Hedonic and incentive signals for body weight control

A great deal is known about the circuits and mechanisms underpinning both hedonic and motivational components of reward, including mechanisms that are common to natural and artificial rewards. As these circuits and mechanisms are covered extensively in other reviews [8, 10‐12], only the key elements are described here. The neurotransmitter ‘dopamine’ is of primary importance for incentive motivation [13], involving especially a key ‘mesoaccumbal’ projection from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAcc) [14], but also via a neuronal network that includes VTA projections to the prefrontal cortex, amygdala and hypothalamus. Studies measuring accumbal dopamine release in rodents have revealed that the mesoaccumbal dopamine pathway is activated in response to sweet tastants [15] by binging on sugar [16] and by corn oil [17]. Consistent with these effects on the dopamine system, such foods also stimulate motivated behaviour for a food reward [18‐21]. In these studies motivated behaviour for a food reward was demonstrated using either operant conditioning experiments in which the animals have to work increasingly hard (eg by pressing a lever) in order to obtain a food reward or by studies incorporating the ‘incentive runway’ paradigm, in which motivated behaviour is reflected in the time taken to reach a goal box. Operant responding for food can be increased by drugs that increase accumbal dopamine signalling (eg amphetamine)[22] and decreased in models of suppressed dopamine signalling [23]. As reviewed elsewhere [12, 13], the mesolimbic dopamine system does not appear to be directly involved in the ‘liking’ of sweet tastants, although it is involved in the reinforcement of their consumption; thus, animals will repeat behaviours that increase accumbal dopamine levels, such as the consumption of food rewards. Dopamine lesions (using 6-OHDA) that deplete forebrain dopamine do not alter food intake per se but do alter facial ‘liking’ reactions (facial affective expressions of taste pleasure) to sweet tastants [24]. In a model of enhanced dopamine signalling in mice (by genetic knockdown of a dopamine transporter gene), ‘liking’ reactions to sucrose did not increase, even although such mice did show increased motivated behaviour for sweet rewards [25, 26]. Indeed, it has been suggested that taste may not be required for food reward. Mice that are unable to process sweet tastes (trpm5 knockout mice) appear to experience reward from sucrose reflected by an increased sucrose preference and by the ability of sucrose to activate the mesoaccumbal system in these mice [27].

The neural networks involved in the ‘liking’ hedonic component of reward include pathways involved in taste processing in the brainstem, pons, nucleus accumbens, ventral pallidum, amygdala and prefrontal cortex [28, 29]. Within these circuits, the mu-opioid system emerges as a key target for the hedonic experience of feeding [26, 30]. Indeed, mu opioid receptor stimulation of the NAcc has been shown to increases the intake of (and preference for) sweet and high fat foods [31, 32]. Indeed, within the extensive opioid-responsive feeding circuits the NAcc has been identified as a primary target for food intake that is associated with “liking” orofacial responses [33]. It has recently been questioned whether the NAcc mu-opioid system may not also be of importance for ‘wanting’ [34]. These authors found that suppression of endogenous mu-opioid in the nucleus accumbens shell using selective antagonists decreased both ‘liking’ of sucrose (reflected by fewer positive hedonic orofacial responses) and the incentive value (‘wanting’) of a food reward, assessed in the incentive runway paradigm. Consistent with this, it was earlier reported that a mu-opioid receptor agonist increases motivated behaviour for a food reward, reflected by the elevated break point for progressive ratio lever pressing [35].

Suppression of the endogenous cannabinoid (endocannabinoid) system resulted in a successful anti-obesity therapy, rimonabant that unfortunately was withdrawn due to adverse psychiatric effects. The cannabinoid receptor 1 (CB1) is widely expressed in the CNS, including areas associated with food intake, food reward and appetitive behaviour. Various parenchymal targets appear to be important for the orexigenic effects of the endocannabinoids, including several nuclei in the hypothalamus and hindbrain [36‐38] as well as the NAcc (shell) [39]. CB1 signalling also appears to be important for food reward, both hedonic and incentive motivation components [40] involving interactions with both dopaminergic and opioid mechanisms [41, 42]. Interestingly, endocannabinoid signalling in the parabrachial nucleus appears to be especially important for the intake of palatable foods [38].

The central orexin signalling system also figures rather prominently in motivated behaviour for artificial and natural rewards (including food), involving a key projection from the lateral hypothalamus to the VTA, where orexin appears to directly target the dopamine cells that project to the NAcc shell [43, 44]. Within the appetitive/reward circuits CB1 and orexin A receptors colocalize and appear to interact, reflected by the effects of a subeffective dose of rimonabant to suppress the effects of centrally administered orexin [45].

The discovery that 1 week of treatment of the adipose-derived hormone, leptin to leptin-deficient obese individuals is able to alter the response of their reward system (especially striatum) to visual food cues [86], confronts us with the realization that metabolic hormones are able to exert a powerful influence on the way we process visual information about food from our environment (eg by advertising). Metabolic status is signalled to the brain, not only by circulating nutrients but also via a number of circulating hormones that include those produced by adipose tissue (eg leptin, adiponectin), by the gut (eg. ghrelin, PYY(3–36), oxyntomodulin, cholecystokinin) and also by hormones regulating glucose homeostasis (eg. insulin, glucagon-like peptide-1). As discussed in a number of recent reviews [87‐89] these circulating signals inform diverse neurobiological circuits, including especially those involved in energy homeostasis in the hypothalamus and brainstem. For many of these hormones, there is increasing evidence that they also target diverse brain areas involved in reward, emotion and cognitive function, including those depicted in Fig. 1. Thus, for example, it is clear that leptin regulates both hedonic and motivational components of reward [80, 81, 90, 91]. Central leptin treatment to rodents suppresses the ability of sucrose and high fat food to condition a place preference [92, 93] and also suppresses operant responding for sucrose [79]. There is considerable evidence that the mesoaccumbal dopamine system appears to be a key target for leptin. Leptin receptors are present in the VTA, including on dopaminergic cells in this region and, moreover, direct injection of leptin into the VTA suppresses food intake, and leptin has been shown to suppress both accumbal dopamine release (basal and food-induced) and the electrical activity of VTA dopamine neurones [94‐96]. Interestingly a sub-population of leptin-responsive VTA neurones have been shown to project to the central nucleus of the amygdala [97], an area strongly implicated in the addiction process. Additional reward targets for leptin include the lateral hypothalamus; leptin receptors have recently been shown to be present on discrete populations of cells in this region, including cells that project both to the VTA and to orexin-cells in the lateral hypothalamus [98].

An important question to address is whether the reward system remains responsive to leptin in obesity, given the key role attributed to leptin resistance in the development of the disease. Rats fed a higher fat diet for 5 weeks were resistant to the effects of centrally-administered leptin on operant responding for a sucrose reward [79]. Interestingly, low serum leptin levels have not been associated with binging episodes (ie a behaviour connected to food reward) in obese patients diagnosed with binge eating disorder [99], arguing against leptin as an acute regulator of food reward in obese patients. In such patients, chronic leptin resistance may be a more important factor, regulating the sensitivity of the brain’s feeding networks to rewarding foods in the long term and thereby increasing the likelihood of binge-eating, rather than having a direct role in individual binge episodes.

Of the other circulating anti-obesity satiety/anorexigenic hormones, several are rather well-studied in the context of food reward. The work of Diane Figlewicz, amongst others, has highlighted the importance of insulin in food reward, acting via similar mechanisms to leptin at the level of the VTA [81]. This could indicate that leptin and insulin potentiate each other’s effects at the level of the VTA as shown previously for the arcuate nucleus [100]. Unfortunately, obesity-associated insulin resistance in rats has also been shown to impact on the ability of the reward circuits to respond to insulin [79] (Fig. 1). PYY(3-36), a lower gut hormone, is released in association with food intake [101], has also been shown to impact upon key reward circuits in the VTA and ventral striatum [102]. Interestingly, these fMRI studies have shown that PYY(3-36) may play an important role in shifting feeding control from hypothalamic homeostatic circuits when hungry to the reward circuits when satiated.

For obesity to prevail, it seems clear that metabolic satiety signals are failing to regain control of appetitive brain networks, including those involved in food reward. There remains good reason for hope, however. Altered gut-brain signalling for appetite control remains a major topic of investigation, not least because the successful outcome of gastric bypass surgery (a bariatric weight loss procedure) appears to include not only a reduction in the amount of food eaten but also an altered attitude to, and preference for, healthier food [74]. Indeed, many metabolic/endocrine signalling systems, especially gut hormones, have been implicated in the successful outcome.

In our research group, we have been especially interested recently in the possibility that future therapies for obesity may include a suppression of the central ghrelin signalling system. Ghrelin is the first identified circulating hormone to be attributed an orexigenic role. Ghrelin levels increase preprandially in association with meal initiation [103, 104] and studies in rodents have shown orexigenic effects after acute central or peripheral administration [105, 106]. It seems clear that ghrelin and synthetic ghrelin mimetics target cells in the hypothalamic arcuate nucleus [107, 108], notably the orexigenic neuropeptide Y cells in this region [109] that are likely involved in ghrelin’s orexigenic effects. The ghrelin receptor, GHS-R1A, is also expressed in tegmental and mesolimbic areas involved in reward, such as the VTA and laterodorsal tegmental areas (LDTg) [110, 111]. Recently, we provided the first evidence that ghrelin targets a key reward circuit, the so-called “cholinergic-dopaminergic reward link”. This link includes a cholinergic afferent projection from the LDTg onto the VTA dopamine cells. We found that central, intra-VTA or intra-LDTg administration of ghrelin increases accumbal dopamine release and locomotor activity, effects abolished by nicotinic cholinergic receptor blockade [112, 113]. Consistent with this, GHS-R1A has been shown to be co-localised both in dopamine (tyrosine-hydroxylase)-containing cells in the VTA [114] and with cholinergic (choline acetyl transferase)-containing cells in the LDTg [115]. In addition to these cholinergic afferents, we also recently found that pharmacological suppression of glutamatergic signalling suppresses ghrelin’s effects on the mesoaccumbal dopamine system [116]. These findings emerged as having direct relevance for reward from addictive drugs [117, 118] as well as from palatable food [119, 120]. Intracerebroventricular injection of ghrelin has been shown to stimulate food intake [121], especially the intake of palatable food [119]. Ghrelin signalling at the level of the VTA appears to be important for these feeding effects as intra-VTA injection of ghrelin increases the intake of palatable food [119]. Moreover, the effects of peripheral ghrelin on food intake were blunted by intra-VTA administration of a GHS-R1A antagonist [114]. More specifically, the cholinergic-dopaminergic reward link is implicated in ghrelin-induced feeding; nicotinic blockade suppressed ghrelin-induced and fasting-induced feeding and also suppresses the ability of food to condition a place preference [115]. Consistent with this, peripheral treatment with a GHS-R1A antagonist decreased preference for palatable food, suppressed the ability of sweet treats to condition a place preference [119] and suppressed motivated behaviour for rewarding foods, both sweet [122] (Fig. 2) and high fat [120] foods. Collectively these data support the idea that the physiological role of ghrelin is to increase the incentive motivation for natural rewards such as food.

There are indications that these studies in rodents are relevant in man as systemic ghrelin administration has been shown to alter the brain response to visual food cues in relevant reward targets area, including the striatum [123]. Although common obesity is associated with a reduction in circulating ghrelin levels [124], food intake appears to be less effective in suppressing ghrelin levels in obese subjects [125]. The relevance of the peripheral ghrelin signal in common obesity could also be questioned as brain ghrelin production may be increased in obese subjects [126] and, moreover, the ghrelin receptor may not require ghrelin for activity as it is possesses a high level of constitutive activity [127]. It remains to be determined whether the central ghrelin signalling system has a role in the pathophysiology of obesity and whether ghrelin antagonists or inverse agonists will provide an effective future therapy, either alone or in combination with drugs/hormones that interfere with overlapping signalling mechanisms.