Skip to main content

The Integrated Neurobiology of Food Intake, Addiction and Stress

Final Report Summary - NEUROFAST (The Integrated Neurobiology of Food Intake, Addiction and Stress.)

Executive Summary:
NeuroFAST is a multidisciplinary project involving clinical, basic and epidemiological research exploring the neurobiological interface between food intake, reward and stress. A key dissemination activity has been the NeuroFAST consensus article on the topic "food addiction" in which we highlight the lack of evidence that foods/ingredients cause addiction in a manner similar to drugs of addiction, including our own work exploring this. We suggest rather that the term "Food Addiction" is a misnomer and would be better described by the term "Eating addiction", a behavior disorder, in which individuals have an addiction-like behavior entailing excessive intake of food. The policy implications of these finding are considerable, no least highlighting the importance of the obesogenic environment for people that suffer from this behavioral eating disorder. Moreover, our research shows that the idea that food addiction can cause obesity is not sustained in a group of adolescent psychiatric patients. A major challenge in this area has been the lack of diagnostic tools that identify and distinguish food/eating-addicted/eating disordered individuals. NeuroFAST researchers have found differences in brain image analysis (by positron emotion tomography) that may help discriminate between food/eating-addicted and non-addicted obese women. Although we lack evidence that foods induce some behaviors consistent with addiction, it seems clear from our neurobiological research that foods can impact upon behaviors that guide our food intake and dietary choice, in ways that promote obesity. Thus, the obesogenic environment can change food-linked behaviors, including motivated- and binge-like behaviors in rodents but we find little evidence to support “sugar addiction”.
 Indeed, in animal studies we found divergence regarding brain pathways involved in reward behavior for a sweet reward from those that specifically modulate addiction-related behaviors.
 We have also found evidence that the human brain is able to detect dietary macronutrients, with immediate effects on eating behavior.
Our epidemiological studies have identified risk factors for the onset of substance use and eating disorders and have found these to differ widely depending on age, gender, sample and individual diagnoses.
Our workplace studies have shown bidirectional effects of stress on eating behavior in man. We also found that shift-workers consumed less food when stressed, whereas day workers consumed more, which has implications for health.
Our physiological studies with ghrelin, a stomach-derived hormone, that promotes food intake, have demonstrated the existence of an endocrine gut-brain reward axis that interfaces food intake and addiction/reward. We have made major advances regarding the overlapping pathways recruited by this hormone, by nicotine, and by psychostimulant drugs; these include energy balance circuits in the hypothalamus and their integration with midbrain areas linked to reward.
Project Context and Objectives:
PROJECT CONTEXT

This multidisciplinary project explored the neurobiology of addiction and eating behaviour and the complex socio-psychological forces that can lead to its dysregulation. These forces include dietary components (e.g. highly palatable foods and alcohol), some of which may have addictive properties, but also cultural and social pressures and cognitive-affective factors (perceived stress and stress regulation, anxiety and depression), and family-genetic influences on these. The project sought to provide new data from human studies that is needed to inform health policy initiatives, underpinned by mechanistic research to establish a solid scientific basis for this advice.

The European added value of this project is indicated by the building up of a necessary critical mass in several fields of expertise. The research team was drawn from seven member states (Sweden, Italy, Hungary, Germany, The Netherlands, Spain and the U.K.) and included clinical international experts crossing boundaries between clinical research and basic mechanisms. Clinical/human expertise included clinical psychology and epidemiology, human genetics related to eating disorders, human nutrition, eating and addictive behaviour disorders, endocrinology/neuroendocrine and human brain imaging. Complimentary preclinical expertise included the basic mechanisms of eating behaviour and addiction, endocrine/neuroendocrine regulators, stress and the mechanisms of opiate dependence, and cannabinoid actions.

To provide scientific support for European public health policies, focus has been a socio-psychological analysis of determinants of food addiction and substance abuse, and of how risk factors like stress in the workplace are driving addictive behaviour. Such support requires a good mechanistic understanding of the underlying cause-effect relationships, and we focussed efforts on key areas where the mechanistic understanding is deficient. This project engaged some of Europe’s leading neurobiologists to address these weaknesses.

The project yielded important information about the common neurobiological regulation mechanisms shared by eating behaviour and addictions. We studied the association between dysfunctional eating behaviour and addictive behaviours, the role of stress and mood as moderating factors, the physiology and neural circuits involved and the mechanisms that can lead to dysfunctional behaviours.
We also sought to explore the addictive properties of individual food components, the potential effects of food components on prevention of addiction, and the reasons leading to eating disorders. We aimed to establish an evidence base for these inter-relationships, linking eating disorder research with obesity research, stress research and addiction research, and involving studies of selected individual food components.

Europe's cultural diversity was taken into account, by understanding the socio-psychological determinants of dysfunctional behaviours and the interaction with gender, environment and genetics. Research has shown the importance of genetic susceptibility for eating disorders, but they are also driven by powerful environmental factors (“gene-environment interactions”). We explored these factors, which include the abundance of energy dense highly palatable foods and their addictive/rewarding properties, stress, including stress in the workplace and socio-psychological factors.

NeuroFAST involved a synergistic combination of controlled laboratory studies, characterization of patient groups, and examination of real-world scenarios based on epidemiological community samples that are relevant to policy development. In parallel, we sought to address gender-specific differences by studies in women and studies of gender differences in reward and appetite pathways, including fundamental research to provide the integrated understanding needed to inform effective strategies for intervention.


LIMITS TO OUR UNDERSTANDING

The intimate relationships between stress, addictive and feeding/eating behaviour and mood are most evident in eating disorders, but knowledge about these pathways is fragmented. In particular,
1) There is evidence of a link between eating behaviour/eating disorders and other disorders associated with reward seeking, such as substance abuse. But it is not known whether dysfunctional eating and substance use (as well as eating disorders and substance use disorders) share common susceptibility factors – this is a critical “missing link” in human data.
2) There is a high prevalence throughout Europe of disordered eating leading to obesity and to a lesser degree also to anorexia and other eating disorders. These are problems that might be characterized as disorders of reward-seeking behaviour, and they seem to be closely related to problems of substance abuse and to environmental stress. But we do not know the relationship between psychopathology, stress, body weight and stimulatory behaviours of the reward system.
3) Evidence suggests that food reward and other reward systems share a common neurobiological substrate. But we do not have a good understanding of what mechanisms are common to food reward and chemical drug reward, including to alcohol.
4) There is evidence of important gender differences in food reward behaviour that may be linked to gender differences in appetite-regulation. But we do not know the importance of ”food addiction” as an obesity factor in women, or what mechanisms underlie gender differences in eating behaviour. The gender differences are likely to be linked to the high density of expression of gonadal steroid receptors at key brain sites, including the PVN and arcuate nucleus, but there is little knowledge of the effects of oestrogen and progesterone on these circuits that regulate eating behaviour.
5) There is increasing awareness of the importance of the interaction between the reward pathways of the brain and the feeding regulatory circuitry. But there is a poor understanding of the neural substrate underling this interaction, and the impact of altered leptin and ghrelin signalling in the clinical features and mechanisms underlying eating disorders.
6) There is a reasonable expectation that this interaction is key to the addictive properties of specific food components and the emergence of disordered eating. But it is poorly understood how food components affect the reward circuitry, and to what extent hormones provide the link between ingestion of food and reward, and we have a poor understanding of the addictive properties of individual food components.
7) There is evidence that environmental factors, including common mild stressors, impact upon the expression of eating disorders, either directly or via effects on reward circuits. But there is a poor understanding of the effect of real world stressors on eating behaviour.
These issues are important for public health policy. For example, are women more vulnerable to developing disordered eating than men in occupationally stressful environments? Is there a risk that addressing the symptoms of eating disorders without understanding the underlying aetiology might have the adverse consequence of an increase in displacement addictive behaviours? Are some foods particularly addictive and others protective against this?
There is a need, across Europe, for a strong scientific evidence base to inform public policy addressing the issue of eating disorders and substance use disorders – addictive behaviours. Large and rigorous observational studies are needed to quantify the risk factors associated with eating disorders, using a variety of approaches to ensure robustness of any conclusions. However, human associational and behavioural studies are insufficient; because so many potential confounding factors may affect interpretation, it is essential also to gain a mechanistic understanding of how these disorders arise, to validate our interpretation of associational and behavioural studies. NeuroFast will integrate the clinical, behavioural and observational studies that are essential to fill important gaps in our knowledge with mechanistic studies that address key gaps in neurobiological understanding; this integrated understanding will provide a scientifically robust foundation for public policy. An important objective of NeuroFAST, addressed in WP12, is to disseminate the integrated understanding gained to other professionals, especially in human nutrition, but also to policy makers and to the lay public, to strengthen the foundations in Europe for public and political support for research in this area.

PROJECT OBJECTIVES

In the project objectives we addressed major gaps in knowledge :
…it is not known whether dysfunctional eating behavior, disorders of eating and substance use share common susceptibility factors – this is a critical “missing link” in human data.
General Objective 1: To test whether eating behavior and addiction share common susceptibility factors.

…we do not know the relationship between psychopathology, stress, body weight and stimulatory behaviors of the reward system
General Objective 2: To determine the relationship between psychopathology, stress, body weight and stimulatory behaviours of the reward system.

.… we do not have a good understanding of what mechanisms are common to food reward and chemical drug reward, including to alcohol.
General Objective 3: To study the common mechanisms of food reward and chemical drug reward, including to alcohol.

… we do not know the importance of ”food addiction” as an obesity factor in women, or what mechanisms underlie gender differences in eating behavior
… there is little knowledge of the effects of oestrogen and progesterone on these circuits that regulate eating behaviour.
General Objective 4: To establish the importance of “food addiction” as an obesity factor in women, and the mechanistic basis of gender differences in food intake.

… there is a poor understanding of the neural substrate underling this interaction, and the impact of altered leptin and ghrelin signalling in the clinical features and mechanisms underlying eating disorders.
General Objective 5: To study the impact of altered leptin and ghrelin signalling in the mechanisms underlying eating disorders.

… it is poorly understood how food components affect the reward circuitry, and to what extent hormones provide the link between ingestion of food and reward, and we have a poor understanding of the addictive properties of individual food components.
General Objective 6: To contribute to a better understanding of the addictive properties of individual food components.

… there is a poor understanding of the effect of real world stressors on eating behaviour and of the neurobiological mechanisms involved.
General Objective 7: To study the effect of workplace stress on eating behaviour, and its mechanistic basis.

…There is a need, across Europe, for a strong scientific evidence base to inform public policy
General Objective 8: To disseminate our understanding to the broader scientific community, to policy makers across Europe, and to the lay public.

Project Results:
NeuroFAST: Main S&T Results/Foregrounds

Note: this document was also uploaded as a PDF

GENERAL OBJECTIVE 1: To test whether eating behaviour and addiction share common susceptibility factors.

We analysed a large representative community sample of more than 3000 adolescents and young adults - data collected over more than 10 years. This provided extensive data on the incidence and co-occurrence of alcohol dependence, nicotine dependence and eating disorders, and provided evidence for three core factors (Key findings 1A-1C):


.... KEY FINDING 1A: The relationship between eating and addiction problems differs by age and gender.

By the end of the time span examined in our study (maximum age of 34), the rate of participants that had ever suffered from a substance use disorder (46%) was much higher than the rate of participants that had ever fulfilled criteria for a clinical or subclinical eating disorder (5%); 18% of the participants regularly consumed alcohol at baseline, and 33% were regular smokers. Strikingly, 89% of participants with any threshold or subthreshold eating disorder up to our last assessment were women, and only 11% were men. Concerning substance use disorders, 59% of cases were men, whereas 41% were women. Accordingly, there were significant gender differences for the distribution of both eating disorders and substance use disorder. For core eating-disorder symptoms, we found that single symptoms of anorexia nervosa and bulimia nervosa, e.g. underweight (27%) and undue influence of weight and shape on self-esteem (18%), were much more frequent than eating disorders. Again, eating-disorder symptoms were more common in females than in males.


... KEY FINDING 1B: Different eating disorders have different patterns of association with substance abuse disorders.

In the 12 months before the first assessment, there were no substantial associations between substance use disorders and anorexia nervosa, but bulimia nervosa was significantly associated with alcohol dependence, nicotine dependence, cannabis abuse and illicit drug abuse. However, over the lifespan of the participants, both anorexia nervosa and bulimia nervosa were significantly associated with substance use disorders. Bingeing and purging phenotypes of anorexia nervosa and bulimia nervosa were significantly associated with substance use disorders or with anxiety- and depressive disorders. On the other hand, restrictive or non-purging subtypes were not associated with substance use disorders (but were associated with depression).


… KEY FINDING 1C: Evidence for pathways involved in the relationship between eating and substance disorder onset.

In the risk factor analysis for eating disorders and substance use disorders, “gender” was the only risk factor predictive of all three outcome categories that were applied (ED, SUD, comorbid ED+SUD): Female gender increased the risk for eating disorders, but decreased the risk for substance use disorders, in accordance with previous studies. We found several risk factors predictive of at least two of the three outcome categories: “Dysfunctional coping”, “novelty seeking” and “having not grown up with both biological parents” increased the risk for substance use disorders and comorbid ED+SUD. One novel finding was that having suffered from a “specific phobia in the last 12 months before baseline” predicted both eating disorders and substance use disorders. The risk for eating disorders was increased by: a somatoform disorder (i.e. a mental illness in which body symptoms cannot be linked to a physical cause), major depressive episode and hypomanic episode (i.e. a mood state characterized by persistent disinhibition and euphoric or irritable mood but generally less severe than full mania) in the last 12 months before baseline as well as a stressed financial situation at baseline. These factors could be early symptoms in the form of bodily sensations, affective vulnerabilities or acute life events, but could also be risk factors (or triggers for) a wider range of mental disorders. Suffering from “general anxiety disorder” in the last four weeks before baseline was a specific risk factor for substance use disorder. Interestingly, a “higher alcohol use at baseline” without fulfilling criteria for abuse or dependence was found to be predictive of a subsequent substance use disorder. A “stressed partnership at baseline” also lowered the risk for subsequent substance use disorder.
These findings may help to inform and improve future preventive interventions for both disorders. In a clinical (i.e. treatment-seeking) sample, both eating disorders and substance use disorders were much more prevalent than in the community-based sample. However, the co-occurrence of eating disorders and substance use disorders was much smaller in the clinical sample, showing the difficulty of comparing results from community studies with clinical studies at an epidemiological level.


GENERAL OBJECTIVE 2: To determine the relationship between psychopathology, stress, body weight and stimulatory behaviours of the reward system.


… KEY FINDING 2A: the view that `Food Addiction´ can cause obesity was not substantiated in adolescent psychiatric patients.

The NeuroFAST team has been heavily engaged in the “Food addiction” debate. In our consensus opinion article [1] we conclude that we lack an evidence base that individual foods/ingredients cause us to become addicted to them (which is very different to chemical substance addiction) and suggest that the term “eating addiction” better describes this behavioural disorder. We also point out that food addiction as defined with the Yale Food Addiction Scale only applies to a smaller subgroup of individuals with obesity (in addition to subjects who are not obese). By no means can obesity in the general population be explained by food addiction. For policy makers it is important to realize that prevention efforts in our opinion should preferentially target obesity per se. We view prevention efforts based only on the target food addiction as too narrow; in addition, the unsubstantiated underlying claim that nutrients/foods lead to a type of substance based addiction, will continuously be questioned (e.g. by the food industry), thus rendering the approach fraught to criticism entailing that stringent prevention efforts will most likely not be initiated. Instead, a focus on the obesogenic environment and ways and means to reduce the risk of susceptible individuals to develop obesity is required to allow the EU and the respective countries to devise successful prevention strategies.
The problem inherent to the “diagnosis” of food addiction is best exemplified by our results pertaining to female patients with anorexia nervosa: These scored highest on the Yale Food Addiction Scale, indicating in addition to other data that `Food Addiction´ is associated with abnormal eating behaviour and cognitions that also characterize individuals with eating disorders. Accordingly, we perceive the need to develop an appropriate tool to disentangle the constructs of food and eating addiction from disordered eating behaviour and from classical eating disorders.
Overall, the diagnosis of “Food Addiction” applied to 16.5% of the 262 psychiatric inpatients (including those 32 inpatients with a diagnosis of an eating disorder). This rate is higher than that of 6% previously reported in a population based study sample. We found that Food Addiction and YFAS symptom counts were higher in the inpatient group than in the outpatient group. This could be due to the fact that the overall severity of psychopathology in inpatients is higher than in the outpatients. The prevalence of 7.5% in the outpatient group comes close to the reported prevalence rate in the general adult population. Whereas this finding requires independent confirmation, it would thus appear that mental illness is associated with above average rates of food addiction.
Presumably, this association is partially due to elevated rates of eating psychopathology in psychiatric patients, because we and others found a correlation between eating disorder symptoms as assessed with validated questionnaires and food addiction symptoms; these correlations remained significant even after exclusion of patients with eating disorders. The YFAS score was particularly correlated with eating disorder symptoms and behaviours associated with impulsivity and loss of control over eating.
Moreover, we find a positive correlation between Food Addiction symptoms and perceived stress. Perceived stress is known to increase the likelihood of eating disorders, behavioural addictions and both a negative and positive energy balance. Interestingly, patients with any substance use disorder (alcohol, nicotine, cannabis use disorder) had lower rates of food addiction than psychiatric patients without substance use disorders. If replicated, this would further indirectly cast doubt on a substance basis of food addiction, because subjects with a particular substance use disorder typically have elevated rates for additional use disorders.
Twelve months after initial assessment the former inpatients still had elevated levels of stimulatory behaviours, perceived stress, self-harm behaviour and eating disorder pathology. In particular and similar to baseline, 16.0% (13/81) fulfilled the criteria for a `diagnosis´ of food addiction according to the YFAS at the one year follow-up. However, the probability that the diagnosis was given at both time points was moderate only. Further studies are required to assess the medium and longer term stability of food addiction.
Apart from our research that focussed on food addiction we pursued other research questions. In the outpatients the magnitude of the effect of BMI-SDS on the score of the Childhood Behaviour Checklist (CBCL) was non-significantly lower than that of body fat percentage as determined by air displacement plethysmography. Nevertheless, measurement of body fat may be a more sensitive indicator for the relationship between body weight and mental symptoms, possibly also entailing the relevance of adipose tissue cytokines, hormones and peptides. We also found significant and moderate correlations with emotional eating, cognitions related to eating, weight and shape concern and BMI-SDS and with body fat percentage, respectively.


GENERAL OBJECTIVE 3: To study the common mechanisms of food reward and chemical drug reward, including to alcohol.

Just as the discovery of the fat-derived hormone, leptin, in 1994 provided a new window on brain function for energy balance, work in NeuroFAST explored the brain targets for another appetite-regulating hormone, ghrelin, a hormone secreted from the stomach. We showed that the brain pathways through which ghrelin operates interface not only food intake, but also food reward. These studies have paved the way for the identification of an endocrine gut-brain reward axis that drives motivated (craving-like) behaviour for food and psychostimulant drugs (including alcohol). Ghrelin is the only known appetite-regulating hormone to drive such behaviours and it does so by engaging brain pathways common to food and chemical drug reward. (Note that, the work reported here regarding ghrelin also addresses GENERAL OBJECTIVE 6 below).


… KEY FINDING 3A: Ghrelin, a metabolic signal, modulates the rewarding value of food.

We showed that ghrelin signalling in the brain is required for reward from chemical drugs such as alcohol [2, 3], cocaine and amphetamine [4, 5] and also for reward from food. Ghrelin orchestrates food-linked behaviours in rodents such as motivated behaviour for a sweet treat (lever-pressing paradigms)[6, 7] and food-anticipatory behaviour [8, 9], including anticipation of a sweet treat [10]. In these paradigms, the willingness to press a lever to get a sweet sugar pellet is increased by ghrelin and decreased by ghrelin antagonists, when delivered peripherally, centrally [7] or directly into the ventral tegmental area [6] (VTA, a key reward area that harbours the midbrain dopamine neurons and is involved in reward-driven motivation). The ability of sweet treats (chocolate) to condition a place preference (in which rats choose to spend more time in a chamber previously coupled with chocolate) was abolished by the ghrelin antagonist [11]. Furthermore, mice and rats show food anticipatory behaviour (heightened locomotor activity) just before scheduled periods of food access, and this was suppressed both in transgenic mice deficient in ghrelin receptors and in rats treated with a ghrelin antagonist [8, 10].
We made considerable progress in determining the neurobiological pathways underpinning ghrelin’s effects, including hypothalamic midbrain and limbic targets[6, 11-19] as well as the downstream mechanisms involved uncovering the role of rapamycin (mTOR), which acts as a cellular sensor of changes in energy balance [19]. For example, we showed that it is possible to drive food-motivated behaviour by delivering ghrelin to the VTA but not to the nucleus accumbens (NAcc, another key reward area where the dopamine neurones terminate)[6]. With neurotransmitter/peptide antagonists we teased apart pathways that drive food intake versus those that drive food-motivated behaviour. For example, we provided evidence that the VTA to NAcc dopamine pathway is engaged by ghrelin for food-motivated behaviour but not for food intake [20]. This is important because it shows that reward behaviour can be regulated by appetite-regulating hormones. In cooperation with another EC-funded project, Full4Health, we showed that another gut-derived hormone, GLP-1 (glucagon-like peptide 1) also targets the reward circuits, in this case, suppressing reward behaviour for food [21] and for alcohol [22]. The full impact of these findings have yet to be realised given that (i) ghrelin antagonists have not get been developed for human administration and (ii) drugs based on GLP-1 signalling are now in therapeutic use for the treatment of type 2 diabetes and even obesity.


…. KEY FINDING 3B: Reward consumption activates brain regions conventionally thought to be involved in homeostatic control of food intake.

Extensive neuroanatomical studies were undertaken to elucidate interactions between the endocrine hypothalamus and reward centres of the brain. For example, we mapped neuronal projections from the hypothalamus to the reward-initiating centre, the VTA. Anterograde and retrograde neuronal tract tracing techniques were used, combined with detection of specific neuronal markers, to identify the biochemical phenotypes of the neurons involved in this communication. We showed that, in addition to the well-established regulatory role of the lateral hypothalamus, the medially distributed hypothalamic nuclei are main regulators of the VTA [23], and many of the connections are reciprocal. Several nuclei in the hypothalamus connect with the VTA, including many that regulate energy balance (including the paraventricular nucleus and ventromedial nucleus). Surprisingly however, the arcuate nucleus contains relatively few neurons connecting with the VTA. This nucleus has been considered as the primary feeding center, as it receives information about the nutritional status of the body through hormones such as leptin and ghrelin. Within the hypothalamic nuclei, we found sub-populations of neurons projecting to dopamine neurons in the VTA, including corticotrophin releasing factor (CRF) neurons from the paraventricular nucleus, MCH and orexin neurons from the lateral hypothalamus projecting to dopamine neurons, and a few POMC neurons. The involvement of CRF neurons is particularly interesting as it indicates cross-talk with the hypothalamic pathways controlling stress responses (CRF neurons control the secretion of ACTH from the pituitary gland to control the adrenal gland). We also found connections between the mammillary nuclear complex and the VTA. Some of the nuclei within this complex are associated with the limbic system and relay hippocampal information via the thalamus toward the cingulate gyrus.
Both dopamine neurons and GABA neurons in the VTA were targeted by projections from hypothalamic nuclei. Interestingly, specific sub-populations of GABA neurons that are important inhibitory elements of the reward machinery were targeted. The projections from the hypothalamus to the VTA include both GABAergic and glutamatergic elements [23], so different hypothalamic nuclei can either facilitate and inhibit the VTA depending on whether the excitatory glutamate or the inhibitory GABA neurons are activated.
In humans, we found a connection between orexin neurons in the lateral hypothalamus and dopamine neurons in the VTA and substantia nigra [24]. Most of the orexinergic contacts targeted the dendrites of dopamine neurons, so this projection may play an important role in reward processing and drug abuse in humans, as well as in rodents. In addition, we found that the neurotransmitter acetylcholine was involved in the regulation of reward response by dopamine neurons in the human VTA.


… KEY FINDING 3C: Central kappa opioid receptors are a suitable drug target for the treatment of obesity and some associated co-morbidities.

Opioids are involved in a broadly distributed neural network that regulates eating behaviour, particularly consumption of highly palatable foods, and opioid antagonists attenuate both addictive drug taking and appetite for palatable food [25]. Opioids are important in reward processes leading to addictive behaviour such as self-administration of opioids and other drugs of abuse such as nicotine and alcohol. There are several opioid systems in the brain, and the one linked to abuse uses mu opioid receptors, at which morphine is a potent agonist. A different opioid system involves kappa opioid receptors, and the natural ligand for these receptors is dynorphin, which is densely expressed in several components of the appetite regulating networks of the brain, including in oxytocin neurons and in a subpopulation of neurons in the arcuate nucleus. While rats become dependent on morphine given chronically, they do not similarly become dependent on kappa agonists, so the involvement of this opioid system in appetite does not imply that food intake is addictive through this system in the way that morphine is addictive. However, the kappa opioid system is nevertheless an important system to understand in relation to food intake.
Importantly, we found that the kappa opioid receptor mediates some of the effects of ghrelin on energy homeostasis [26]. Specifically, we found that the orexigenic actions of ghrelin depend, at least in part, on the hypothalamic proDyn/KOR pathway This mechanism appears to be independent of ghrelin-induced hypothalamic AMPK activation but modulates levels of the transcription factors and orexigenic neuropeptides triggered by ghrelin. In addition, we showed that the KOR pathway is also involved in the central control of energy homeostasis exerted by other regulatory signals. Thus, we found that KOR are not only involved in the orexigenic effect exerted by MCH, but also in other central actions of this neuropeptide such as peripheral lipid homeostasis. Similar findings were uncovered in relation to nicotine, a substance like MCH, that play a major role in both energy homeostasis and food reward. We found that blockade of the KOR subtype is not only able to influence the effects of MCH and nicotine on energy homeostasis but also to prevent their effects, exerted at central level, on peripheral lipid homeostasis. This finding has important clinical implications (NAFLD/NASH) whose pharmacological development is being explored [27].


… KEY FINDING 3D: Nicotine acts at the ventromedial nucleus of the hypothalamus to regulate energy expenditure by brown adipose tissue.

We explored mechanisms underpinning the effects of nicotine on weight loss. We found that nicotine-induced weight loss is associated with inactivation of hypothalamic AMPK, decreased orexigenic signalling in the hypothalamus, increased energy expenditure as a result of increased locomotor activity, increased thermogenesis in brown adipose tissue (BAT), and caused alterations in fuel substrate utilization. Conversely, nicotine withdrawal or genetic activation of hypothalamic AMPK in the ventromedial nucleus of the hypothalamus reversed nicotine-induced negative energy balance [28]. In keeping, chronic peripheral nicotine treatment reduced body weight by decreasing food intake and increasing brown adipose tissue thermogenesis in both low fat diet and diet-induced obese (DIO) rats. This overall negative energy balance was associated to decreased activation of hypothalamic AMP-activated protein kinase in both models. Furthermore, nicotine improved serum lipid profile, decreased insulin serum levels, as well as reduced steatosis, inflammation, and endoplasmic reticulum stress in the liver of DIO rats. We have now added to this knowledge by showing that oestrogen is a key regulator of this VMH AMPK- BAT axis. Dysregulation of this axis could account for changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis. (SEE SECTION 4E).


… KEY FINDING 3E: Neuropeptides downstream of leptin signalling affect reward circuitry in lateral hypothalamus, NAcc and VTA and enhance motivation for palatable rewards

We linked another key hypothalamic system to food motivation – the melanocortin system (a system targeted by the anorexic hormone, leptin). The melanocortin system includes a subpopulation of neurons in the arcuate nucleus of the hypothalamus that express POMC – this is a large precursor peptide that is cleaved to produce two important neuropeptides – the opioid peptide beta endorphin, and the “melanocortin” alpha melanocyte stimulating hormone (alpha-MSH). Alpha MSH is a potent anorectic (appetite-inhibiting) peptide that acts in the brain through two receptors: the MC3 receptor and the MC4 receptor. Another population of neurons in the arcuate nucleus makes two important neuropeptides that are both potent orexigens – neuropeptide Y and agouti-related peptide (AgRP). AgRP acts at the MC4 receptor to promote food intake. We found that melanocortin signalling in the VTA increases motivation for palatable food via the melanocortin 3 (MC3) receptor. Interestingly, AgRP and neuropeptide Y signalling in the NAcc also increased this motivation [29, 30], and neuropeptide Y also increased motivation when injected into the VTA [29]. Thus different neuropeptide pathways affect different aspects of food-related behaviors, in which motivation can be dissociated from consumption.


…. KEY FINDING 3F: Different neural circuitry is implicated in different aspects of addictive behaviour; the role of the VTA to NAcc projection is especially important for motivated behaviour for a sweet reward, and different neuropeptides specifically modulate addiction-related behaviors.

We examined the role of the VTA to NAcc dopamine pathway in addictive-like behaviours for food, drawing on knowledge from the field of addiction biology that this pathway is important for food-motivated behaviour. While enhanced VTA dopamine tone (previously linked to addiction like behaviour) was as effective for inducing motivated behaviour for food as for cocaine, other addictive-like behaviours were unaffected [31].


…. KEY FINDING 3G: The ventromedial nucleus of the hypothalamus, formerly characterised as the brain’s “satiety centre”, cannot be a final common pathway for satiety.

There is still little understanding of how appetite-related signals are processed and encoded by hypothalamic neurones under physiological conditions. Our electrophysiological recordings in an intact, fully integrated system in vivo contribute to this understanding, as we can systematically study neuronal responses to appetite-regulating stimuli administered physiologically and at a range of physiologically relevant concentrations. The ventromedial nucleus of the hypothalamus is a large nucleus which has long been thought to be a satiety centre, but which is also involved in sexual behaviour and aggressive behaviour. Our results with oxytocin and cholecystokinin (CCK, an appetite-inhibiting hormone released from the duodenum) contradict this assumption. The most prevalent response to CCK in the ventromedial nucleus is inhibition; conversely the most prevalent response to oxytocin, a potent appetite-inhibiting neuropeptide, is excitation. Thus these two appetite-inhibiting stimuli have opposite effects on the same neurons at this site, and so it is clear that this cannot be a common pathway for mediating satiety.
We characterised neuronal subpopulations in the ventromedial nucleus by their electrophysiological phenotype and by their expression of a transcription factor, SF1,that is uniquely expressed in the brain at this site. Electrophysiological phenotype predicted responsiveness to CCK and oxytocin, but did not correlate with SF1 expression. The electrophysiological features of these subpopulations indicate a clear pattern of interneuronal coupling, involving a balance of mutual excitation and intrinsically generated activity dependent inhibition. This is interesting, because such an organisation gives rise to a “bistability” of electrical activity – meaning that neurons fire at a high rate or at a low rate with little in between. This in turn indicates that the role of the ventromedial nucleus is in categorical “decision making.” It appears now that a key role of the ventromedial nucleus is to regulate the motivation to eat and the motivation for sex in a reciprocal fashion: thus when energy stores are low, food finding is prioritised at the expense of reproduction.


…. KEY FINDING 3H: The supramamillary nucleus of the hypothalamus is potently activated by food reward and by ghrelin.

We conditioned rats to expect to receive a palatable food reward (a small volume of condensed milk) at a certain time of day for one week. After a week, the rats were divided into four groups. The first group received the reward at the expected time; a second group did not receive the reward at the time they were expecting it, a third group received the reward at an unexpected time, and a control group neither expected nor received the reward. We also used rats that had been fed a high-energy palatable diet for five weeks. This overweight group was conditioned in the same way and on the test day all expected the reward but only some received it. In these rats, we mapped the neural pathways that were activated by studying neuronal expression of the immediate-early gene c-fos, a marker for neuronal activation that we have used extensively for mapping neural pathways involved in appetite. In rats receiving the reward, whether they were expecting it or not, we saw a strong activation of the arcuate nucleus (a region strongly associated with homeostatic feeding behaviour). However, we also observed activation in rats that were expecting the reward but did not receive it. This suggests that this region, even during satiety, is involved in signalling receipt of rewarding food and also in reward expectation. In palatable-fed rats there was significantly less activation during expectation of reward suggesting a blunting of reward response after chronic exposure to palatable foods.
In addition, and very unexpectedly we observed strong activation in the hypothalamic supramammillary nucleus (SuM), a brain structure not previously linked to food intake. We observed moderate activation of the SuM by anticipation or receipt of a predicted reward but very strong activation by receipt of an unexpected reward. We have now shown electrophysiologically that neurons in the SUM are also powerfully activated by systemic administration of ghrelin.


GENERAL OBJECTIVE 4: To establish the importance of “food addiction” as an obesity factor in women, and the mechanistic basis of gender differences in food intake.


… KEY FINDING 4A: Food addiction-related overweight/obesity cannot be identified using anthropometric, metabolic, biochemical or adrenal hormonal parameters

We characterized the anthropometric, metabolic, biochemical and hormonal profile of an overweight/obese group of patients featured by food addiction, defined as the presence of 3 or more symptoms on the Yale Food Addiction Scale questionnaire (YFAS) vs BMI/age matched group with fewer than three symptoms. The two groups did not differ significantly in age, weight, BMI, waist. No significant differences in white blood count, reactive C protein, erythrocyte sedimentation rate, fibrinogen, total and HDL cholesterol, triglycerides, fasting glucose and insulin, glycated hemoglobin, glycaemia and insulin, area under the curve (during Oral Glucose Tolerance Test) were found. Basal ACTH, cortisol and minor adrenal steroids were not different, and there was no difference in diurnal, nocturnal or urinary free cortisol, or in salivary cortisol measured at 7 am and at 11 pm or in the cortisol awakening response (a marker of adrenal axis reactivity).


…KEY FINDING 4B: Multisensory palatable stimulation enhances activation in brain regions involved in reward as well as in those involved in metabolic homeostasis

In Positron Emission Tomography (PET) brain imaging studies, the hypothalamus and midbrain were more activated in food-addicted women than in non-addicted women, and there was an inverse association between the severity of addiction and the activation of the orbitofrontal and prefrontal cortex (involved in inhibitory control). Eleven women (7 food addicted and 4 not food addicted) completed the protocol involving PET scans before and after a three-month period of diet. Weight, BMI and waist circumference were lower after dieting, but comparing the food addicted and non-food addicted women, there was no significant difference in anthropometric, metabolic, biochemical responses to the diet. However, brain activation occurring during multisensory palatable stimulation was reduced more in the food-addicted women, achieving significance in the hypothalamus, midbrain, orbitofrontal, prefrontal, occipital cortices in the food addicted group. Altogether, the data indicate that overweight/obese women showing identical anthropometric and metabolic/hormonal profiles are characterized by a distinct brain pattern of glucose metabolism relating with their food addiction symptoms. Thus, their brain reacts to food sensing and to dieting in a more pronounced fashion than the brain of non-addicted women. The pattern observed in food-addicted women was consistent with a greater reaction of brain regions to the expected pleasure of consuming palatable foods. The data also suggest that a progressive decline in the response of prefrontal regions may underlie disinhibited overeating, as this decline was significantly associated with a growing number of Yale Food Addiction Scale (YFAS) symptoms in the food-addicted women. Moreover, the diet seems to exert a brain metabolic effect only in the addicted group, whose brain activation during the palatable stimulus seems to normalize to the values measured in the control group. As for other metabolic outcomes, the more affected subjects seem to benefit the most from dietary intervention.


… KEY FINDING 4C: Cerebral positron emission tomography can discriminate between addicted and non-addicted obese/overweight women.

Not addicted and addicted obese/overweight women (identified using the Yale Food Addiction Scale) did not show any difference at the phenotype level. By PET imaging we found that food addiction resulted in a significantly increased activation in the thalamus, hypothalamus, midbrain, putamen, sensory and occipital cortex activation and an inverse association was found between the activation in the orbitofrontal cortex and YFAS score. A three month diet similarly reduced BMI and waist in not addicted and addicted obese/overweight women. The diet seems to exert a brain metabolic effect only in the addicted group, normalizing the brain glucose uptake. Reduction of brain glucose uptake in response to food was not correlated with reduction in body weight, indicating that the effect the intervention on brain metabolism is not (or not only) mediated by the loss of body mass.


… KEY FINDING 4D: In rodents, reward signals in the prefrontal cortex depend on the estrogen environment of the brain.

In studies on rats, we explored the effects of the female sex steroid hormone estradiol on the mesocortical dopamine system. The dopamine pathway from the VTA to the prefrontal cortex contributes to the processing of reward signals, and is regulated by gonadal steroids. We found that estradiol can powerfully modulate the responsiveness of this pathway, increases the expression of key genes related to dopamine neurotransmission and augments the dopamine content of the prefrontal cortex [32]. The findings indicate that reward signals in the prefrontal cortex depend on the estrogen environment of the brain.


… KEY FINDING 4E: In rodents, females are more vulnerable than males to weight gain in response to intermittent sweet treats.

Rats were given, in addition to their normal bland food, intermittent sweet “treats” – sweetened condensed milk, to study how this would affect their total energy intake and weight gain. When the treats had an energy value of about 25% of their total daily intake, male rats compensated reducing their bland food intake, resulting in maintenance of a stable body weight. However, female rats did not compensate fully and increased their body weight when given equivalent rewards. In males, compensation is not due to learning, as treats presented in an irregular and unpredictable way were still compensated for. The gender difference is quite small but may be sufficient to account over time for substantial weight gain in females. This work links not only to GENERAL OBJECTIVE 6 but also to GENERAL OBJECTIVE 1. However, even in males, compensation is limited - these rats did not reduce their food intake linearly with increasing reward access, so when treats exceeded 60% of average daily intake they started to gain weight. Exactly how the rats compensate for additional energy intake was studied by mapping the neural pathways that are activated when a treat is eaten, and one key pathway that is activated is the hypothalamic oxytocin system: as oxytocin is an anorectic neuropeptide, this is likely to be involved in a reduction of appetite after ingestion of the treat.

See also key finding 3D (Nicotine acts at the ventromedial nucleus of the hypothalamus to regulate energy expenditure by brown adipose tissue): dysregulation of this axis could account for changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis; key finding 5E: within which we studied the role of estradiol and effects of ghrelin in male and female rats. We found that: 1) Central estradiol (E2) promotes negative energy balance; 2) central E2 increases thermogenic sympathetic nerve activity; 3) Central E2 inhibits AMPK, specifically in the VMH, through ERα; 4) The VMH AMPK-SNS-BAT axis mediates the central actions of E2 on energy balance. Furthermore we showed that ghrelin modulates hypothalamic and mesolimbic structures controlling energy balance in both sexes, and that, in females, the estradiol milieu does not influence the ghrelin-induced neuronal activity.


GENERAL OBJECTIVE 5: To study the impact of altered leptin and ghrelin signalling in the mechanisms underlying eating disorders.

Many key findings linked to ghrelin signalling for eating behaviour are already mentioned under objective 3 above, in particular key finding 3A (Ghrelin, a metabolic signal, operates at the neurobiological interface between food intake and addiction) We also showed that oestrogen is a key regulator of the regulation of brown adipose tissue by the ventromedial nucleus of the hypothalamus (see key finding 3B).


… KEY FINDING 5A: Hypothalamic oxytocin neurons are a target for leptin actions

In late pregnancy, all mammals increase their fat stores in anticipation of the metabolic demands of lactation, and this has been thought to involve a desensitisation to the appetite-inhibiting effects of leptin that arises from the steroid environment of pregnancy. This is important to understand, as it suggests that this physiological adaptive process might also underlie the propensity of women for diet-induced obesity. In rodents we showed that one of the hypothalamic targets for leptin is the magnocellular oxytocin system; however we showed that at this site there is little evidence of leptin resistance in pregnancy [33].


… KEY FINDING 5B: Key role of the lateral hypothalamus in leptin resistance

In obese rats, leptin resistance arises in the lateral hypothalamus (a hunger centre involved in homeostatic regulation of appetite, but not in the VTA. We showed that leptin resistance in the lateral hypothalamus regulates body weight and food intake, and that leptin signalling within the lateral hypothalamus is crucial in mediating motivation for sucrose. (Manuscript in preparation).


… KEY FINDING 5C: A novel mechanism by which anorexia may result in amenorrhea.

We identified a new and unexpected target system for ghrelin in the rodent brain, the gonadotropin-releasing hormone (GnRH) network which orchestrates reproduction centrally. We found that GnRH neurons express the ghrelin receptor, and are inhibited by ghrelin administration; this effect involves endocannabinoid retrograde signaling and depends on the estrogen milieu [34]. The results contribute to the better understanding of anorexia nervosa, a severe eating disorder characterized by high level of circulating ghrelin, amenorrhea and severe weight loss.


KEY FINDING 5D. The feeding and food reward effects of ghrelin involve central opioid receptor signalling in addition to pathways linked to dopaminergic, glutamatergic, NPY Y1 and cholinergic signalling.

We explored whether the orexigenic and food reward effects exerted by ghrelin could be mediated by opioid receptors, and obtained clear evidence for a role for both mu-opioid [18] and kappa opioid receptors [26]. We also implicated, amongst others, glutamatergic [15], cholinergic [13] and NPY Y1 [18] signalling pathways in these effects.
Using functional magnetic resonance imaging (fMRI) in rats, we showed that ghrelin regulates both hedonic and homeostatic regulatory centers of feeding in both male and female rats, and studied the role of endocannabinoids and estradiol [35]. We found that ghrelin modulates hypothalamic and mesolimbic structures controlling energy balance in both sexes, and that the endocannabinoid signalling system contributes to ghrelin induced neuronal activity in a region-specific manner. We found that, in females, an estradiol milieu does not influence the ghrelin induced neuronal activity.



GENERAL OBJECTIVE 6: To contribute to a better understanding of the addictive properties of individual food components.


…. KEY FINDING 6A: The human brain can detect dietary macronutrients that initiate immediate effects on eating behaviour.

We explored the effects of macronutrients on food intake, food choices and food preference in humans in a series of studies that involved manipulation of food macronutrients and testing of the effects on gut hormone secretion, food intake and food preference in lean and obese people. In studies of sucrose preference, we showed that increasing sweetness is associated with increased liking for food, although high sucrose concentrations (60%) were aversive to some people. There were no differences in liking response or total energy intake between lean and obese people. In studies of fat preference, people were offered foods of different fat content that were identical in appearance; we found no difference in the liking scores for the meals, when tested before and after meal consumption. In contrast, in people with heterozygous complete loss of function mutations in the melanocortin 4 receptor gene, MC4R, we observed a higher preference for dietary fat versus sucrose demonstrating that the response to fat in the diet has a strong biological basis.
In lean participants, we compared high sucrose vs sweetener containing meals. Consumption of the isocaloric (high volume) erythritol meal was associated with reduced hunger scores compared to the sucrose control meal. No differences were seen in obese people. Post-prandial plasma glucose and insulin levels were higher after the sucrose control meal than after the erythritol meals, but PYY and GLP-1 responses were similar between the sucrose control and isovolumic erythritol meal in both lean and obese groups. Food intake and sucrose preference during the ad libitum lunch were similar in all conditions in both groups. Thus partial replacement of sucrose by the sweetener erythritol does not attenuate acute behavioural and hormonal parameters of satiety or preference for sucrose in a subsequent ad libitum meal in lean or obese people. These results demonstrate the usefulness of evaluating individual sweeteners, which may interact in unique ways with sweet-taste receptors, vary 1000-fold in sweetness and dosing in food and which may have different absorption kinetics and metabolic fates after consumption.
In studies of high protein vs high fat vs high carbohydrate content meals, we found that PYY levels were highest after the high protein breakfast. GLP-1 levels were highest after the high protein breakfast at 120 min and remained higher throughout the study. These differences did not translate into differences in food intake in lean people.


…. KEY FINDING 6B: In rodents, the hypothalamic oxytocin system is promptly and robustly activated by intragastric delivery of high calorific food.

The finding that the human brain can detect dietary macronutrients that initiate immediate effects on eating behaviour is paralleled by our findings in rodents of neuronal activation and gene expression. In rodents, the direct effects of food ingestion on neuronal activity in the hypothalamus were studied. Intragastric gavage of sweetened condensed milk rapidly and potently activated identified oxytocin cells in the hypothalamus – these neurons are known to have an important appetite-inhibiting role, acting in part on the motivation to eat by the actions of oxytocin at the ventromedial nucleus of the hypothalamus. We identified the brain regions that are activated by release of oxytocin within the brain by mapping expression of the immediate-early gene c-fos after central administration of oxytocin; two sites of strong activation are the amygdala, and the ventromedial nucleus of the hypothalamus.


… KEY FINDING 6C: In humans, calorie restriction affects the sleep/wake cycle.

In a study of changes in energy balance on the sleep/wake cycle, twelve adult male volunteers were studied before and after caloric restriction for 48 h (calorie intake was restricted to 10% of the 24h energy restriction. In the following 48 h, participants were offered a 20 MJ-containing buffet in three meals, and additional snacks that were later weighed. We found that the energy deficit due to caloric restriction was compensated after two days of free feeding. Acute changes in energy balance were reflected in multiple metabolic parameters such as leptin, with a drop to 20% of baseline level after caloric restriction. In free feeding, leptin reverted back to a higher level than at baseline (126%). There was no change in the duration of light sleep and REM sleep, but deep sleep was increased by 18% after caloric restriction and decreased back to baseline levels during free feeding. Interestingly, the increase in deep sleep was entirely due to a marked increase in the duration of stage 4 sleep with no significant difference in stage 3 sleep.

Today’s society is exposed to a wealth of palatable high-caloric foods, making overeating and obesity an inevitable consequence. In NeuroFAST we have sought to explore how the brain reward circuitry is affected when exposed to an obesogenic environment. We found that a combination of a fat and sugar diet results in leptin insensitivity and also highlight the role of leptin signalling at the level of the lateral hypothalamus to suppress motivated reward behaviour for palatable foods. Interestingly, we also demonstrated that the post ingestive effects of sucrose (glucose) can be rewarding in nature. We have also assessed the rodent sucrose addiction model at behavioural and molecular levels but find little evidence to support it based on studies in rodents [36].

… KEY FINDING 6D: The obesogenic environment can change food-linked behaviours, including motivated- and binge-like behaviours in rodents but we find little evidence to support “sugar addiction”.

Sugar-rich foods are known to engage brain reward systems, which may promote unhealthy eating habits. Sucrose can influence these systems via its sweet taste as well as via its postingestive effects. Indeed, it has previously been shown that the sweet taste and the postingestive effects of sucrose differentially influence its intake and associative learning processes. We investigated the contribution of sweet taste and postingestive effects to incentive motivation. Rats were trained to respond for saccharin (a non-caloric sweetener) or maltodextrin (a carbohydrate with similar postingestive effects as sucrose, but without the sweet taste) and motivation for these solutions was evaluated under a progressive ratio schedule of reinforcement. Initially, the animals responded more for saccharin than for maltodextrin. However, after a learning phase, in which the animals associated the taste of maltodextrin with its postingestive effects, the incentive value of maltodextrin increased compared to saccharin. Although initially, bodyweight was not associated with motivation for either solution, there was an association between body weight and motivation for maltodextrin after the incentive learning phase. Furthermore, maltodextrin, but not saccharin intake was strongly associated with body weight (de Jong, in preparation).


… KEY FINDING 6E: Sweet taste and postingestive effects of food both support motivation for food. The postingestive effects of carbohydrates increase the motivation for food through an incentive learning mechanism.


GENERAL OBJECTIVE 7: To study the effect of workplace stress on eating behaviour, and its mechanistic basis.

We completed extensive food intake and stress measures in the workplace environment, a controlled laboratory experiment and web-tool intervention study in over 750 men and women in the UK, to assess the effect of stress on eating behaviour. This includes detailed measurements on shift workers.


… KEY FINDING 7A: `Stress´ has bi-directional impact on eating behaviour and future interventions need to recognise this if they are to be effective

Stress can influence our health, directly or indirectly through behavioural change. This includes feeding behaviour, specifically the type and quantity of food consumed, where some people will eat more and some people will consume less calories under stress (bi-directional response). We explored in the laboratory setting (and in the free-living setting), that some people over-consume calories when stressed while others under-eat, and how this is linked to individual personality profile and eating behaviour profile. Over-consuming calories when stressed is a risk factor for obesity and diseases including type 2 diabetes and cardiovascular disease, while under-consuming calories is a risk factor in the workplace for performance and wellbeing. Interventions to manage stress in the workplace need to target the right phenotype to result in behaviour change. In our laboratory study of 60 people, 53% consumed more energy when stressed, 43% consumed less energy, and 4% did not change food intake. The energy intake changes were dramatic, at +60% more and -66% less calories consumed, respectively, when stressed, which if continued over several days, would be a significant influence on energy balance and body weight.
- Thirty-two volunteers (mean BMI 25.7 kg/m2) were classified as ‘stress susceptible increase’. They had significantly higher energy intake on the stress test day than on their control day (703 kcal vs 438 kcal).
- Twenty-six (mean BMI 24.6 kg/m2) were categorised as ‘stress susceptible decrease’, consuming significantly less on the stress test day (397 kcal vs 604 kcal).
- Two (mean BMI 22.2 kg/m2) were classified as stress-resistant, their eating behaviour remained unchanged.
These data show that our approach of phenotyping with regard to eating behaviour response (calorie intake when stressed) is a valuable for assessing the type of intervention to apply. If our data had simply been analysed as a group, many of the effects would be missed (and thus initiatives are not likely to target the right people). These data will contribute to evidence base, which strongly suggest that targeting those people who over-eat when stressed, is a valuable means to tackle overweight and obesity, especially in the workplace. Furthermore the group that consume less calories are interesting, as they become anorexic when stressed, which does not put them at risk of obesity related over consumption, but will impact on productivity and concentration, which are other indicators that employers are interested in. This work will provide data for future targeted interventions in the workplace.


… KEY FINDING 7B: Shift-workers consumed less when stressed, whereas day workers consumed more: this has implications for health policy and meal provision in the workplace.

Longitudinal studies have suggested that elevated stress can increase desire for hedonically pleasing, highly palatable energy-dense foods. One in five workers in Europe are employed on shift work involving night work and more than 1 in 20 work extended hours. We recruited emergency responders (fire service & ambulance) and prison staff, all working variable shifts; 93 male and 24 female shift workers with a mean age of 38.7 years and mean BMI of 26.8 kg/m2. We analysed data using subjects as their own control, to examine variables as ‘on shift’ v’s ‘off shift’. Perceived stress was measured using hourly visual analogue scales over 7 days. The shift workers reported elevated stress when on shift compared to off shift, with energy intake (measured by 7-d weighed intake food diary record) and energy expenditure (assessed using an accelerometer) monitored. The shift workers report eating significantly less calories at a meal eating episode when on shift, in comparison to off shift days, which is reflected in significantly higher protein, fat, carbohydrate and alcohol intake when off shift. Unsurprisingly, these subjects were in physically demanding jobs, and thus, physical activity and number of steps were significantly higher when on shift. As we often eat two or more meals a day at work, these data support the ethos that shift workers require access to healthy food to support adequate nutrition and hydration during working hours. Some shift work professions do not have protected break time, which can lead to unhealthy eating styles of snacking or grazing on smaller meals, which tend to be high in energy density. Although these shift workers consumed less and expended more calories on shift, they compensate by consuming calories when off shift, (or even over-compensated), as they did not lose weight over the diary week reporting.


… KEY FINDING 7C: Shift-workers have a detrimental health profile

Working conditions are associated with employees’ health behaviour and health, and shift work in particular has been linked to adverse health and unhealthy behaviours including obesity cardiovascular disease, increased snacking, fatigue, sleep and digestive problems, depression, anxiety, disruptions in circadian rhythm and perceived stress. Our studies confirm the detrimental effects of shift work on health. There was more visceral fat (the fat which surrounds the internal organs of the body, and which is particularly associated with a greater risk of diseases such as cardiovascular disease and diabetes) in shift workers than in non-shift workers. There was no significant effect of mean energy intake, stress or total number of daily hassles/week on visceral fat level after controlling for age, BMI and shift pattern. Shift workers worked an average of 46 h/wk significantly more than non-shift workers (40 h/wk). The difference between genders was also significant, with men working an average of 45 h/wk and women 40 h/wk. There were no significant differences in hours worked between age groups. The BMI group corresponding to overweight participants showed most mean hours worked (44 h/wk).


… KEY FINDING 7D: No effect of caffeine consumption on stress

We examined the role of caffeine and stress, as increased caffeine consumption has been related to periods of work-stress, and caffeine influences the neuroendocrine system associated with psychophysiological stress responses. There was a significant relationship between age and caffeine intake, and stress level and caffeine intake, although no significant effects of shift pattern. Additionally, hassle severity (an indicator of stress) affected caffeine intake although there was no effect in relation to number of hassles. The Food Frequency Questionnaires provided complete habitual caffeine intake information from 415 volunteers from different workplaces including shift and non-shift workers. Perceived stress, depression and anxiety levels were measured using the DASS-21 self-reported questionnaire. Additionally, the ‘Daily Hassles’ Questionnaire measured frequency and severity of daily stressors yielding a greater detail of subjective stressful events. Ordinal regression models controlling for age, gender, BMI and shift pattern were used to determine the relationship between caffeine and stress and stress-related disorders (depression and anxiety). Mean caffeine intake was not significantly different between non-shift workers and shift workers or between men and women, and was not associated with BMI, but was significantly higher in older workers than in those under 45 years 185 vs 157 mg/day). The results showed significant effects of stress and hassle severity, a marginal significant effect of depression, and non-significant effects of anxiety and hassle frequency.


… KEY FINDING 7E: The type of stress is important for the behavioural response.

Daily stressors or hassles are events, thoughts or situations which, when they occur produce negative feelings such as annoyance, irritation, worry or frustration, and/or make you aware that your goals and plans will be more difficult or impossible to achieve. In terms of stress research, the use of daily diaries is becoming more popular, and this is the approach we used, to allow respondents to record temporal changes in day-to-day minor life events or daily stressors/hassles that are part of everyday life and have the advantage of not constraining respondents to a limited number of events. Stressful events are associated with a variety of behavioural responses and generally people use different coping strategies. The foods that have been reported to be over-consumed were snack foods including crisps, chocolate and biscuits. We found significant differences between non-shift and shift workers for DASS21 questionnaire stress and anxiety as well as for ‘Daily Hassle’ frequency and severity. Non-shift workers were more likely than shift workers to have higher levels of perceived stress and anxiety and to rate daily hassles as more frequent and severe. There were non-significant effects of the shift pattern on DASS21 depression. An increase in hours worked during the weekend is marginally associated with greater perceived stress.


… KEY FINDING 7F: Workplace interventions need to be evidence-based

When experiencing stress, individuals are more likely to eat high fat and high sugar snacks between meals (e.g. chocolate, crisps, cakes and biscuits) and less likely to eat fruit and vegetables. People who do not maintain a balanced diet are at increased risk of developing heart disease and cancer as they get older. Daily hassles and stressors can be formally broken down to different types of stress: ego-threatening, interpersonal, work-related, physical and environmental, which were all monitored in the present study. We examined if a public health initiative called Healthy Working Lives, influenced outcomes in indices of stress and food intake.
We recruited public sector workers as follows:
• Workplace 1 comprised staff from Aberdeen College and the University of Aberdeen, with both organisations holding the government initiative Healthy Working Lives
• Workplace 2 secondary schools in Aberdeen and Aberdeenshire with no Healthy Working Lives initiative
We compared workplace 1 and 2, to identify whether the Healthy Working Lives initiative at work is effectively (positively) influencing staff behaviour (eating and physical activity) and stress levels. The two groups were well matched: in Workplace 1 there were 150 subjects (41 male, 109 female) with a mean age of 41 yrs and mean BMI of 25 kg/m2, and in Workplace 2 there were 155 subjects (42 male, 113 female) with a mean age of 44 yrs and mean BMI of 26 kg/m2.
We found no major effects of workplace type on the data examined. The HWL initiative does not appear to influence energy intake, energy expenditure, energy balance or stress. We examined total intake and snack intake, and found no significant differences between workplaces. We assessed energy expenditure by accelerometry, and again found no differences between workplaces. We assessed total hours worked and total hours slept, and found no significant differences for age, BMI, gender or Workplace. Five types of daily hassles were identified: Ego-Threatening; Interpersonal; Work-Related; Physical; and Environmental. Ironically, the staff working in the institutions with the Healthy Working Lives initiative report significantly higher stress, reporting more total hassles per day higher total hassles duration per week.
The HWL may have other health benefits (such as smoking cessation or mental health), but the effects on stress and nutritional profile seem limited, from the current dataset. If obesity and unhealthy behaviours are to be discouraged in the workplace, this requires evidence based intervention and robust evaluation. This work highlights the fact that public health initiatives should be evaluated to assess potential health benefits.


… KEY FINDING 7G: Web-based tool is useful to target and influence individual responses to stress

Workplace health and wellness is important, as employee wellbeing is linked to increased productivity and reduced absenteeism, and we have provided evidence that ‘Workplace Wellness’ makes financial sense to reduce modifiable risk factors for non-communicable disease (cardiovascular disease, cancer, type 2 diabetes, chronic lung disease) by creating ‘health-promoting environments,’ In the UK for example, 65% of fire fighters, 30% of office workers and 47% of offshore shift workers are overweight and there is need for evidence based advice for workplace health initiatives.
Our findings suggest that conscientiousness and neuroticism may influence future health status. These influences can be both direct, through facilitating performance of health-enhancing behaviours and/or reducing exposure to daily stressors, and indirect, by buffering the negative effects of stress on health behaviours, and promoting health-enhancing behaviours (such as exercise). These results are important as they indicate that conscientiousness may have a counterintuitive influence on different types of health behaviours. These small effects are also likely to reflect that the relationships between personality, daily hassles, and health behaviours are influenced by many other variables.
Unfortunately, stress is an inescapable feature of everyday modern life, particularly in the workplace. However, we have shown that a web-based workplace health initiative, can be implemented to provide individual advice, by encouraging behaviour change. This provides an online behaviour change programme based on implementations intentions [37] with remote motivational support to aid the development of healthier lifestyle behaviours. Food intake, stress and body weight can all be individually tracked using this tool in the workplace to allow employees to assess and manage stress. The tool will help people tackle stress, anxiety and depression and related conditions such as weight management for obesity.



The NeuroFAST ROADMAP

At our final meeting, we reflected over current (2015) key gaps in knowledge with a few to the provision of a roadmap beyond this project for future EC research. These are summarized below and we have prepared a flier for circulation of this material (submitted).

NeuroFAST OUTCOME: We provide evidence that subtypes of obesity exist and show that neither being “Food/Eating addicted” nor being “stressed” are consistent determinants of becoming overweight or obese.
FUTURE: If we are to develop personalised strategies for overweight and obesity, future research will need to address why different people respond differently in terms of weight gain to the same environmental stimuli that include stress.

NeuroFAST OUTCOME: We provide a platform for a working definition of the term “Food Addiction” (or “Eating Addiction”, as we prefer to describe it). We made progress towards its validation in obese women by brain imaging and also show that being food addicted is not a constant determinant of being overweight/obese.
FUTURE: Further validation and implementation of clinical tools for the diagnosis of “Eating addiction” is warranted – this evidence base is needed to structure policies that guide the environment of those affected and also that provide better health care for those diagnosed.

NEUROFAST OUTCOME: We show that the reward value of food and anticipatory behaviours for it are not only associated with its taste but are also influenced by our gut, exemplified here by the effects of ghrelin on reward behaviour for food.
FUTURE: Appetite-regulating hormones provide a window on brain function for appetite control: by studying their brain mechanism at many levels, we can discover new mechanisms for appetite control – both how much and what we eat.

NeuroFAST OUTCOME: We show that diet impacts on certain food-linked behaviours that can be obesity-promoting but find little evidence to support the idea that the pathways engaged by foods are those that orchestrate addiction-like behaviour.
FUTURE: We need to strengthen behavioural science showing impacts of diet on subsequent choice behaviour for food and the environmental influences involved.

NeuroFAST OUTCOME: Research on causal factors underlying diet induced alterations in energy balance showed that energy-sensors such as AMPK or mTOR are at the core of orchestrating a variety of brain functions (body temperature, energy and metabolic homeostasis) in response to nutritional status and/or diet intake.
FUTURE: As behavioral models in rodents become more sophisticated and can be validated to some extent in a non invasive way in humans it should be feasible to carry out the circuitry analysis linking energy sensors and neuropeptides/ neurotransmitters involved in diet-induced alterations in energy and metabolic homeostasis opening the way for novel clinical approaches to treat obesity and comorbidities.


REFERENCES

1. Hebebrand, J., et al., "Eating addiction", rather than "food addiction", better captures addictive-like eating behavior. Neurosci Biobehav Rev, 2014. 47: p. 295-306.
2. Jerlhag, E., et al., Requirement of central ghrelin signaling for alcohol reward. Proc Natl Acad Sci U S A, 2009. 106(27): p. 11318-23.
3. Jerlhag, E., et al., The alcohol-induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice. Alcohol, 2011. 45(4): p. 341-7.
4. Jerlhag, E., et al., Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference. Psychopharmacology (Berl), 2010. 211(4): p. 415-22.
5. Egecioglu, E., et al., Hedonic and incentive signals for body weight control. Rev Endocr Metab Disord, 2011. 12(3): p. 141-51.
6. Skibicka, K.P. et al., Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience, 2011. 180: p. 129-37.
7. Skibicka, K.P. et al., Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addict Biol, 2012. 17(1): p. 95-107.
8. Verhagen, L.A. et al., Acute and chronic suppression of the central ghrelin signaling system reveals a role in food anticipatory activity. Eur Neuropsychopharmacol, 2011. 21(5): p. 384-92.
9. Cardona Cano, S., et al., Role of ghrelin in the pathophysiology of eating disorders: implications for pharmacotherapy. CNS Drugs, 2012. 26(4): p. 281-96.
10. Merkestein, M., et al., Ghrelin mediates anticipation to a palatable meal in rats. Obesity (Silver Spring), 2012. 20(5): p. 963-71.
11. Egecioglu, E., et al., Ghrelin increases intake of rewarding food in rodents. Addict Biol, 2010. 15(3): p. 304-11.
12. Skibicka, K.P. and S.L. Dickson, Ghrelin and food reward: the story of potential underlying substrates. Peptides, 2011. 32(11): p. 2265-73.
13. Dickson, S.L. et al., Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents. Neuroscience, 2010. 171(4): p. 1180-6.
14. Hansson, C., et al., Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence. Neuroscience, 2011. 180: p. 201-11.
15. Jerlhag, E., et al., Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system. Addict Biol, 2011. 16(1): p. 82-91.
16. Alvarez-Crespo, M., et al., The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence. PLoS One, 2012. 7(10): p. e46321.
17. Menzies, J.R. et al., Neural Substrates Underlying Interactions between Appetite Stress and Reward. Obes Facts, 2012. 5(2): p. 208-220.
18. Skibicka, K.P. et al., Ghrelin interacts with neuropeptide Y Y1 and opioid receptors to increase food reward. Endocrinology, 2012. 153(3): p. 1194-205.
19. Martins, L., et al., Hypothalamic mTOR Signaling Mediates the Orexigenic Action of Ghrelin. PLoS One, 2012. 7(10): p. e46923.
20. Skibicka, K.P. et al., Divergent circuitry underlying food reward and intake effects of ghrelin: dopaminergic VTA-accumbens projection mediates ghrelin's effect on food reward but not food intake. Neuropharmacology, 2013. 73: p. 274-83.
21. Dickson, S.L. et al., The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J Neurosci, 2012. 32(14): p. 4812-20.
22. Shirazi, R.H. S.L. Dickson, and K.P. Skibicka, Gut peptide GLP-1 and its analogue, Exendin-4, decrease alcohol intake and reward. PLoS One, 2013. 8(4): p. e61965.
23. Kalló, I., Molnár,S.C. Szőke. S.E. Hrabovszky E., Fekete, C. Liposits, Z., Hypothalamic afferents to the ventral tegmental area in the rat. 2015. submitted.
24. Hrabovszky, E., et al., Orexinergic input to dopaminergic neurons of the human ventral tegmental area. PLoS One, 2013. 8(12): p. e83029.
25. Nogueiras, R., et al., The Opioid System and Food Intake: Homeostatic and Hedonic Mechanisms. Obes Facts, 2012. 5(2): p. 196-207.
26. Romero-Pico, A., et al., Hypothalamic kappa-opioid receptor modulates the orexigenic effect of ghrelin. Neuropsychopharmacology, 2013. 38(7): p. 1296-307.
27. Seoane-Collazo, P., et al., Nicotine improves obesity and hepatic steatosis and ER stress in diet-induced obese male rats. Endocrinology, 2014. 155(5): p. 1679-89.
28. Martinez de Morentin, P.B. et al., Nicotine induces negative energy balance through hypothalamic AMP-activated protein kinase. Diabetes, 2012. 61(4): p. 807-17.
29. Pandit, R., et al., Limbic substrates of the effects of neuropeptide Y on intake of and motivation for palatable food. Obesity (Silver Spring), 2014. 22(5): p. 1216-9.
30. Pandit, R., et al., Central melanocortins regulate the motivation for sucrose reward. PLoS One, 2015. 10(3): p. e0121768.
31. de Jong, J.W. et al., Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation. Neuropsychopharmacology, 2015.
32. Sarvari, M., et al., Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats. Brain Res, 2014. 1583: p. 1-11.
33. Velmurugan, S., J.A. Russell, and G. Leng, Systemic leptin increases the electrical activity of supraoptic nucleus oxytocin neurones in virgin and late pregnant rats. J Neuroendocrinol, 2013. 25(4): p. 383-90.
34. Farkas, I., et al., Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH) neurons in an estrous cycle and endocannabinoid signaling dependent manner. PLoS One, 2013. 8(10): p. e78178.
35. Sarvari, M., et al., Ghrelin modulates the fMRI BOLD response of homeostatic and hedonic brain centers regulating energy balance in the rat. PLoS One, 2014. 9(5): p. e97651.
36. de Jong, J.W. et al., Low control over palatable food intake in rats is associated with habitual behavior and relapse vulnerability: individual differences. PLoS One, 2013. 8(9): p. e74645.
37. Adriaanse, M.A. et al., Do implementation intentions help to eat a healthy diet? A systematic review and meta-analysis of the empirical evidence. Appetite, 2011. 56(1): p. 183-93.



Potential Impact:
NeuroFAST: the Potential Impact

Note: this document was also uploaded as a PDF

In accordance with General Objective 8 of the NeuroFAST project – ‘To disseminate our understanding to the broader scientific community, to policy makers across Europe, and to the lay public’, the consortium has sought to maximise the impact of NeuroFAST research through a range of dissemination and exploitation activities targeted at a spectrum of end-users and stakeholders. In relation to the original call text, we report that NeuroFAST has provided added value by building up the necessary critical mass across diverse fields of research encompassing epidemiology, human nutrition, psychiatry, human brain imaging, psychology, obesity, metabolism, neuroendocrinology, neuroanatomy and neurophysiology. Collectively we have strengthened European research capacity, evidenced by the large number of publications and dissemination activities, thereby providing sound scientific support to European public health policies. The European dimension has been an important aspect of the overall success of this project in which there has been much added value in cross-fertilizing ideas, sharing technologies and providing early stage scientists with sufficient training for a future strength in this area. “Determinants of food addiction” has been a major activity (see below) and risk factors important for substance abuse disorders (including alcohol) and eating disorders” have been explored. We have therefore added to knowledge that is important for developing a better understanding of addiction patterns and their potential adverse effects.


IMPACT:

The NeuroFAST project has had impact, or has potential for impact, at a number of different inter-related levels – conceptual, in clinical practice, and in informing public health policy. Examples are given below.

A major impact of the NeuroFAST project has been at the conceptual level in redressing the imbalance that existed relating to the use of the term “food addiction”, and in particular in the discussion of this term and its applicability in the popular media, where the real evidence base is frequently overlooked in the drive for a high profile news story. The role of the consortium in critically evaluating the food addiction concept has been recognised and applauded in a variety of fora and by a range of stakeholders from national regulators to the food and drink industry and nutritional scientists. We specifically propose that the term “food addiction” is a misnomer, because evidence in humans to justify this term is scant – single nutrients and/or particular foods including snacks have not been shown to result in the development of addiction. Instead, we suggest that susceptible individuals can develop a behavioural addiction to eating. It will be important to define criteria for the proposed diagnosis of “eating addiction” and to pinpoint the overlap with the criteria which have already been delineated for “food addiction”. The diagnosis “eating addiction” would have repercussions at many levels – for health care, for the food industry and for those involved in policy, all of whom share the responsibility to help individuals that suffer from this currently undefined disorder.

Furthermore, on a practical level, we have extended the evidence base showing that normal weight and even underweight individuals can fulfil the criteria for “food addiction”, thus clearly demonstrating that this ‘diagnosis’ is not specific to obese individuals. There appears to be substantial overlap between “food addicted” individuals and individuals with a disordered eating behaviour as illustrated by the high rate of “food addiction” in patients with anorexia nervosa. However, using the YFAS questionnaire for the identification of individuals with “food addiction”, work in NeuroFAST has shown that such individuals can also be characterised through brain imaging studies, thereby validating the use of this questionnaire for diagnosis. We assume that substantial overlap exists to constructs commonly used for eating disorders (e.g. restrained eating, disinhibition). Ongoing work additionally shows that subjects who fulfil the criteria for “food addiction” also show higher stress levels.

In light of the dire therapeutic situation for obesity, we are witnessing an unfolding discussion on the relevance of addiction in this condition. If substances in food lead to addiction, pressure would mount to pursue structural prevention: social, economic and policy strategies to curtail obesity rates. On the other hand, if eating addiction is best conceptualized as a behavioral addiction, the affected individual is seemingly at fault, reducing this pressure. Irrespective of whether scientific evidence will justify use of the term food and/or eating addiction, most obese individuals have neither a food nor an eating addiction. Obesity frequently develops slowly over many years; only a slight energy surplus is required to in the longer term develop overweight. Genetic, neuroendocrine, physiological and environmental research has taught us that obesity is a complex disorder with many risk factors, each of which have small individual effects and interact in a complex manner. The notion of addiction as a major cause of obesity potentially entails endless and fruitless debates, when it is clearly not relevant to the great majority of cases of overweight and obesity. The danger is that prevention efforts based on a single, minor cause of obesity risk undermining a holistic strategy that aims to reduce weight gain. We need strategies for preventing obesity that do not overly depend on any particular etiology of obesity. Lessons can be learned from previous successful public health programs such as the large-scale immunization programs which have all but wiped out specific contagious diseases, and programs aimed at preventing traffic accident casualties. The food industry must contribute to obesity prevention irrespective of whether, and to what extent, addiction is involved.

Elsewhere in the project, the outcomes achieved prospectively in a large community sample of adolescents are in accordance with several important findings of cross-sectional studies and of studies with clinical samples. Female participants suffered from an eating disorder (ED) about ten times as often as male participants; furthermore, our data confirmed the period of adolescence as the time period associated with the highest risk for developing an ED. These findings imply the importance of targeted preventive interventions focussing specifically on this age group and gender. We also found life-time comorbidities of around 50% with substance use disorders (SUDs) in individuals with EDs and significant cross-sectional associations between bulimia nervosa and SUDs, which is again similar to findings obtained from studies with clinical samples. These outcomes emphasize that comorbid SUDs should receive special attention in the treatment of EDs, since they are highly prevalent comorbid conditions. Additionally, the high prevalence rates of core ED-symptoms further emphasize the need for prevention and early detection programmes. Our results considering stability rates of EDs further add to this point; in light of greater chronicity of threshold EDs and given that only about half of the individuals with EDs in our sample fully remit from the disorder, these programmes should receive greater societal attention and financial resources. The observed differential cross-sectional comorbidity patterns for anorexia nervosa and bulimia nervosa may also highlight the need for the development of specific interventions for different diagnostic groups of EDs. The obtained outcomes regarding temporal associations between EDs and SUDs moreover indicate a necessity to prevent incident depressive and anxiety disorders in individuals that have remitted from an ED or SUD, respectively.

The analysis for common and specific risk factors of EDs and SUDs identified a range of variable risk factors and fixed markers including the most potent risk factors for ED, SUD and comorbid ED+SUD. Compared with previous risk factor studies, the current analysis in a sample of adolescents and young adults therefore demonstrates complex pathways to onset of individual disorders (ED, SUD) as well as comorbid ED+SUD. It provides important information for factors to be targeted by universal, selective and indicated preventive interventions thus informing the development of future preventive approaches for these disorders. As for the comparison between community samples and clinical samples, studies addressing different comorbidities of eating disorders yielded highly inconsistent results due to major methodological differences. By using the same assessment instrument and applying the same case definitions for the most prevalent comorbid mental disorders in the comparison of a community-based sample and a clinical sample we tried to overcome some of the previous limitations. Overall, based on our comparison of a large, representative community sample and a clinical sample the pattern of results found demonstrates the large differences in both prevalence and comorbidity rates between the samples. Only some of the findings of this comparison are in accordance with previous results. The comparison demonstrates impressively that prevalence and comorbidity rates reported on the basis of clinical samples should therefore generally be considered with caution since they may reflect treatment specifications and referral practice rather than “true” epidemiological associations.

Workplace health initiatives around the world are growing in number and scope, as employers come to realize that addressing employee health & wellness is linked to increased productivity and reduced absenteeism, and that the returns on this strategic investment and overall health cost savings are high. Since many adults spend a substantial amount of their time at work and consume at least one meal at work each day, a healthy workplace environment is important, particularly as jobs become more sedentary. An increased prevalence of obesity among employees can have indirect economic consequences for employers, in terms of productivity through illness and absenteeism. The research in the workplace as part of NeuroFAST sought to provide an evidence base to influence health interventions aiming to promote work wellness. Influences on eating behaviour are complex, and particularly the role of stress on food intake and food choice is a challenging research area. However, the approach adopted in the NeuroFAST project has addressed both psychological and physiological aspects and has the potential to make recommendations about the management of stress for public health and policy practitioners.

We compared workplaces with and without the Healthy Working Lives (HWL) award, to identify whether this UK initiative at work is effectively (positively) influencing staff behaviour (eating and physical activity) and stress levels. Comparing workplaces with and without the award did not reveal any notable differences in eating behaviour or nutritional profile in the employees. Thus, the HWL initiative does not appear to influence energy intake, energy expenditure, energy balance or stress in the employees who participated in the NeuroFAST study. Indeed, employees in the workplace with a public health initiative had higher levels of stress than those working in alternative environment. If obesity and unhealthy behaviours are to be addressed in the workplace, evidence based intervention and robust evaluation will be required. Compared to individuals who work during the day, shift workers have been identified to be at greater risk of metabolic related disorders. Other factors such as protected break time for shift workers could be targeted to ensure better nutrition profile and less reliance on snack foods that are often nutrient poor.


DISSEMINATION

Project concepts and outputs have been disseminated to a wide range of stakeholder groups using a range of contemporary media and strategies appropriate to the subject matter and the intended audience.

Website
The NeuroFAST website was established in the first months of the project and incorporated materials related to the project aims and objectives and the consortium partners that were appropriate to visitors from all different stakeholder communities who might visit the site looking for scientific information and news in a digestible form. The intention was to maintain an active vibrant website conveying the breadth and scope of activity within the NeuroFAST project. The website was relaunched halfway through the duration of the project. Since then the focus has been on incorporating a steady flow of news-type material highlighting the dissemination activity of scientists within the consortium, and thereby drawing attention to the science behind the project and the research being performed. The focus has remained on material that will be accessible to a wide range of stakeholders from policy, the media, the industrial sector and the interested public, as well as members of the scientific community, with news items, web-links and podcasts designed to draw visitors into other parts of the site. News items were uploaded reporting project activities and dissemination events, mainly focussed on the publication of the consensus review, supporting its message to the scientific community (who might access the article from a conventional science database) with materials (published paper, video, podcast, press coverage etc) appropriate to a wide range of stakeholders in the wider community.

Briefing notes/reviews
Briefing notes have been prepared and made available for download from the NeuroFAST website. An introductory briefing document outlining the project was backed up by four Research Briefs, all available for reading and download from the website. Three of these covered areas of major scientific interest within the project and were intended as scientific summaries and position statements representing the position of the NeuroFAST consortium on key areas of scientific debate that were particularly relevant to the project. These documents were entitled ‘The biology behind “food addiction”’, ‘Food addiction and the psychiatric classification of addiction’, and ‘Can stress make you fat?’. A fourth briefing document presented an overview of a public engagement event developed by the NeuroFAST consortium and was entitled ‘Public engagement with science’. These documents were written to be accessible to policy colleagues, the media, interested members of the public, and other stakeholders.

Conference presentations
Consortium scientists have presented research findings at a wide range of scientific congresses in the topic areas of physiology, psychology, psychiatry, obesity, feeding behaviour and public health, amongst others. Many of these presentations, oral and poster, have been accompanied by press releases, review articles and podcasts, thereby expanding the reach of the project and its research beyond the immediate audience. The consensus position of the consortium on ‘food addiction’ has also been the topic of a number of presentations to diverse audiences.

Public engagement
A wide range of public engagement activities have been undertaken by the consortium throughout the lifetime of the project, including participation in major ‘set piece’ events such as the International Science Festivals in Gothenburg and Edinburgh, the Annual British Science Festival, and the European Researcher Nights. Project scientists have been interviewed for the print, broadcast and online media, with material carried in the popular press (including a detailed report on `food addiction´ in the prestigious German newspaper Frankfurter Allgemeine Zeitung) and in the Spanish Newspaper “El Pais”, on radio and television, and in online for a such as CommNet, MedicalXpress and EC ‘top news’. Other examples include an article on stress and obesity in Sceptic magazine (UK), and a MOOCs (Massive Open Online Course) run by the University of Edinburgh and the University of Aberdeen that use food addiction as a debating point for course learners.

Policy engagement
High level engagement with policy makers and advisors and key stakeholder groups was achieved when the first consensus statements of the consortium related to food addiction were presented to the EU Platform for Action on Diet, Physical Activity and Health and the High Level Group of Member States on Nutrition and Physical Activity in February 2013. It is hoped that the NeuroFAST project, along with the FP7 projects Full4Health, SATIN and Nudge-it, will be invited back to these meetings to continue the engagement with these important fora. The first step in the process of re-engagement will be the production of a ‘highlights’ briefing document communicating key outputs and concepts to gauge interest amongst the programmers of these meetings.

Consensus review on food addiction and eating addiction
In the final year of the project a consensus review on food addiction was authored by consortium members and published in a prestigious review journal with the specific intention of engaging with a wide range of stakeholders from scientific, healthcare, policy, and industry communities, and with the wider public throughout Europe and internationally. The review was intended to disseminate key messages originating from the NeuroFAST project, and was promoted through a range of print and broadcast media, online resources, and face-to-face interactions with relevant groups and individuals. A wide range of promotional activities were planned around the release of the review article on-line, with the article itself and supporting material (video, podcast etc) available for download on the NeuroFAST website. There were co-ordinated press releases across Europe, which spawned interviews with print media, radio and television, resulting in widespread coverage. The review paper generated invitations to talk at a number of meetings across Europe including The European Food Information Council Scientific Advisory Board, the European Federation of the Associations of Dieticians (DIETS-EFAD), and a public meeting of the Food Safety Authority of Ireland. This consensus paper was only possible due to prior efforts of the group to address the implications of research in their fields; the respective articles were published within a special issue of Obesity Facts titled “NeuroFAST – the Integrated Neurobiology of Food Intake, Addiction and Stress”.


EXPLOITATION

It is still early to fully realise the extent to which the results from our project will be exploited. Much of our “product” is new knowledge, and exploitation of this knowledge will be likely to inform policy and practice, public understanding of science, and, in the longer term, design and composition of foods, drinks and diets, and drug development and target rationalisation. Examples of some of these routes to exploitation are detailed below.

Concepts
As already mentioned, we believe that the NeuroFAST consensus on “Food Addiction” has the potential to be the catalyst for an important shift in the way that the concept is considered and discussed. Our dissemination effort in this direction has gone some way to countering the sensationalist headlines that are all too frequently generated from the ‘food addiction’ concepts, with a more rational, balanced perspective being picked up on by the popular media. Thus, output from NeuroFAST has already been exploited for the benefit of public understanding of science, countering the unhelpful message that could take hold that food addiction somehow explains the obesity epidemic, thereby rendering the individual powerless to influence their own condition. Further opportunities to promote this more balanced perspective and the concept of ‘eating addiction’ as opposed to ‘food addiction’ are likely to emerge over the coming months and years. The NeuroFAST consortium will continue to actively engage with these opportunities to deliver a more balanced assessment of the evidence base in this area, whilst also pursuing opportunities for further research to convert the ‘eating addiction’ concept into a diagnosable condition of clinical relevance.

Clinical practice
Our epidemiological studies identified both common and specific risk factors of EDs, SUDs and comorbid ED+SUD. Outputs suggest that interventions should be more targeted in terms of age group and gender, and that comorbid SUDs and EDs should receive special attention. These results provide important information for factors to be targeted by universal, selective and indicated preventive interventions thus informing the development of future preventive approaches to be developed by both scientists and policy makers for these disorders.

Public health policy
Our “stress in the workplace” studies have shown that different individuals respond differently to the same stressful situation in terms of their dietary habits and body weight. We have only just completed this study but expect the work to receive considerable attention by relevant stakeholders including employers and those involved in policy. Public health policies such as those applied to the workplace need to be effective, based on an evidence foundation, and need to be evaluated for effect. If current initiatives do not produce any measurable benefit, we need to understand why this is, and what we should do instead. Consequently, studies such as those conducted in the NeuroFAST project have a real potential to inform the debate surrounding public health policy.

Drug targets and patenting
The outcomes achieved in relation to Objectives 11.1 ‘To determine whether the opioid receptors are required for the rewarding properties of food’ and 11.2. ‘To investigate the biochemical basis of the interaction between the ghrelin system with the different opioid-receptor subtypes and the relationship of the later to food preference and the motivation to eat’ led to two important findings:
1) that kappa opioid receptor subtype is a suitable drug target for the treatment of obesity and some associated co-morbidities such as NAFLD and NASH
2) that the ghrelin system influences energy homeostasis at central level via an energy sensor driven pathway involving p53/sirt-1/AMPK.
These findings attracted the interest of the Technology Transfer Division at Beneficiary 9 and led to the development of two patents. One is already filed (‘p53 as drug target for the treatment of obesity and its comorbidities’/ REF P201130250-SPAIN). As follow up of this patent we conducted preclinical studies showing that this was a feasible approach and have a partner (INNOPHARMA) which is carrying out studies related to the development of more selective compounds and oral formulations before translation/transference to the clinic. In addition we have another patent ‘KOR-antagonists in the treatment of obesity and its comorbidities’ whose draft is currently under consultation with the Legal Office of Beneficiary 9, and where there is optimism from data generated during NeuroFAST showing that the KOR are involved in the effects exerted at central level by several relevant signals (ghrelin, MCH, nicotine) involved in energy homeostasis as well as by our unpublished observations (see fourth period report) showing that it prevents diet-induced NAFLD/NASH.

List of Websites:
www.neurofast.eu
Professor Suzanne L Dickson
Dept Physiology/Endocrine
Institute of Neuroscience and Physiology
The Sahlgrenska Academy at the University of Gothenburg
Medicinaregatan 11
SE-405 30 Gothenburg
Sweden

email: suzanne.dickson@neuro.gu.se
telephone +46 703 693568
final1-logo-final.png