ghrelin also has the ability to increase food motivation acting on hypothalamic and extra-hypothalamic areas implicated in motivational and incentive behavior, -VTA and NAc- (Naleid et al., 2005, Skibicka et al., 2011), in learning and memory -hippocampus and amygdala- (Alvarez-Crespo et al., 2012, Diano et al., 2006, Kanoski et al., 2013,
Ghrelin and the mesolimbic dopamine pathway
Many studies indicate that DA is the main mediator of the actions of ghrelin on the reward system. DA is implicated in reward-associated behaviors and the mesolimbic pathway is a key component of food motivational aspects (Palmiter, 2007). Ghrelin activates the mesolimbic DA pathway (Abizaid et al., 2006, Jerlhag et al., 2006, Jerlhag et al., 2007). Ghrelin administration into the VTA induces feeding (Abizaid et al., 2006, Jerlhag et al., 2006, Naleid et al., 2005, Skibicka et al., 2011) and
Ghrelin interactions with the opioid system
The endogenous opioid system is an important regulator of appetite and metabolism (Bodnar, 2017, Nogueiras et al., 2012). In fact, several pharmacological studies have demonstrated that agonists of the three opioid receptors (mu, kappa, and delta) increase food intake, whereas antagonists of these receptors decrease food intake (Bodnar, 2016, Bodnar, 2018). Apart from these orexigenic effects, the opioid system regulates food reward and motivation. Opioids act on the mesolimbic DA system
Ghrelin and endocannabinoids
Several interactions between ghrelin and the endocannabinoid system have been reported at the periphery and in brain areas regulating food intake and energy balance, indicating a crosstalk between these two systems (Kola et al., 2008, Senin et al., 2013). Endocannabinoids have a strong implication in the control of feeding as indicated by their ability to increase consumption of palatable liquids and foods in satiated animals and motivated behaviors [see (Kirkham, 2009) for a review]. The
Neuropeptides implicated in the actions of ghrelin
Ghrelin induces feeding by activating GHSR1a (Sun et al., 2004), which is expressed in the ARC (Guan et al., 1997), a nucleus containing AgRP- and NPY-positive neurons (Luquet et al., 2005). AgRP is an antagonist at melanocortin receptors [for review see (Dieguez et al., 2011)], whose endogenous agonist is Ī±-MSH. Genetic deletion of both NPY and AgRP is required to block ghrelin-induced feeding (Chen et al., 2004). Moreover, feeding induction by ghrelin is partially recovered in GHSR1a knockout
Concluding remarks
The mesolimbic system, including the VTA and the NAc, is the main final pathway for most ghrelin's actions on food reward-associated behaviors. Control of DA plays a key role in ghrelin actions on the reward system, which also involve endogenous opioid peptides and endocannabinoids. This interdependence shows the complexity of feeding control, in which multiple neurotransmitters are coordinated to achieve a proper behavioral and physiological equilibrium. In physiological conditions, the
Conflicts of interest
The authors declare that they have no conflicts of interest in the authorship or publication of this work.
Acknowledgements:
Work in the laboratory of JAG is supported by Inserm, Sorbonne UniversitƩ (formerly UniversitƩ Pierre et Marie Curie, UPMC, Paris-6), and grants from ANR MALZ-2013, the King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research award (#OSR-2015-CRG4-2602), Fondation pour la Recherche MƩdicale and Labex Bio-Psy. Work in the laboratory of RN and CD is supported by grants from MINECO (CD BFU2017-87721 and RN: BFU2015-70664R); Xunta de Galicia (RN: 2015-CP080 and
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2022, Current Opinion in Behavioral SciencesCitation Excerpt :Second, gastrointestinal hormones such as insulin, ghrelin, leptin, or glucagon-like peptide 1 (GLP-1), can additionally directly regulate dopaminergic activity by binding to their respective receptors on DA neurons in the VTA and NAc. While orexigenic hormones (e.g. ghrelin) increase DA levels in the NAc and subsequent motivational behavior for food rewards [45,46], postprandial hormones (insulin or GLP-1) reduce motivated behavior for food by downregulating dopaminergic transmission [47ā50]. Similarly, the adipocytokine leptin, that reflects energy storage in the form of fat tissue, reduces food-reward behavior [51,52].