International Journal of Obesity (2009) 33, S30–S33 & 2009 Macmillan Publishers Limited All rights reserved 0307-0565/09 $32.00 www.nature.com/ijo OVERVIEW The neurobiology of appetite: hunger as

A Dagher

Department of Neurology, Montreal Neurological Institute, McGill University, Montre´al, Que´bec, Canada

Obesity is now being recognized as a neurobehavioral disorder. Although the view of appetite as an addiction to food is controversial, there are useful lessons to be learned from the neuroscience of addiction for understanding obesity. The speakers in this symposium all addressed different aspects of the neurobiology of feeding and obesity. In this overview and the associated reviews, the behavioral, genetic and neural factors that promote over-eating in animals and are discussed. International Journal of Obesity (2009) 33, S30–S33; doi:10.1038/ijo.2009.69

Keywords: ; ; ; insula; orbitofrontal cortex

In 1949, Donald Hebb1 suggested that hunger could be a less controversial position could be that we have much to viewed as an addiction, an idea he attributes to the learn about obesity from the neuroscience of addiction.6 physiologist AJ Carlson in 1916. Hebb proposed that hunger Neural systems implicated in feeding are depicted in was a learned behavior, in which eating is initially rein- Figure 1. According to this model four heavily intercon- forcing because it reverses an unpleasant bodily signal nected structures (shown in gray in the figure), the (change in nutrient levels in blood, hunger hormones and amygdala/hippocampus, insula, orbitofrontal cortex (OFC), stomach contractions). With time the behavior becomes and striatum are the central elements in the control of organized and food cues, such as the sight and smell of food, appetitive behavior. Although a specific role for each node develop the ability to induce craving, approach and within the network can be differentiated, as a group these consumption, much as drug-associated cues do. Later, Roy structures are involved in (1) learning about (food) rewards; Wise2 showed that dopamine receptor blockade with a (2) allocating attention and effort towards (food) rewards; neuroleptic attenuated the reinforcing effects food, as it (3) setting the incentive value of stimuli in the environment; did for stimulant drugs and electrical stimulation, (4) integrating homeostatic information about energy stores leading him to conclude that addictive drugs act on brain and gut contents with information about the outside world circuitry that controls feeding. The notion of hunger as (such as the availability of food). Homeostatic and gastro- addiction has been criticized in the media,3 and for intestinal information is conveyed by circulating hormones seemingly contradictory reasons: referring to the obese as and nutrients, acting primarily on the , but ‘addicts’ either unfairly stigmatizes them or undeservedly also on other brain structures, and by the vagus nerve. The exculpates them. (Note that even the view of drug addiction amygdala, insula, OFC and striatum all respond to condi- as a brain disease is still rejected by some.) On the other tioned stimuli predictive of reward (for example, food cues), hand, some governments are sold on the analogy, having as assessed in animals by using microelectrode recordings, mandated cigarette-style health warnings on food advertise- and in humans by using functional magnetic resonance ments.4 It must be admitted, however, that opponents of the imaging. These responses are seen equally with food and addiction model are correct in pointing out the paradox of drug stimuli (the latter only in drug addicts or animals ascribing energy intake, the most basic survival behavior, to trained to self-administer the drug). For example, lesions or aberrant function of neurobiological systems. Nonetheless, disconnection of the amygdala and OFC abolish a behavior evidence of parallels between addiction and feeding behavior known as sensory-specific satiety, in which a cue associated continues to accumulate at the neurobiological and beha- with a food fed to satiety loses its incentive properties.7 More vioral levels (for example, see Grigson5 for a review). Perhaps generally, this network assigns incentive value to food (or drug) cues, and to the associated actions that lead to the consumption of the food (or drug). Lesions of any of these four regions impair feeding behavior in some way. Cognitive Correspondence: Professor A Dagher, Department of Neurology, Montreal influences on appetite are mediated by the , Neurological Institute, McGill University, 3801 University St., Montre´al, Que´bec, Canada H3A 2B4. which exerts modulatory control over appetitive regions. A E-mail: [email protected] key component of the is the ensemble of Neurobiology of appetite A Dagher S31 but is particularly abundant in feeding-related areas in the hypothalamus, including the arcuate nucleus.13 The arcuate has a direct projection to the LHA, an area long implicated in reward. Indeed, the LHA through its outputs to the striatum () and brainstem autonomic and motor nuclei is the main hypothalamic output nucleus for the control of feeding behavior. It is also one of the sites where electrical brain stimulation is most rewarding.14 The product of the MC4-R gene, the gene with the strongest association with obesity, is also abundantly expressed in the arcuate nucleus and LHA.15 LHA neurons contain the neurotrans- mitter orexin, named because of its role in controlling feeding behavior, but which has also recently been impli- cated in drug addiction.16 Indeed, in animals conditioned to associate a certain environment with food or drugs such as or cocaine, orexin neurons in the LHA play a Figure 1 A brain network for appetitive behavior. (Not all connections are critical role in the expression of the preference, and in its depicted.) PFC, prefrontal cortex; OFC, orbitofrontal cortex; VTA, ventral reinstatement after extinction.17 This finding further sup- tegmental area; DA, dopamine. ports the idea of overlapping brain systems that mediate drug addiction and feeding. More compellingly, an allele of dopamine neurons that originate in the midbrain (especially the Taq1A polymorphism (the A1 allele) has been associated the ) and project to the striatum, with both addiction and obesity.18 This polymorphism amygdala, OFC, insula and prefrontal cortex. Dopamine has seems to regulate dopamine D2 receptor expression, suggest- long been implicated in addiction, as it is released by all ing that it plays a role in the function of the reward system. drugs of abuse, as well as food and food cues.8 Dopamine Feeding is controlled in part by peripheral signals that blockade abolishes responding for food or drugs.9 convey information about the energy state of the individual. The ability of reward-associated stimuli to trigger appeti- Four such metabolic signals have been shown to act on brain tive states is a feature of both drug addiction and eating. reward centers, indirectly through the hypothalamus, but Abstinent drug addicts report that drug cues or thoughts also through direct effects on the mesolimbic dopamine cause them to crave the drug, and everyone knows the system. Leptin, ghrelin and insulin all modulate food intake feeling of seeing a proffered dessert at the end of a meal, or and act directly, though not exclusively, on dopamine walking past a bakery. The ability of cues to trigger appetite is neurons.19–21 Functional magnetic resonance imaging stu- thought to be a major component of the obesogenic dies in humans have confirmed that the appetite-stimulating environment, which bombards us with foods, food odors, hormone, ghrelin, enhances the response of the reward advertising, brand names and logos. This phenomenon has system to food cues22 whereas the anorexigenic peptides, been extensively studied in animals. A neutral stimulus PYY and leptin, also act on reward related brain areas.23,24 paired repeatedly with food acquires the ability to trigger Another similarity between feeding and addiction is the consumption of that food even in sated animals, apparently important role of stress in both behaviors. Stress is a major by making the paired food seem more palatable. This cue- cause of relapse among abstinent drug users and also a potentiated feeding is thought to be a form of craving rather significant cause of failure in dieters.25 During stressful than a non-specific increase in appetite, as it is only the food periods, most individuals increase their energy intake (in that was paired with the conditioned stimulus that is particular, of saturated and carbohydrates). At the neural consumed (by analogy with drug cues, which do not cause level, stress can act at many levels. The brain areas that make a non-specific incentive state, but a specific craving for the up the appetitive network depicted in Figure 1 are all stress- drug itself). A similar phenomenon is described in humans, sensitive. An interesting aspect of Hebb’s theory of hunger in whom food odors or thoughts only cause increased discussed earlier is that stress can actually become a consumption of the target food.10 Petrovich, Gallagher, conditioned incentive for food, possibly explaining the and Holland11 have, in a series of animal experiments, phenomenon of comfort food. delineated the neural network for cue-potentiated feeding. Conditioned cues do more than inform the individual Key components include the , lateral about available rewards; they energize the individual by hypothalamic area (LHA) and medial prefrontal cortex creating an incentive state, motivating them to approach including the OFC. In particular, a projection from basolat- and consume food or other rewards with great vigor, a eral amygdala to LHA is crucial as disconnecting these phenomenon that seems to be mediated in large part by regions abolishes cue-potentiated feeding. dopamine.26 One often mentioned difference between food Many obesity genes appear to act on reward circuitry.12 and drugs is that drugs of abuse act directly on the brain, The FTO gene is expressed throughout the body and brain, whereas the effects of food are indirect, as they are mediated

International Journal of Obesity Neurobiology of appetite A Dagher S32 by the gut. The strong connections between gut peptides and properties of foods, such as texture, temperature and the dopamine system described above provide a mechanism olfactory and visual properties. The insula is also the sensory for food to act on reward systems as rapidly as some abused cortex for visceral information from the gut.31 Moreover, drugs. insula activity is modulated by cognitive and emotional The four speakers in this session presented work that views factors, including hunger and attention, and by gut peptides appetite and obesity from the standpoint of addiction such as ghrelin.22 De Araujo and Simon have found that the neuroscience, and confirmed the usefulness of this ap- multimodal sensory features of foods in the mouth are proach, as it relies on close to 50 years of neuroscience encoded by neuronal ensembles within the insula, and that research and sophisticated and well-validated models of the activity within these ensembles is hunger/satiety depen- learning and addiction. Caroline Davis has investigated the dent.32 They have also recently shown that transgenic mice relationship between personality measures of sensitivity to that lack the trpm5 taste receptor, and are hence unable to reward, as assessed by questionnaires, and preference for sense sweet taste, can still learn to prefer a sucrose-contain- high-energy foods and body mass index. One theory is that ing solution because of the post-ingestive effects of sucrose.33 certain individuals react to appetitive signals with greater Insular lesions disrupt this phenomenon. The insula is drive. Although considerable evidence exists for this model therefore primed to integrate multiple sources of informa- in the addiction literature, there is a paucity of data with tion about foods and their post-ingestive effects for the respect to obesity. Davis’s work confirms that reward purpose of learning. Animals with insula lesions, for sensitivity seems to predict appetitive behavior, as predicted example, fail to attribute incentive value to calorie-rich by the addiction model of obesity; however; the relationship foods. Interestingly, further support for the addictive theme between the personality measure and body mass index is not comes from a recent report of cigarette smokers who were monotonically ascending, but U-shaped, suggesting a com- able to quit smoking with relative ease following insula plex, and possibly bidirectional, interplay between reward damage (for example, from stroke).34 sensitivity and obesity.27 In the current issue, Davis discusses Finally, Dana Small uses functional magnetic resonance these findings, and other work from her laboratory on the imaging to understand the neural correlates of vulnerability relationship between putative reward genes, behavior and to obesity in humans. The premise here is that the response body weight. Her work also investigates the role of of regions in the appetitive network (Figure 1) to food cues , defined loosely as a tendency to act without and food consumption may play a role in this vulnerability. due consideration of long-term consequences, and which Her work confirmed that the amygdala responds to food has been shown to predict drug addiction in humans28 and cues, in this case food odors predictive of food delivery. The animal models.29 Impulsivity may be, in part, a consequence amygdala may be specifically involved in responding to cues, of enhanced reward drive. Davis discusses how impulsivity as it does not seem to be activated by ingesting palatable may interact with our obesogenic environment to promote foods (milkshake delivered to subjects in the MRI camera). excess energy intake and obesity. Finally, she refers to her Food receipt itself involves the insula and OFC, and the recent work linking attention deficit hyperactivity disorder, response to food in these areas seems to differ between obese impulsivity and body weight. and lean individuals.35 Finally, the striatum also shows a Allen Levine summarized his work on the role of opioids in response to food intake that seems to vary with body mass feeding. Opioid neurotransmitters act throughout the appe- index.36 Interestingly, the relationship between body mass titive regions outlined in Figure 1 to promote the consump- index and the functional magnetic resonance imaging signal tion of highly palatable (typically high energy) food.30 In the was modulated by the Taq1A polymorphism. current issue Gosnell and Levine allude to the concept of In summary, the articles in this special issue point to the homeostatic versus hedonic eating, the one driven primarily very clear overlap at many levels between neural systems by energy needs, and the other by the palatable qualities of involved in food intake and drug addiction. The novel view food and the expectation of reward. Their work supports the of obesity as a neurobehavioral disorder caused by an theory that opioids are typically associated with the hedonic interaction between a vulnerable brain and an obesogenic aspects of rewarded behavior, and especially feeding, but also environment37 is entirely reminiscent of models of drug provides evidence of an opioid effect on purely homeostatic addiction. It is to be hoped that research on the neurobiol- feeding. They suggest that opioids may also contribute to ogy of feeding will contribute to a solution to the obesity increased food intake by delaying satiety during a meal. They epidemic. finally review in some detail the evidence for and against the concept of addiction to sweet foods. De Araujo and Simon focus on the role of the insula in multimodal processing of food sensations. The anterior Conflict of interest insula is referred to as , because it is the first cortical relay of information from taste receptors in the oral A Dagher has received grant support from Canadian cavity. However, their work shows that the insula is not only Institutes for Health Research, National Cancer Institute of the taste cortex: neurons there respond to many other Canada and NIDA.

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