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Food additives, food and the concept of ‘food addiction’: Is stimulation of the brain reward circuit by food sufficient to trigger addiction?
Accepted Manuscript Title: Food additives, food and the concept of ‘food addiction’: Is stimulation of the brain reward circuit by food sufficient to trigger addiction? Authors: A.Y. Onaolapo, O.J. Onaolapo PII: DOI: Reference:
S0928-4680(17)30175-X https://doi.org/10.1016/j.pathophys.2018.04.002 PATPHY 939
To appear in:
Pathophysiology
Received date: Revised date: Accepted date:
2-12-2017 26-2-2018 7-4-2018
Please cite this article as: Onaolapo AY, Onaolapo OJ, Food additives, food and the concept of ‘food addiction’: Is stimulation of the brain reward circuit by food sufficient to trigger addiction?, Pathophysiology (2010), https://doi.org/10.1016/j.pathophys.2018.04.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Food additives, food and the concept of ‘food addiction’: is stimulation of the brain reward circuit by food sufficient to trigger addiction?
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Onaolapo AY1 and Onaolapo OJ2*
Behavioural Neuroscience/Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of
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Technology, Ogbomoso, Oyo State, Nigeria. [email protected],
Behavioural Neuroscience/Neuropharmacology Unit, Department of Pharmacology, Ladoke Akintola University
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of Technology, Osogbo, Osun State, Nigeria. [email protected].
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*Corresponding Author:
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Graphical abstract
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Abstract In the last few years, the concept of ‘food addiction’ has continued to gain popularity, with human and animal studies demonstrating the differential effects of foods that are high in fat,
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sugar or protein on appetite, satiety, eating behaviour and the development of food addiction. However, a number of studies have disputed the occurrence of food addiction in humans.
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Questions have also arisen regarding the possible impacts that food additives may have on the development of food addiction or eating disorders. Also, it is known that alterations in food
composition and the presence of food additives (flavour enhancers, sugars, sugar substitutes,
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and non-nutritive sweeteners) are factors that generally influence the sensory perception of
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food. Our understanding of the potential roles of central neurotransmitters (such as
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dopamine) and certain neuropeptides in the evolution of food addiction is also evolving; but
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presently, there isn’t sufficient scientific evidence to consider any food ingredient, micronutrient or standard food-additive as addictive. In this review, the relevant literatures
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dealing with the concept of ‘food addiction’ are examined, and the factors which may
sugars,
sugar
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predispose to food addiction are discussed. The possible influences that flavour-enhancers, substitutes
and
non-nutritive
sweeteners
may
exert
on
central
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neurotransmission, neurotransmitter/receptor interactions, appetite, satiety, conditionedpreferences and the brain reward system are also highlighted.
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Keywords: Brain reward system; Conditioned preference; Food addiction; Flavour enhancer; Food sweeteners; Overeating
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Introduction
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‘Food addiction’ is a behavioural addiction that is characterised by compulsive
consumption of palatable foods, which is associated with activation of the brain reward system in humans and animals (Olsen, 2011; Hebebrand et al., 2014). It has also been defined as a clinically-significant physical and/or psychological dependence on high sugar, high fat,
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and highly-palatable foods (Brownell and Gold, 2012, 2013). Over the last few years, the concept of food addiction has become increasingly popular and this is reflected not only in
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the volume of media reports and health blogs (Marlow, 2013; Avena and Talbott, 2014; Tarman and Werdell, 2014) but also in a substantial increase in scientific literature (Corwin
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and, Grigson, 2009; Gearhardt et al., 2011a; Krashes and Kravitz, 2014; Muele, 2015; Schulte
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et al., 2016) dedicated to the topic. Addiction to food has been implicated in foodcraving/bingeing and is also considered an important predisposing factor to obesity (Davis et
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al., 2011; Gearhardt et al., 2011a; Schulte et al., 2016). An ‘addictive’ food, nutrient, or food ingredient is believed to possess an inherent ability to induce dependence (Hebebrand et al.,
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2014). Hence, the concept of food addiction is based on the idea that certain foods (or their additives) may have addictive potentials (Muele, 2015). Human and animal studies have
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continued to report the differential effects of high-fat, high-sugar or high-protein diet on eating behaviour (Avena et al., 2008a, 2008b; Avena et al., 2012a; Schulte et al., 2015;
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Tulloch et al., 2015; Schulte et al., 2016) and brain neurotransmitter chemistry (Bocarsly et al., 2010). A number of rodent studies have also demonstrated the effects of exposure to
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sugars, fats and highly-palatable diets on food-preferences, brain-reward functioning and the risk for obesity (Avena et al., 2008a, 2008b, 2012a; Johnson and Kenny, 2010; Borengasser et al., 2014). Genetic traits that may predispose to food addiction have also been studied (Velázquez-Sánchez et al., 2014).
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Food additives are substances that are added to foods or drinks to maintain/enhance safety, freshness, texture, appearance, taste or flavour (WHO, 2017). For centuries, humans have used salt to preserve meats and fish, herbs and spices to enhance food flavour and sugars to preserve fruits. However, in recent times, the list of indications for food additives is expanding and they are increasingly being used to make food safe, stable, nutritious,
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convenient, colourful, flavourful and affordable. Hence, different types of food additives have been (and are still being) developed to meet the growing demands of the food industry.
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Food additives can be synthetic or derived from plants/animals, and they have been grouped
by the World Health Organisation and the Food and Agricultural Organisation into three
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broad categories (Flavour enhancers, Enzymes and Others), which are based on their function
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(WHO, 2017). Flavour enhancers constitute the majority of additives used in foods and they
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include salt and monosodium glutamate. Enzyme preparations include additives which may
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be naturally-occurring proteins or synthetic compounds which assist in breaking down larger molecules into their smaller building blocks, such as yeasts used in improving the dough or
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for alcohol fermentation. Other additives include nutritive (sugars) or non-nutritive (aspartame and saccharin) sweeteners and food preservation/colouring agents.
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Recently, interests in the potential associations of food additives, processed foods and food addiction have increased (Morris et al., 2008; Cocores and Gold, 2009; Blaylock, 2014), with
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suggestions that consumption of highly-processed foods promotes food addiction (Johnson and Kenny, 2010; Gearhardt et al., 2011b). These suggestions are related to the fact that
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while many food ingredients lack intoxication capacity, studies have shown that certain foods or their additives (e.g saccharin) appear to induce reinforcement behaviours that are similar to or possibly exceed those associated with drugs of abuse (Lenoir et al., 2007; Gearhardt et al., 2011b). Also, in similarity to drugs of abuse, they may trigger addiction-like neuroadaptive responses in the brain reward circuits (Johnson and Kenny, 2010). Again, highly-processed
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foods may have been altered in ways similar to addictive drugs (Gearhardt et al., 2011b) and certain formulations of processed foods have been designed to maximise palatability and/or reward (Spence, 2012). However, a number of researchers are of the opinion that while there are speculations regarding the factors that are present in foods which may stimulate addiction, there isn’t sufficient scientific evidence yet to consider any food ingredient, micronutrient or
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standard food-additive as addictive (Hebebrand et al., 2014). In this review, we highlight the results of studies on the possible addictive potential of selected food additives (culinary
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flavour enhancers and food sweeteners) by examining the relevant scientific literature on the associations that exist among factors such as food, food additives, the brain reward system
1.1
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and food addiction. Food and food addiction
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The construct “food addiction” was first introduced by T.G. Randolph in 1956,
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around a period when addictive-like consumption of wheat, corn, potatoes, chocolate, coffee, milk and eggs were reported (Randolph, 1956). However, in recent years, this construct has
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become popular because it helped to understand the influences that psychological factors could exert on weight gain (Brownell and Gold, 2013), especially following an increase in the
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prevalence of obesity in the United States of America (and world-wide) in the last few decades (Finucane et al., 2011; Ogden et al., 2012). Food addiction is not currently
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recognised as a disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM5). However, studies evaluating the occurrence of food addiction in humans (Flint et al.,
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2014; Pursey et al., 2015) have utilised the Yale Food Addiction Scale (YFAS), a validated and reliable instrument based primarily on the diagnostic criteria for substance dependence in the DSM-IV-TR (APA. 2000) which measures behavioural indicators of eating disorders (Gearhardt et al., 2009). Despite the fact there is a paucity of population-based prevalence rates for food addiction, studies in subjects not diagnosed with an eating disorder had
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reported prevalence rates of 5 to 26% (Ziauddeen and Fletcher, 2013); while in studies that have included subjects with a diagnosed eating disorder, higher rates of food addiction have been reported (Pursey et al., 2014). There are growing interests in defining the roles played by the food reward system in regulating food intake, as well as the possible links that may exists between this system and
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the development of food addiction in humans. In recent times, questions have also arisen
about the roles played by food additives like sugars, non-nutritive sweeteners and culinary
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flavour enhancers in modulating the food reward towards food addiction (figure 1). Studies in laboratory animals have suggested the presence of homeostatic factors that control energy
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intake and energy demand, in effect precisely modulating body weight over prolonged
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periods of time (Woods, 2009). A few other studies have also reported that the hedonic
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properties of food may influence feeding beyond the daily energy requirements, in essence
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possibly contributing to weight gain and obesity (Kenny, 2011). The regulation of food intake (figure 2) has been demonstrated to involve strong associations
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that exist between homeostatic and non-homeostatic factors, the balance of which ensures the maintenance of body weight (Hagan and Niswender, 2012). The homeostatic control
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(regulated by energy stores and energy demands) which mediates how much food an individual consumes is usually subject to non-homeostatic or hedonic (consumption
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motivated by reward systems) influences. It has been observed that reward-related signals can override homeostatic signals, essentially contributing to the consumption of more foods
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above the body’s immediate energy requirement (Begg and Woods, 2013; Alonso-Alonso et al., 2015). In last few decades, the consumer response to the availability of high-energy and/or highly-palatable foods may be a reflection of the influences that such reward-related signals can exert.
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The additive potential of some foods and food substances may be comparable to that of common drugs of abuse (like cocaine, marijuana and methamphetamine) whose use is characterised by episodes of negative consequences (abuse) and physiological dependence (Alonso-Alonso et al., 2015). These drugs are known to enhance
dopamine release (from
dopaminergic neurons in the ventral tegmental area) to brain regions that are associated with
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the reward system, such as the prefrontal cortex, amygdala and the nucleus accumbens. In the
brain reward system, the patterns of neural responses associated with palatable foods have
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been shown to be similar to those associated with drugs of abuse (Ahmed et al., 2002; Kalivas and O'Brien, 2008; Janes et al., 2010). Similarly, palatable or highly-processed foods
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have reinforcing effects which may be mediated by dopamine’s influences on the brain
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reward system (Alonso-Alonso et al., 2015). Also, palatable foods have been observed to
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activate reward-learning regions of the brain, as well as dopamine signalling (Small et al., 2003). Repeated intake of foods that are high in sugar is associated with increased D1
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receptor binding (in the shell and core of the NA) and increased μ-opioid receptor binding in
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the cingulate cortex, hippocampus, accumbens shell and locus coeruleus; changes which are similar to those associated with a number of drugs of abuse (Colantuoni et al., 2001). A
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down-regulation of post-synaptic D2 receptors in the nucleus accumbens shell and dorsal striatum (as seen in drug addicts) had also been reported in animals that were fed high-
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fat/sugar foods (Johnson and Kenny, 2010; Bello et al., 2002; Stice et al., 2010a). The exposure of obese subjects to palatable food cues has also been associated with hyper-
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responsiveness in the reward-related brain regions (Stoeckel et al., 2008; Stice et al., 2010b). From the aforegoing, dopamine is linked to the reinforcing effects of food, and studies have demonstrated that food consumption results in striatal (dorsal) dopamine release with the degree of pleasure derived from eating correlating positively with the quantity of dopamine released (Small et al., 2003). Administration of dopamine antagonists has also been
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associated with increased food intake and weight gain, while dopamine agonists cause a reduction in food intake and an ensuing weight loss (Epstein et al., 2007). Neuropeptides (orexigenic and anorexigenic) which are involved in the regulation of food consumption and metabolism have also been evaluated for their roles in the neurobiological responses of drug and alcohol-dependence (Thiele et al., 2003; Barson and Leibowitz, 2016).
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The brain expression of these neuropeptides has been reported to be altered following bingelike consumption of palatable foods (Alcaraz-Iborra et al., 2014) or drugs (Navarro et al.,
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2008; Carvajal et al., 2015). Central administration of Agouti-related peptide (a melanocortin
receptor antagonist) activates midbrain dopamine neurons and induces consumption of fat
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and sugar-enriched foods (Davis et al., 2011). Ghrelin, leptin and insulin are homeostatic
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regulators of food intake and via their influences on the dopaminergic systems, they mediate
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between the homeostatic and hedonic mechanisms of food intake (Kenny, 2011; Egecioglu et
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al., 2011; Hebebrand et al., 2014).With the discovery of leptin receptors expression on midbrain dopamine neurons (Elmquist et al., 1998), there have been suggestions that
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mesolimbic dopamine pathways could also mediate the effect of leptin on food intake (Lerma-Cabrera, et al., 2016).
Anatomy of the brain reward system
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1.2
The brain reward system is made up of a group of neurons, nerve cells and brain
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nuclei that are involved in the modulation and control of associative learning, pleasure and incentive salience (Berridge, 2012; Berridge and Kringelbach, 2015; Schultz, 2015). Reward
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is the ability of an object to stimulate appetitive or approach behaviour, choices and emotional behaviour (Schultz, 2015). The association between a feeling of reward and substance use has been linked to the reason why humans use these substances, or why laboratory animals self-administer them (Wise, 2009). The rewarding effects of substances have been linked to their ability to increase dopamine (DA) secretion in the brain regions that
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mediate reward (especially in the nucleus accumbens) (Di Chiara and Imperato, 1988; Nestler et al., 2004); although studies have also demonstrated that DA’s role in reward does not usually equate with hedonic responses which are mediated partly by endogenous opioids and cannabinoids. The neural circuitry tasked with the mediation of reward and/or addiction involves a network of brain regions that continues to evolve in number and/or complexity
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(Wise and Koob, 2014).
Brain regions that constitute the reward system are located primarily within a cortico-basal
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ganglia-thalamo-cortical loop (Yager et al., 2015), which modulates the development and
maintenance of addiction (Nestler, 2013, van Huijstee and Mansvelder, 2014). DA neurons in
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the ventral tegmental area (VTA) of the midbrain are very important (Lammel et al. 2012),
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because they form strong reciprocal connections with several other brain regions like the
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nucleus accumbens, lateral hypothalamus, and prefrontal cortex (Calabresi et al. 2007; Luo et
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al., 2015). The striatum (dorsal striatum and nucleus accumbens) is also very important in the reward pathway, as it serves as the main integration site for the cortico-basal ganglia-thalamic
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circuitry by receiving a variety of inputs. It receives GABAergic inputs from striatal interneurons (Dautan et al., 2014), cholinergic inputs from the interneurons of the striatum
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and brainstem (Yager et al., 2015), as well as dopaminergic inputs from the VTA (Swanson, 1982) and the substantia nigra (Yager et al., 2015). It also receives glutamatergic inputs from
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the prefrontal cortex, amygdala, hippocampus and thalamus (Finch, 1996, Britt et al., 2012). For a detailed discussion on the brain reward system, see Berridge and Kringelbach (2015)
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and Schultz (2015). 1.3
The food reward system Intrinsically, eating has rewarding and reinforcing effects, and studies have
demonstrated that food consumption activates the regions associated with reward in the brain (Hebebrand et al., 2014). However, food consumption is regulated by a neural circuitry that
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includes the dorsolateral prefrontal cortex, striatum, amygdala, midbrain and the hypothalamus (Berthoud, 2011). Together, these systems regulate all aspects of feeding behaviour, including both homeostatic and hedonic food consumption (Hebebrand et al., 2014). The food reward system consists of at least of two parts, a sensory and/or a postingestive component (Avena et al., 2008a, 2008b). Gustatory information (usually
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perceived by the taste receptors) send signals that ascend through the thalamus, terminating in the orbitofrontal cortex and anterior insula/frontal operculum (Kobayakawa et al.,1999;
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Small, 2006); while the amygdala makes reciprocal connections at all levels of the gustatory
pathway (Yang, 2010). Mesolimbic DA system also aids the hedonic recognition of the
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stimulus and satiation that follow consumption of palatable foods (Goldstein and Volkow,
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2002; Haltia et al., 2007; Stice et al., 2008).
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Imaging studies have revealed an increased activation in the lateral orbitofrontal cortex,
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insula, amygdala, frontal operculum and striatum in anticipation of palatable food (Stice et al., 2008) and in response to pictures of palatable foods (Rothmund et al., 2007; Stoeckel et
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al., 2008) in obese compared to control subjects. In humans (unlike laboratory animals), the influence of cognition and executive functioning influences behavioural drives for palatable
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food. This executive functioning support self-regulation of eating and have been mapped to brain regions which include the dorsolateral prefrontal cortex, the dorsal anterior cingulate,
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and the parietal cortex (Alonso-Alonso et al., 2015). 1.4
Food, food constituents and food consumption
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Foods and/or food constituents have been shown to have varying abilities for
induction of satiation. Studies have reported that foods that are high in dietary protein tend to increase the perception of satiety (Labayen et al., 2004; Schoeller and Buchholz, 2005; Luhovyy et al., 2008; Thomas and Chapman, 2008). Several studies have also reported that foods that are high in protein are less liked than low-protein foods (Johnson and Vickers,
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1992; Vanderwater and Vickers, 1994). High-protein foods have also been shown to produce an increase in sensory-specific satiety, compared to low-protein foods (Johnson and Vickers, 1992; Vanderwater and Vickers, 1994; Sivertsen et al., 2010). Sugar- and fat-rich foods are highly palatable, and studies have shown that foods rich in sugar and/or fat can promote overeating (Berthoud, 2011; Egecioglu et al., 2011; Ryan et al., 2012).
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The ability of sweet taste and fatty flavour to activate the brain reward systems and promote
food consumption has been demonstrated by a number of animal studies (Hajnal and
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Norgren, 2008; Liang et al., 2006). Also, the ability of these foods to cause obesity in rodents
has been observed (Sclafani, 1993; Speakman et al., 2008). It is now generally accepted that
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food can be made more palatable by: the addition of biopolymers like transglutaminase
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(which improves food texture), adding soy protein sauce or carrageenan mix, varying the fat
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content (Muguruma et al., 2003; Pietrasik and Duda, 2000), addition of flavour enhancers
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{like monosodium glutamate, inosine-5-monophosphate (IMP-5) (Bellisle, 1999; Yamaguchi and Ninomiya, 2000) and sodium guanoate}, or food sweeteners like non-nutritive
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sweeteners.
How do high-fat/high-sugar diets promote overeating and/or food addiction?
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There have been reports showing that foods that are rich in sugar and/or fats can stimulate segments of the reward system (including taste receptors, postingestive signals and
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neuropeptide systems) enough to result in overeating or binge eating. A number of rodent studies have also demonstrated that foods that are rich in both sugar and fat stimulate
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excessive eating. Consumption of foods that are high in sugar has been associated with increased secretion of DA and acetylcholine (ACH) in the nucleus accumbens (Avena et al., 2012b). Increasing palatability of food or food constituents (as it occurs with high-sugar or high-fat diets) has also been associated with a reduction in the effectiveness with which intestinal and post-absorptive satiation signals suppress food intake (Sclafani, 2013). Johnson
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and Kelly (2010) also demonstrated that excessive intake of highly-palatable food results in a down-regulation of the expression of striatal D2 receptors. The body controls food intake and energy expenditure by a series of impulses which include satiation. Satiation represents a cumulation of the inhibitory signals that are induced by the ingestion of food substances. These signals may be cognitive, digestive, sensory or hormonal.
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Satiation results in a feeling of being full and ultimately signals the end of a meal (Woods and D'Alessio, 2008). The duration or intensity of satiety that follows a meal and persists
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until hunger pangs begin is also modulated by various signals which form part of the satiety cascade (Blundell et al., 1993). Studies have shown that sensory and cognitive processes
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interact with post ingestive and post absorptive peripheral and central mechanisms that help
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to maintain satiety. Satiation signals generally reflect the nutrient and caloric content of a
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meal. The gut peptides involved in the induction of satiation include cholecystokinin,
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enterostatin, amylin, glucagon-like peptide, peptide tyrosine-tyrosine, apolipoprotein A-IV, glucagon, oxyntomodulin and members of the bombesin family of peptides (Moran, 2004;
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Woods and D’Alessio, 2008).
In addition to satiation signals, there are also adiposity signals which in conjunction with
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satiation signals modulate food intake and metabolism. Adiposity signals reflect the amount of stored body fat, insulin which is secreted by the pancreatic β-cells and leptin secreted from
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adipocytes; with both insulin and leptin correlating with the body’s total adiposity and energy store (Polonsky et al., 1988; Frederich et al., 1995; Schwartz et al., 1996). Increased flux of
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insulin or leptin stimulates receptors in the hypothalamus and other brain regions to reduce food intake (Woods et al., 1979; Brief and Davis, 1984; Seeley et al., 1996); while a reduction of adiposity-signalling in the brain (in experimental animals) has been associated with hyperphagia (Cohen et al., 2001; Obici et al., 2002). Adiposity signals (unlike satiation signals) exert long-lasting effects spanning several meals or days, and stabilising adipose
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stores (Ryan et al., 2012). Studies have shown that chronic exposure to foods that are high in fat raises the body’s adiposity and satiation threshold, such that higher levels of signals are required to suppress feeding (Ryan et al., 2012). Apart from the direct effects of palatable flavours of high-sugar and high-fat foods in preventing satiation, studies have also revealed that sugar and fat can induce post-oral
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processes which stimulate food intake and food-preference (Sclafani and Ackroff, 2012). In
the central nervous system, molecular lipid sensors have been discovered, which link high fat
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diets to over-eating and/or food addiction. The peroxisome proliferator activated receptors
(PPARs) are nuclear receptors which are usually activated by intracellular lipids and regulate
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gene expression. An isoform of this molecule (PPARγ) which has been located in key regions
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of the hypothalamus that are associated with the regulation of energy balance (Sarruf et al.,
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2009) is also expressed in adipocytes, where it acts as a master regulator of adipogenesis
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(Tontonoz et al.,1994; Patel et al., 2003) and lipogenesis (Patel et al., 2003; Lehrke and Lazar, 2005). From the results of some studies (Lu et al., 2011; Ryan et al., 2011),
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researchers have deduced that central activation of PPARγ (most likely hypothalamic) result in increased food intake and the accumulation of body fat, whilst the effects of local
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administration of antagonist (Ryan et al., 2011) or neuron- specific gene deletion (Lu et al., 2011) resulted in a decrease in the consumption of diets that are high in fat. So from the fore-
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going, for any food or food constituent to stimulate or induce food addiction, it must influence at least one or more of the different peripheral or central signals that the body uses
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to maintain food and energy balance. 1.5
Flavour, taste and food preference The flavour of food which is perceived by smell, texture and/or taste is a sensation
that provides individuals with information relating to the nutritional quality of food. This sensation may also stimulate cephalic phase digestive responses which facilitate food
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utilisation, as well as induce a hedonic response that either stimulate likeness or distaste for the food, regardless of the presence (or not) of a homeostatic need for food (Smeets et al., 2010; Berthoud et al., 2011). Studies have revealed that taste stimulation acts directly on the brain reward system to drive eating behaviours, while in addition to taste cues, smell and/or texture stimuli provide conditioned reward signals (Hajnal and Norgren, 2008; Yamamoto
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and Shimura, 2008). Three basic tastes have been described with regards to food preferences;
the sweet taste of sugar, the taste for fat or lipids in some species (Khan and Besnard, 2009),
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and umami, which is the taste of glutamate and certain nucleotides that add a savoury flavour
to food (Yamaguchi and Ninomiya, 2000). While there may exist an innate preference for
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sweet, fatty and umami tastes, generally, most flavour preferences are learned (Yamamoto
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and Ueji, 2011; Sclafani and Ackroff, 2012) and can be enhanced by the postoral actions of
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sugars (Myers and Sclafani, 2001) or other nutrients. The hedonic response to the
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consumption of fat derives from an innate preference modulated by orosensory factors and learned preferences that can be modulated by postoral factors (Ackroff and Sclafani, 2010).
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Studies have revealed that in humans (Drewnowski et al., 1992) and rodents (Takeda et al., 2000; Yoneda et al., 2007a. Yoneda et al., 2007b), a conditioned flavour, taste or place-
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preference for fat exists. This preference also increases with higher concentrations of fat (Figlewicz and Benoit, 2009; Manabe et al., 2010). Some fats have also demonstrated the
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presence of a concentration-dependent conditioned place-preference (Figlewicz, 2004; Imaizumi et al., 2000) and reinforcing effect in an operant task in rodents.
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1.6
Is food addiction a disease, or the consequence of disease? Several scientists and researchers have questioned the validity of the term ‘food
addiction’, with scientific literature for and against the validity of the construct, as well as a large body of work examining the clinical presentations and neuroscience of food addiction (Randolph, 1956; Gearhardt et al., 2009, 2011a, 2011b; Davis et al., 2011; Ziauddeen and
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Fletcher, 2013; Brownell and Gold, 2013; Hebebrand et al., 2014; Pursey et al., 2015; LermaCabrera et al., 2016). While evidences for its existence and implications in humans are still evolving, the possibility of food addiction being a cause, co-morbidity or possibly a consequence of obesity is still being debated. Its relationship to the development of compulsive eating and/or obesity has also been queried (Ziauddeen and Fletcher, 2013). A
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number of researchers have suggested that while arguments and evidences showing that
obesity may indeed result from an addictive tendency to consume food (Davis and Carter,
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2009; Gearhardt et al., 2009), caution against solely attributing the development and
neurobiology of obesity to food addiction should be exercised (Volkow et al., 2012). There
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have also been suggestions that food addiction may correlate more with binge eating-
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disorder (Davis et al., 2011; Avena et al., 2012a; Gearhardt et al., 2012) which is
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characterised by excessive consumption of highly palatable food within short periods of time,
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followed by loss of control over eating (Velázquez-Sánchez et al., 2015). Rats exposed to an operant limited access to a sucrose diet have an escalation in their response to the diet and
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show excessive food intake within a short period of time (Blasio et al., 2013; Cottone et al., 2012; Velazquez-Sanchez et al., 2014).
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The conditioned place or flavour-preference paradigm has been applied widely to study the reward value of a number of drugs of abuse (Tzschentke 1998, 2007). One of the advantages
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of the paradigm is that it allows the assessment of the reward value of substances over a relatively brief exposure period, thereby rapidly offering insights into their additive
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potentials. The conditioned place preference (CPP) utilises the pairing of a conditioned stimulus (chamber) with an unconditioned stimulus (administered drug or flavour) to unmask the behavioural response to stimulation (or otherwise) of the brain reward system (Watanabe, 2013). This paradigm usually involves a two-choice test that ascertains the flavour preference for two flavours; one (the conditioned stimulus) which is paired with a nutrient that is orally
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consumed or infused via a post-oral route such as the intragastric infusion and a second flavour (the unconditioned stimulus) which is paired with a nonnutritive source ((Sclafani and Ackroff, 2012). In a rat model of binge-eating, an increased conditioned place preference, heightening of food-seeking behaviour and inflexible response to palatable food were observed (Velázquez-Sánchez et al., 2015).Presently, there is no sufficient scientific evidence
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to support the classification of food addiction as a disease entity; neither can a conclusion be reached on its precise relationship with other eating disorders. However, research into this
2.0
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area continues to unfold.
Food additives and the stimulation of the brain reward system
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The development of the food industry in the 21st century has allowed the creation and
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modification of food and food additives, resulting in the production of large quantities of
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highly-palatable foods that may have the ability to stimulate the reward centres of the brain.
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An obvious up-side to the development and use of food additives is their inherent ability to enhance food-palatability and increase the consumption of low calorie foods that on their
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own are not palatable. This has become important to food scientists and researchers who have suggested that it may be possible (through food-reformulation) to produce foods that not only
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suppress appetite, but are also desirable to eat; in a bid to influence behavioural change and facilitate the consumption of healthier low-energy foods. The possible down-side to the use
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of food additives may have been reiterated by food critics and a number of other scientists (Yang, 2010; Cargil, 2017) who are of the opinion that the inclusion of food additives (which
A
have the tendency to stimulate the reward centres and/or increase DA secretion, especially in brain regions that modulate the reward system) in foods would result in overeating and/or compulsive eating (which occur with food addiction), ultimately predisposing to obesity or binge eating disorder. However, there is a dearth of scientific literature on the possible addiction-like potential of the commonly-available food additives (when administered alone
16
or especially when added to foods) either in humans or animals. Hence, the debates for and against food additives continue. In the remaining sections of this review, we examine available scientific literature for and against the possible addictive potential of some common food additives (flavour enhancers and food sweeteners), and the implications (if any) for human health and well-being. Flavour enhancers
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2.1
Flavour is the sensory impression or biological perception of food or food substances,
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which is determined primarily by perceptions from the chemical senses of taste. The
perception of flavours depends on structure, texture and oral manipulation of food. The
U
flavour of the food can be modified with the use of flavours or flavour enhancers. Flavourants
N
or flavouring agents include all types of natural or synthetic mixtures used for impacting a
agents
are
now
available
to
the
modern
food
industry,
M
flavouring
A
defined flavour or enhancing an inherent flavour. A wide range of natural and synthetic
with monosodium glutamate and inosine monophosphate being common examples of
ED
culinary flavour enhancers. 2.1.1 Monosodium glutamate
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Monosodium glutamate (MSG), a sodium salt of glutamate, is found in various concentrations in numerous food products. Glutamate (either in the non-protein or protein-
CC E
bound forms) has been a part of culinary flavour component of human diets for many years. MSG’s effect in humans (Geha et al., 2000; He et al., 2008) and rodents have been evaluated
A
by a number of studies (Falalieieva et al., 2010; Leshchenko et al., 2012; Onaolapo OJ et al., 2011, 2015, 2016a, 2016b; Onaolapo AY et al., 2013). MSG is a widely-available culinary flavour enhancer approved by food-regulating agencies all over the world for use in improving the palatability of foods and food substances. In recent times, there have been suggestions of a possible addictive potential associated with its use; and this has continued to
17
be the focus of health and nutrition debates, and the central theme in a number of nutrition and health-related blogs (Moskin, 2008; Blaylock, 2014). MSG is the prototype of the umami taste sensation (Hayakawa and Kawai, 2003), the fifth basic taste, which evokes the taste of glutamate and similar nucleotides present in animal protein, vegetables and cured foods like cheese. Its savoury flavour (McCabe and Rolls,
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2007) has been used to improve the palatability and acceptability of a wide variety of foods
and food substances (Yamaguchi and Kumiko, 2000; Prescot, 2004) worldwide. The
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consumption of MSG has been reported to be in excess of 2.5 million tons per year, with
suggestions that this widespread use may be due to its role as a flavour enhancer as well as its
U
possible physiological and nutritional role in metabolism (Torii, 2013). The flavourenhancing property (Mathey et al., 2001) and possible low satiety value (Rogers and
A
N
Blundell, 1990) have been suggested as important factors in MSG’s potential for sustaining
M
higher energy intake (Masic and Yeoman, 2013). There have also been reports suggesting that MSG, possibly through its effects at the umami taste receptors may cause the detection of
ED
certain nutrients and therefore enhance their consumption (Bachmanov et al., 2009). Studies have however revealed that diets supplemented with MSG are associated with a long-term
PT
maintenance of stable energy intake (Schiffman et al., 1994; Essed et al., 2007), and that MSG, by its interaction with macronutrients like proteins has the potential to enhance satiety
CC E
over time (Viarouge et al., 1992). MSG has been reported to increase hedonic stimulation, hence, it may have the potential to stimulate appetite and/or food intake, and it may also help
A
to maintain stable energy levels (Yeomans, 1996; Masic and Yeomans, 2013). Debates regarding the ability of MSG to cause overeating or induce compulsive eating in predisposed individuals have continued till date, with a consensus that individuals differ in their perception of the umami or glutamate taste (Lugaz et al., 2002; Raliou et al., 2009). These variations, which may be genetic (Chen et al., 2009; Shigemura et al., 2009; Raliou et al.,
18
2009) has also been demonstrated in rodents (Ninomiya et al., 1992). However, the possible effects MSG on induction of satiety and satiation are yet to be determined (Masic and Yeomans, 2013). It is also not known if the variations in taste perception of glutamate induces or modulates glutamate preference or intake (Bachmanov et al., 2009). Also, there have been suggestions that variations in umami taste responsiveness may be associated with
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postingestive effects (Bachmanov et al., 2009) that may be mediated by different
mechanisms. Such mechanisms include nutritive value (which is dependent on the energy
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generated from its catabolism), stimulation of vagus activity, the release of hormones and
changes in gastrointestinal secretion of peptides (Niijima, 1991; Wu, 1998; Brosnan, 2000;
U
Kondoh et al., 2000).
N
While examining the influence of MSG on appetite (by studying the effects of consuming
A
soups of varying concentrations of MSG and macronutrient content) in 24 non-obese males,
M
Masic and Yeomans (2013) reported that: a) food-added MSG significantly increased palatability which was associated with a smaller decrease in hunger immediately after
ED
ingestion of soup b) there was a reduction in the feeling of fullness immediately after ingestion of the high-protein soup c) the MSG added to protein soup resulted in a lower
PT
increase in satiety compared to MSG added to carbohydrate, and no MSG added soups conditions d) the increase in hunger and the decrease in the feeling of satiety that were
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observed in the subsequent 2 hour period were significantly lower in the individuals that had MSG conditioned with the protein than the groups with no MSG added to protein soup within
A
30 and 60 min post-ingestion. They concluded that MSG may have a bi-phasic effect on appetite, a hedonic satisfaction (Yeomans, 1996, Masic and Yeomans, 2013) that reduces satiation and stimulates appetite and intake, and a potential for enhancing post-ingestive satiety, particularly in relation to protein ingestion (Masic and Yeomans, 2013).
19
MSG’s role as a flavour-enhancer ordinarily suggests that its presence in foods will enhance consumption, which may result in weight gain. However, inspite of MSG’s ability to enhance preference for itself and other flavours related to it (or elicit a conditioned preference), the reports of its effects on body weight remain conflicting. There have been studies suggesting an increase (Oleksandra et al., 2014), a decrease (Kondoh et al., 2008; Onaolapo OJ et al,
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2015, 2016a), or no effect (Onaolapo AY et al., 2012; Tordoff, et al., 2012). Studies in which MSG was administered to neonatal rats reported weight gain (Oleksandra et al., 2014). In
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studies using adult rodents, no change in body weight was observed when MSG is added to
food or water (Tordoff, et al., 2012). However, when administered by gavage, a dose-related
U
weight loss has been observed (Onaolapo OJ et al, 2015, 2016a).
N
Other issues that have been raised include the possibility of MSG inducing reward or
A
addiction (Onaolapo et al., 2017), and till date, studies continue to examine the possible
M
rewarding or addiction-like effects of oral MSG in rodents (Bachmanov et al. 2000, 2009, Ackroff et al. 2012; Ackroff and Sclafani, 2013, 2016; Onaolapo OJ et al., 2017). It has been
ED
shown that MSG has a post-oral reward component, evidenced by low MSG intakes and the lack of expression of preference for MSG, relative to water (in MSG-naïve C57BL/6J mice)
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on exposure to ascending concentrations of MSG. An increase in intake and preference across a range of MSG concentrations was also observed in MSG-conditioned C57BL/6J mice
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(Bachmanov et al. 2000; Ackroff et al. 2012). The enhancement of MSG preference (with experience) has led to suggestions that a flavour-conditioning process may be involved,
A
which could be related to the post-oral effects of MSG, which increases flavour preference due to its association with rewarding effects that are detected in the gut (Ackroff et al. 2012; Sclafani and Ackroff 2012). There are also studies that have revealed that MSG reinforces (through conditioning) preferences for its own flavour and flavours related to it (Ackroff and Sclafani, 2013). MSG (at increasing concentrations) was associated with the induction of
20
conditioned taste preference for either MSG itself or MSG-paired flavours (Bachmanov et al. 2000, 2009, Ackroff et al. 2012; Ackroff and Sclafani, 2013, 2016). Also observed in a number of these studies were the strain differences in MSG intake, preference and flavourconditioning (Ackroff and Sclafani, 2013, 2016). In a recent study, Onaolapo et al. (2017) examined the effects of oral MSG in MSG-naïve (no prior MSG exposure) and MSG-
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pretreated (administered increasing doses of MSG daily for 21 days via an oral cannula, prior
to conditioning) mice exposed to the conditioned place preference paradigm (CPP paradigm).
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The results obtained suggested that the administration of MSG was rewarding, and an
association was learnt, as both MSG-naïve and MSG-pretreated mice showed ‘MSG-paired’
U
chamber preference. However, pre-treatment with MSG potentiated MSG’s ability to induce
A
2.1.1.i Glutamate and the brain reward system
N
CPP (Onaolapo OJ et al., 2017).
M
There have been reports (Tzschentke and Schmidt, 2003; Kawasaki et al., 2005; He et al., 2014) that suggest that endogenous brain glutamate plays a role in the development and
ED
maintenance of drug addiction. This could possibly be related to its effects on processes such as reinforcement, sensitisation, reinforcement learning and habit learning (Tzschentke and
PT
Schmidt, 2003). The dopaminergic projections that link the different brain regions (VTA to the NAc, and the VTA to the PFC) are crucial pathways of the reward system, through which
CC E
many drugs of addiction act. The glutamate system is believed to have a modulatory role on the activities of the dopaminergic system in the evolution and sustenance of drug addiction
A
(Tzschentke and Schmidt, 2000). However, this does not mean that exogenous glutamate would have similar effects on the brain reward system. Researchers examining the mechanisms involved in glutamate consumption or its effect on appetite have suggested that it may be related to the chemosensory perception of its taste and/or its postingestive effects (Bachmanov et al., 2009). Consumption of MSG has been linked to a direct or indirect
21
increase in brain stimulation. Kondoh et al. (2009) demonstrated that a luminal presence of glutamate results in the stimulation of gut L-glutamate receptors that activates vagal afferent nerve fibres, which via vagal inputs then go on to stimulate brain regions (like the habenular nucleus) which exerts an influence on other regions of the brain. Functional magnetic resonance imaging and blood oxygen level dependent (BOLD) signals have shown that an
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intragastric load of MSG results in the activation of brain regions such as amygdala, insular cortex, lateral hypothalamus, medial preoptic area and the dorsomedial hypothalamus
SC R
(Tsurugizawa et al., 2009; Uematsu et al., 2009; 2010; Tsurugizawa and Torii, 2010).
Hence, the luminal presence of glutamate is linked to its ability to influence the brain regions
U
that modulate reward. However, despite the fact that some studies may have demonstrated
N
that MSG has the potential to stimulate the brain reward system, its ability to ultimately
A
induce addiction (or potentiate the addictive potential of other food macronutrients) still
M
needs further evaluation.
2.1.2 Purine nucleotides: inosine monophosphate
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Purine nucleotides like inosine monophosphate and guanosine monophosphate have both health and economic benefits in the food and biotechnology industries, where they have
PT
found value as food flavouring agents that also have nutritional and pharmaceutical properties (Ledesma-Amaro et al., 2013). The umami taste sensation is also the taste quality of inosine
CC E
monophosphate (IMP), guanosine monophosphate (GMP) and a few other L-amino acids. IMP and GMP have flavour enhancing capabilities via exerting synergistic effects in
A
enhancing the umami flavour when combined with MSG (Jinap and Hajeb, 2010). Studies have also revealed that these purine nucleotides (inosine and guanosine) have health benefits that are related to their antioxidant, cardiotonic, immunomodulatory and neuroprotective properties (Aviado, 1983; Hasko et al., 2004; Shen et al., 2005; Tsuda, 2005).
22
IMP was discovered in 1913 when it was found that the active ingredient in dried bonito (which is traditionally used amongst the Japanese to make dashi, a soup stock) was 5′inosinate (salt of 5′-inosinic acid) (Kodama, 1913; Kurihara, 2015). IMP and GMP are synthesised industrially by microbial fermentation, using either RNA extraction with subsequent breakdown into free nucleotides; or by improved metabolic biosynthesis with
IP T
excretion of the nucleosides into the culture medium, and subsequent enzymatic or chemical
phosphorylation (Ledesma-Amaro et al., 2013; 2015). In vivo, IMP is the first nucleotide to
SC R
be formed during purine synthesis and is present in nucleic acids and adenosine triphosphate, which are the body’s chemical energy store in muscles and other tissues (Watterson et al.
U
2007).
N
IMP is a colourless, odourless, white crystalline compound that is usually marketed alongside
A
MSG. IMP (like MSG) elicits the umami taste sensation in humans and rodents, via its ability
M
to stimulate gustatory cells in taste buds and interact with taste receptors like T1R1 and T1R3 heterodimers (Ninomiya et al., 2000; Nelson et al., 2002). IMP and MSG are marketed
ED
together because studies have shown that compounds that elicit umami display synergism (Kumazawa and Kurihara, 1990; Yamaguchi and Ninomiya, 2000). There is scientific
PT
evidence demonstrating that the addition of 0.5 mM IMP to MSG resulted in an increase in preference scores without significantly affecting detection thresholds in food (Schiffman et
CC E
al., 1994). Zhang et al. (2008) reported that the combination of MSG and IMP augmented the umami taste sensation via stimulation of the T1R1 and T1R3 receptors in the oral cavity. de
A
Araujo et al. (2003) showed that both compounds are recognised in the brain as the same taste. Tsurugizawa et al. (2011) reported that the gastrointestinal stimulation resulting from an intragastric load of MSG and IMP induced BOLD signals in the same brain regions, but with differences in the time course of the BOLD response. They also reported that while MSG and IMP induced BOLD signals in the lateral hypothalamus, nucleus of the solitary
23
tract and insular cortex, only MSG increased the BOLD signals in the amygdala. This observation led to the suggestion that the mechanism of perception of MSG and IMP in the gastrointestinal tract differed from that of the taste-sensing system of the oral cavity (Tsurugizawa et al., 2011). Questions regarding the possible effects of the MSG/IMP synergism on appetite and satiety
IP T
have been raised, with only a few studies examining this effect. Masic and Yeomans (2014)
concluded that in addition to increasing the flavour pleasantness of foods, a combination of
SC R
MSG/IMP (when added to a low-energy preload like a high protein diet) elicited a biphasic
effect. First, by stimulating appetite during ingestion (an appetiser effect), and secondly, by
U
enhancing postingestive satiety.
N
There is a dearth of scientific literature examining the possible rewarding or addiction-like
A
effects of IMP or MSG/IMP combinations, either in humans or rodents. However, a number
M
of studies have examined the effects of dried bonito dashi (a broth that is made from dried bonito tuna, which is frequently used in Japanese cuisine) that contains IMP amongst other
ED
amino acids. The taste component of dashi per 100g stock includes about 108 mg inosinate and glutamate (Honda et al., 2006). There are suggestions that the taste preference for dashi
PT
solution in rats is not solely linked its umami-salty taste (Kawasaki et al. 2008). The results of a conditioned taste aversion experiment in mice also revealed that the dashi flavour includes
CC E
the five recognised basic taste qualities (Delay and Kondoh 2013). There is also evidence suggesting that both olfactory and taste stimuli are needed, but not exclusive to the induction
A
of the dashi preference (Kawasaki et al. 2008) in rodents, and that post-oral nutritive feedback enhances dashi preference (Kondoh et al. 2012a, 2012b). Ackroff et al (2014) examined the effect of dashi on reward, using a series of three experiments. The first experiment showed no evidence for postoral dashi preference following an intragastric selfinfusion, while the second experiment showed an inability of the preferred dashi solution to
24
condition a preference when orally consumed. In the third experiment using taste-impaired genetically modified mice, it was observed that dashi preference in mice depended upon the Trpm5 signalling system which mediates the taste cell response to umami, sweet and bitter tastes. Although C57BL/6J mice did not acquire preferences for dashi-paired flavours, oral exposure to 0.1% inosinate enhanced subsequent dashi preference. However, the
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concentration of IMP and other umami components in dashi may not be sufficient to induce post-oral flavour conditioning (Ackroff et al., 2014). Studies using the CPP have
SC R
demonstrated that dashi is able to mediate reward only in combination with a nutritive
sweetener like dextrin (Kawasaki et al. 2011). This suggests that dashi may be an orally-
U
attractive substance without an inherent post-oral reward component. It could be deduced
N
from the foregoing that while IMP and/or MSG may be able to condition flavour or taste-
A
preference, in food, they are usually present in concentrations that are insufficient to
2.2
M
stimulate the brain reward system. However, more studies are needed to validate this theory. Food sweeteners
ED
Sweeteners are food additives which are used to impart a sweet taste in food and food substances. They elicit pleasurable sensations, in addition to providing nutritive or non-
PT
nutritive energy. Concerning their regulation, nutritive sweeteners like sucrose or sucrose substitutes (monosaccharide, disaccharide and polysaccharide polyols) are generally
CC E
recognised as safe (GRAS), or have petitions filed for GRAS. Sugar is a term that refers to sweet, soluble carbohydrates, which are food additives used to
A
sweeten food and food substances. There are different forms of sugars, with simple sugars (also known as monosaccharides) including glucose, fructose and galactose. Another type of sugar is the disaccharides, including sucrose (which is commonly available as either granulated sugar or table sugar), maltose and lactose. Oligosaccharides or polysaccharides are sugars with longer chains. Sucrose is present in all green plants, where it is an early product
25
of photosynthesis and the main agent for the translocation of carbon to the rest of the plant. In sugarcane and sugar beet, high concentrations of sugars are found which is sufficient for commercial extraction. In the last few decades, there are questions regarding the health implications of diets that are high in sugars, more especially refined sugars. Although studies examining the health impacts remain inconclusive, excessive use of sugar has been linked to
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an increased risk of cardiovascular disease (Brown et al., 2008; Stanley et al., 2009), diabetes
mellitus (Apovian, 2004; Gross et al., 2004), obesity (de Ruyter, et al., 2012), cognitive
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decline (Lakhan and Kirchgessner, 2013; Chiavaroli et al., 2014) and tooth decay (Zero et al., 2009; Jacob et al., 2016). More recently, diets that are high in sugars have been implicated in
U
the development of food addiction or specifically sugar addiction, and obesity.
N
Polyols or sugar alcohols are nutritive, low calorie, digestible carbohydrates that have been
A
associated with the addition of sweetness to foods without significantly increasing energy.
M
Polyols are obtained from the substitution of an aldehyde group with a hydroxyl (Shankar et al., 2013). Examples of polyols include hydrogenated monosaccharides (mannitol, sorbitol),
ED
hydrogenated disaccharides (isomalt, lacitol, maltitol) and hydrogenated starch hydrolysates (Shankar et al., 2013; Grembecka, 2015). There are also mixed compounds like polydextrose
PT
which is a combination of corn sugar and sorbitol. Polyols tend to occur in small quantities in animals and plants (Mäkinen, 1984). Acceptable daily intake (ADI) levels are yet to be
CC E
specified for these polyols. However, when consumed in large quantities, they have been associated with potent laxative effects and gastrointestinal symptoms like abdominal
A
discomfort, bloating and flatulence (Grabitske and Slavin, 2008; EFSA, 2011). In addition to their ability to impart a sweet taste, polyols have been shown to improve the texture, holding moisture and cooling sensation of food products in the mouth, as well as serve as preservatives (Health Canada, 2005). Polyols also have prebiotic and anti-cariogenic effects, and help with the normalisation of intestinal function (Grabitske and Slavin, 2008; EFSA,
26
2011). They have also been associated with weight loss and reduction in energy intake, due to their lower caloric value (Grabitske and Slavin, 2008). They are recommended for use in diabetics because they induce only a small increase in blood glucose or insulin secretion (Nakamura, 2005; Grabitske and Slavin, 2008; Wheeler and Pi-Sunyer, 2008; EFSA, 2011).
from about 25 to 100 %, compared with sucrose (Grembecka, 2015).
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Erythritol and xylitol are widely used as bulk sweeteners. The sweetness of polyols varies
Six non-nutritive sweeteners (acesulfame-K, aspartame, neotame, saccharin, sucralose and
SC R
stevia) with intense sweetening potential are approved and classified as generally recognised as safe (GRAS) for use in humans by the United states Food and Drug Administration (FDA)
U
and the European Food Safety Authority (FDA, 2015; EFSA, 2015). Siraitia Grosvenorii
N
Swingle Fruit Extract (SGFE) known as Luo Han Guo in Chinese, is a traditional Chinese
A
herbal-based sweetener which was also granted GRAS status by the FDA (FDA, 2014). Two
M
others which have been approved for use in other regions of the world, but not in the United States of America are alitame (approved for use in Australia, China, Mexico and New
ED
Zealand) (Ellis, 1995; Australia New Zealand Food Authority, 2002) and cyclamate ( used in over fifty countries). Non-nutritive sweeteners (NNS) are usually about 30–13000 times
PT
sweeter than sucrose (Shankar et al., 2013), and have established acceptable daily intake limit currently available for each of them. However, there are ongoing debates on the safety of
CC E
(NNS), with a number of studies examining the possible effects of the different NNS in humans or rodents (Weihrauch and Diehl, 2004; Akihisa et al., 2007; Magnuson et al., 2007;
A
Lin and Curhan, 2011; Gardner et al., 2012; Pepino et al., 2013; Liu et al., 2013; Suez et al., 2014). Aspartame is made up of two amino acid isolates (phenylalanine, aspartic acid) and methanol in a ratio of 5:4:1. It also breaks down into these components on ingestion. The central effects of aspartame have been credited to alterations in the concentrations of catecholamines
27
such as epinephrine, norepinephrine and dopamine (Coulombe and Sharma, 1986). In recent studies examining the effects of increasing doses of aspartame in mice, dose-related behavioural, biochemical and morphologic changes involving different regions of the brain (Onaolapo AY et al., 2016, 2017a, 2017b) were observed. Acesulfame-potassium (acesulfame) is a white crystalline powder and a potassium salt of 6-methyl-123-axathiazine-
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4(3H)-one 2, 2-dioxide. It has a bitter after-taste when used alone as a sweetener (Horne et al.
2002), so it is usually combined other sweeteners (sucralose or aspartame) allowing the
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sweeteners mask each other’s after-taste, with an increased sweetness derived. Acesulfame is
excreted unmetabolised in humans; therefore, in addition to being a non-caloric sweetener, it
U
does not alter potassium metabolism (ADA, 2004). Sucralose is derived from a process that
N
substitutes 3 chloride atoms for 3 hydroxyl groups on the sucrose molecule. The bulk of
A
sucralose is not metabolised in humans and as it is excreted in the faeces unchanged, and
M
while 14–20% of it is absorbed from the gastrointestinal tract, this is also excreted in the urine within 5 days (Roberts et al., 2000; John et al., 2000).
ED
2.2.1 Nutritive Sweeteners (Sugars and modified-sugars) and food addiction Food sweeteners have the ability to increase palatability and consumption of nutrient-
PT
dense foods or beverages, thereby promoting a healthy diet. However, questions continue to be raised over the possible effects of food sweeteners on appetite, satiety, brain reward
CC E
system and food addiction. Studies investigating the construct ‘sugar addiction’ have been conflicting in their reports, with some researchers and food scientists asserting that
A
consumption of high sugar diets or sugar stimulates the brain reward system in ways that are similar to drugs of addiction (Avena et al., 2008b).Whereas, others have suggested that sugar addiction does not occur in humans (Hedebrand et al., 2014; Westwater et al., 2015). Studies have shown that sugar is easily detected by the sweet taste receptors in the oral cavity, and it elicits a strong taste or flavour preference in many animals (Bachmanov et al., 2011). Also,
28
sugars can be detected by gut chemosensors, as well as chemosensors in post-absorptive sites (like liver, pancreas and brain), providing a possible source of the positive feedback signals of sugar-conditioned flavour preferences. In humans and rodents, the sweet taste sensation of sugar has been linked to stimulation of the heterodimeric T1R2+T1R3 sweet receptor which are located in taste buds on the tongue and palate (Bachmanov et al., 2011; Treesukosol et al.,
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2011). This activates an intracellular signalling mechanism that is coupled to the inositol 1,
4, 5-trisphosphate receptor 3, G protein α-gustducin phospholipase Cβ2 and the transient
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receptor potential cation channel Trpm5 (Chaudhari and Roper, 2010). Intragastric or intraduodenal infusion of sugars has been associated with a post-oral enhancement of the
U
conditioned flavour-preference in rodents (Sclafani and Glendinning, 2005) and humans
N
(Yeomans et al., 2008). Once developed, conditioned flavour-preference for sugars has been
A
observed to persist for days, and is also resistant to extinction (Myers, 2007). This suggests
M
that conditioning to sugar produces a long-lasting increase in the reward value (Sclafani and Ackroff, 2012). The mechanism by which sugars may cause or potentiate food addiction has
ED
been discussed in section 1.4.1.
In the light of studies that have demonstrated the possible deleterious metabolic effects of
PT
excessive consumption of sugar and its ability to increase the risk of addiction to foods; there has been an increase in the advocacy for the substitution of sugar with either nutritive low
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calorie sweeteners like polyols, or non nutritive sweeteners like aspartame. However, there are still debates on the possible effects that these sugar substitutes may exert on appetite and
A
satiety (or their ability to influence the brain reward system), since they also stimulate the same sweet taste receptors as sugars, and may therefore elicit the same postingestive and/or post-absorptive effects. While there is a dearth of scientific literature examining the ability of sugar alcohols to condition preferences or activate the brain reward circuit, studies have evaluated the effects
29
of polyols (xylitol, lacitol) and glucose polymers like polydextrose (PDX) on appetite and satiety (Gee and Johnson, 2005; King et al., 2005; Olli et al., 2011; Kumar et al., 2012; Ibarra et al., 2016). PDX has been shown to increase satiety when administered as a supplement about 60-90 minute before an ad libitum lunch (exerting no such effect when administered with breakfast) and it also reduces energy intake (Hull et al., 2012; Astbury et al., 2013;
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Ranawana et al., 2013). It has also been associated with enhanced satiety and satiation when
it replaced 30% of the other available carbohydrates in a diet (Konings et al., 2014).
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However, effects of supplementation of lower concentrations of PDX on appetite and satiety
were inconsistent (King et al., 2005; Schwab et al., 2006; Astbury et al., 2013). PDX is high
U
in fibre and this is believed to be partly responsible for its effects on appetite and satiety,
N
although other factors have also been considered. A recent study examining the effects of a
A
PDX-supplemented meal on appetite regulation in obese participants, reported that PDX-
M
supplemented diet enhanced satiety and reduced hunger after a high-fat diet (Olli et al., 2011).These effects were associated with stimulation of the postprandial secretion of
ED
glucagon-like peptide 1, a satiety hormone (Olli et al., 2011). Other studies have also associated PDX with increase in the secretion of glucagon-like peptide 1 and peptide YY, and
PT
lower ghrelin levels in lean men (Astbury et al., 2014). The impact of polyols on satiety and satiation has also been reported (Kumar et al., 2012). Polyols have been observed to enhance
CC E
satiety, stimulate the secretion of glucagon-like peptide1, and increase acute postprandial concentrations of plasma peptide YY (Massimino et al., 1998; Gee and Johnson, 2005;
A
Lesniewska et al., 2006). Polyols also delay gastric emptying, which has been suggested to be partly responsible for their effects on satiety. 2.2.2 Non-Nutritive Sweeteners and food addiction There is increasing evidence to suggest that artificial sweeteners (like aspartame and saccharin) activate the food reward circuit, using pathways that differ from those used by
30
sugar and other natural sweeteners. NNS are low calorie sweeteners, so this could possibly eliminate the postingestive component (Yang, 2010) that is dependent on metabolic products of the food (Sclafani and Ackroff, 2004). Therefore, NNS activate the gustatory component of the reward pathway differently from caloric sweeteners. The ingestion of sucrose (compared to saccharin) was associated with an increased activation of higher gustatory areas
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like the orbitofrontal cortex, insula and amygdala (Haase et al., 2009). Imaging studies comparing the effects of sucrose and sucralose on central taste pathways demonstrated that
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although both sucrose and sucralose activated primary taste pathways, sucrose elicits a
stronger brain response in the anterior insula, frontal operculum, striatum and anterior
U
cingulate, compared to sucralose (Frank et al., 2008). Also, only sucrose stimulates
N
dopaminergic midbrain areas, suggesting that the brain probably distinguishes caloric from
A
non-caloric sweeteners (Frank et al., 2008). Functional imaging studies (in male subjects with
M
normal weight) following sucralose ingestion also revealed an absence of the prolonged hypothalamic signal depression that was observed with glucose ingestion (Smeets et al.,
ED
2005). The results obtained from a human study also suggested that habitual use of NNS was associated with alterations in reward-processing of sweet taste and modulation of
PT
consumption (Green and Murphy, 2012). Rudenga and Small (2012) also tested the hypothesis that sweet taste may produce a differential response in brain regions that signal the
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post-ingestive effects of flavours. They observed an inverse relationship between amygdala response to sucrose and artificial sweetener use, and a trend towards a similar effect in the
A
insula. These findings also support suggestions that experiencing sweet taste without calories degrades the predictive capacity of sweet sensation in the amygdala and insula (Davidson and Swithers, 2004). Studies have evaluated the effect of NNS on appetite, satiety and weight, with conflicting reports. There have been suggestions that because NNS are sweet, they could potentiate
31
sugar-craving and sugar dependence (Yang, 2010) leading to overeating and weight gain. A number of studies have suggested that acute administration of NNS in vehicles that are energy deficient (water or chewing gum) result in an increase in hunger compared to vehicle alone (Black et al., 1993; Blundell and Hill, 1986; Rogers et al., 1988; Tordoff et al., 1990). However, when administered with high energy vehicle, no alteration of hunger, relative to
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vehicle alone or vehicle sweetened with sucrose (Rolls et al., 1989; Maone et al., 1990; Drewnowski et al., 1994) was observed. Some studies have however suggested that low
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calorie NNS neither promote nor suppress appetite (Bellisle and Drewnowski 2007; Renwick and Molinary, 2010). A study evaluating the effects of NNS-containing beverages (compared
U
to sugar-sweetened beverages) on satiety, reported no difference in satiety ratings in children
N
over an 18-month intervention trial (de Ruyter et al. 2013); similar effects were observed in
A
adults in another study (Anton et al., 2010). Studies in rodents have also demonstrated
M
preference for non nutritive sweeteners like stevia compared to water (Martínez et al., 2016), and conditioned flavour preference; although preference for nutritive sweeteners exceeded
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that observed for NNS (Sclafani and Ackroff, 2017). From the foregoing it can be said that NNS do not elicit the same effects on appetite, satiety, conditioned preferences or the brain
PT
reward circuit as observed with sugars. Also, they are not likely to potentiate the effects of
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other foods or food substances. Conclusion
In conclusion, while the validity of the concept of food addiction continues to be debated,
A
studies have continued to show that deliberate alterations in the composition of foods can change the behavioural response to their consumption, due to differences in sensory perception. However, the scientific evidences in support of food addiction are not yet sufficient to categorically state that any particular food ingredient, micronutrient or standard food-additive is addictive.
32
Therefore, research needs to focus more on understanding the mechanisms by which food constituents may modulate the brain response to their consumption. Also, the probable longterm changes (in brain chemistry and structure) that may accompany the consumption of
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certain foods or food-additives need to be further investigated.
Acknowledgement
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This research did not receive any specific grant from agencies in the public, commercial, or not-for-profit sectors.
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Conflict of interest:
Onaolapo AY declares no conflict of interest related to the content of this manuscript.
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Onaolapo OJ declares no conflict of interest related to the content of this manuscript.
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Ethical statement
This article does not contain any studies with human participants performed by any of the authors. All studies
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referenced in this article performed by the authors using animal were in compliance with international, national,
A
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and/or institutional guidelines for the care and use of animals.
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297. Figure legends Figure 1: Can food additives in food stimulate the brain reward circuit resulting in food addiction? Does eating excessively potentiate the reward system that includes the substantia
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nigra (SNc) and the ventral tegmental area (VTA) enough to perpetuate food addiction?
Figure 2: The regulation of food intake involves a balance between homeostatic factors
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(regulated by energy stores and energy demands) and hedonic influences (consumption
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motivated by reward systems).
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S0928-4680(17)30175-X https://doi.org/10.1016/j.pathophys.2018.04.002 PATPHY 939
To appear in:
Pathophysiology
Received date: Revised date: Accepted date:
2-12-2017 26-2-2018 7-4-2018
Please cite this article as: Onaolapo AY, Onaolapo OJ, Food additives, food and the concept of ‘food addiction’: Is stimulation of the brain reward circuit by food sufficient to trigger addiction?, Pathophysiology (2010), https://doi.org/10.1016/j.pathophys.2018.04.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Food additives, food and the concept of ‘food addiction’: is stimulation of the brain reward circuit by food sufficient to trigger addiction?
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Onaolapo AY1 and Onaolapo OJ2*
Behavioural Neuroscience/Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of
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Technology, Ogbomoso, Oyo State, Nigeria. [email protected],
Behavioural Neuroscience/Neuropharmacology Unit, Department of Pharmacology, Ladoke Akintola University
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of Technology, Osogbo, Osun State, Nigeria. [email protected].
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*Corresponding Author:
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Graphical abstract
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Abstract In the last few years, the concept of ‘food addiction’ has continued to gain popularity, with human and animal studies demonstrating the differential effects of foods that are high in fat,
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sugar or protein on appetite, satiety, eating behaviour and the development of food addiction. However, a number of studies have disputed the occurrence of food addiction in humans.
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Questions have also arisen regarding the possible impacts that food additives may have on the development of food addiction or eating disorders. Also, it is known that alterations in food
composition and the presence of food additives (flavour enhancers, sugars, sugar substitutes,
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and non-nutritive sweeteners) are factors that generally influence the sensory perception of
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food. Our understanding of the potential roles of central neurotransmitters (such as
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dopamine) and certain neuropeptides in the evolution of food addiction is also evolving; but
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presently, there isn’t sufficient scientific evidence to consider any food ingredient, micronutrient or standard food-additive as addictive. In this review, the relevant literatures
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dealing with the concept of ‘food addiction’ are examined, and the factors which may
sugars,
sugar
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predispose to food addiction are discussed. The possible influences that flavour-enhancers, substitutes
and
non-nutritive
sweeteners
may
exert
on
central
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neurotransmission, neurotransmitter/receptor interactions, appetite, satiety, conditionedpreferences and the brain reward system are also highlighted.
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Keywords: Brain reward system; Conditioned preference; Food addiction; Flavour enhancer; Food sweeteners; Overeating
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1.0
Introduction
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‘Food addiction’ is a behavioural addiction that is characterised by compulsive
consumption of palatable foods, which is associated with activation of the brain reward system in humans and animals (Olsen, 2011; Hebebrand et al., 2014). It has also been defined as a clinically-significant physical and/or psychological dependence on high sugar, high fat,
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and highly-palatable foods (Brownell and Gold, 2012, 2013). Over the last few years, the concept of food addiction has become increasingly popular and this is reflected not only in
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the volume of media reports and health blogs (Marlow, 2013; Avena and Talbott, 2014; Tarman and Werdell, 2014) but also in a substantial increase in scientific literature (Corwin
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and, Grigson, 2009; Gearhardt et al., 2011a; Krashes and Kravitz, 2014; Muele, 2015; Schulte
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et al., 2016) dedicated to the topic. Addiction to food has been implicated in foodcraving/bingeing and is also considered an important predisposing factor to obesity (Davis et
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al., 2011; Gearhardt et al., 2011a; Schulte et al., 2016). An ‘addictive’ food, nutrient, or food ingredient is believed to possess an inherent ability to induce dependence (Hebebrand et al.,
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2014). Hence, the concept of food addiction is based on the idea that certain foods (or their additives) may have addictive potentials (Muele, 2015). Human and animal studies have
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continued to report the differential effects of high-fat, high-sugar or high-protein diet on eating behaviour (Avena et al., 2008a, 2008b; Avena et al., 2012a; Schulte et al., 2015;
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Tulloch et al., 2015; Schulte et al., 2016) and brain neurotransmitter chemistry (Bocarsly et al., 2010). A number of rodent studies have also demonstrated the effects of exposure to
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sugars, fats and highly-palatable diets on food-preferences, brain-reward functioning and the risk for obesity (Avena et al., 2008a, 2008b, 2012a; Johnson and Kenny, 2010; Borengasser et al., 2014). Genetic traits that may predispose to food addiction have also been studied (Velázquez-Sánchez et al., 2014).
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Food additives are substances that are added to foods or drinks to maintain/enhance safety, freshness, texture, appearance, taste or flavour (WHO, 2017). For centuries, humans have used salt to preserve meats and fish, herbs and spices to enhance food flavour and sugars to preserve fruits. However, in recent times, the list of indications for food additives is expanding and they are increasingly being used to make food safe, stable, nutritious,
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convenient, colourful, flavourful and affordable. Hence, different types of food additives have been (and are still being) developed to meet the growing demands of the food industry.
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Food additives can be synthetic or derived from plants/animals, and they have been grouped
by the World Health Organisation and the Food and Agricultural Organisation into three
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broad categories (Flavour enhancers, Enzymes and Others), which are based on their function
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(WHO, 2017). Flavour enhancers constitute the majority of additives used in foods and they
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include salt and monosodium glutamate. Enzyme preparations include additives which may
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be naturally-occurring proteins or synthetic compounds which assist in breaking down larger molecules into their smaller building blocks, such as yeasts used in improving the dough or
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for alcohol fermentation. Other additives include nutritive (sugars) or non-nutritive (aspartame and saccharin) sweeteners and food preservation/colouring agents.
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Recently, interests in the potential associations of food additives, processed foods and food addiction have increased (Morris et al., 2008; Cocores and Gold, 2009; Blaylock, 2014), with
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suggestions that consumption of highly-processed foods promotes food addiction (Johnson and Kenny, 2010; Gearhardt et al., 2011b). These suggestions are related to the fact that
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while many food ingredients lack intoxication capacity, studies have shown that certain foods or their additives (e.g saccharin) appear to induce reinforcement behaviours that are similar to or possibly exceed those associated with drugs of abuse (Lenoir et al., 2007; Gearhardt et al., 2011b). Also, in similarity to drugs of abuse, they may trigger addiction-like neuroadaptive responses in the brain reward circuits (Johnson and Kenny, 2010). Again, highly-processed
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foods may have been altered in ways similar to addictive drugs (Gearhardt et al., 2011b) and certain formulations of processed foods have been designed to maximise palatability and/or reward (Spence, 2012). However, a number of researchers are of the opinion that while there are speculations regarding the factors that are present in foods which may stimulate addiction, there isn’t sufficient scientific evidence yet to consider any food ingredient, micronutrient or
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standard food-additive as addictive (Hebebrand et al., 2014). In this review, we highlight the results of studies on the possible addictive potential of selected food additives (culinary
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flavour enhancers and food sweeteners) by examining the relevant scientific literature on the associations that exist among factors such as food, food additives, the brain reward system
1.1
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and food addiction. Food and food addiction
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The construct “food addiction” was first introduced by T.G. Randolph in 1956,
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around a period when addictive-like consumption of wheat, corn, potatoes, chocolate, coffee, milk and eggs were reported (Randolph, 1956). However, in recent years, this construct has
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become popular because it helped to understand the influences that psychological factors could exert on weight gain (Brownell and Gold, 2013), especially following an increase in the
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prevalence of obesity in the United States of America (and world-wide) in the last few decades (Finucane et al., 2011; Ogden et al., 2012). Food addiction is not currently
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recognised as a disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM5). However, studies evaluating the occurrence of food addiction in humans (Flint et al.,
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2014; Pursey et al., 2015) have utilised the Yale Food Addiction Scale (YFAS), a validated and reliable instrument based primarily on the diagnostic criteria for substance dependence in the DSM-IV-TR (APA. 2000) which measures behavioural indicators of eating disorders (Gearhardt et al., 2009). Despite the fact there is a paucity of population-based prevalence rates for food addiction, studies in subjects not diagnosed with an eating disorder had
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reported prevalence rates of 5 to 26% (Ziauddeen and Fletcher, 2013); while in studies that have included subjects with a diagnosed eating disorder, higher rates of food addiction have been reported (Pursey et al., 2014). There are growing interests in defining the roles played by the food reward system in regulating food intake, as well as the possible links that may exists between this system and
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the development of food addiction in humans. In recent times, questions have also arisen
about the roles played by food additives like sugars, non-nutritive sweeteners and culinary
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flavour enhancers in modulating the food reward towards food addiction (figure 1). Studies in laboratory animals have suggested the presence of homeostatic factors that control energy
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intake and energy demand, in effect precisely modulating body weight over prolonged
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periods of time (Woods, 2009). A few other studies have also reported that the hedonic
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properties of food may influence feeding beyond the daily energy requirements, in essence
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possibly contributing to weight gain and obesity (Kenny, 2011). The regulation of food intake (figure 2) has been demonstrated to involve strong associations
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that exist between homeostatic and non-homeostatic factors, the balance of which ensures the maintenance of body weight (Hagan and Niswender, 2012). The homeostatic control
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(regulated by energy stores and energy demands) which mediates how much food an individual consumes is usually subject to non-homeostatic or hedonic (consumption
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motivated by reward systems) influences. It has been observed that reward-related signals can override homeostatic signals, essentially contributing to the consumption of more foods
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above the body’s immediate energy requirement (Begg and Woods, 2013; Alonso-Alonso et al., 2015). In last few decades, the consumer response to the availability of high-energy and/or highly-palatable foods may be a reflection of the influences that such reward-related signals can exert.
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The additive potential of some foods and food substances may be comparable to that of common drugs of abuse (like cocaine, marijuana and methamphetamine) whose use is characterised by episodes of negative consequences (abuse) and physiological dependence (Alonso-Alonso et al., 2015). These drugs are known to enhance
dopamine release (from
dopaminergic neurons in the ventral tegmental area) to brain regions that are associated with
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the reward system, such as the prefrontal cortex, amygdala and the nucleus accumbens. In the
brain reward system, the patterns of neural responses associated with palatable foods have
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been shown to be similar to those associated with drugs of abuse (Ahmed et al., 2002; Kalivas and O'Brien, 2008; Janes et al., 2010). Similarly, palatable or highly-processed foods
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have reinforcing effects which may be mediated by dopamine’s influences on the brain
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reward system (Alonso-Alonso et al., 2015). Also, palatable foods have been observed to
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activate reward-learning regions of the brain, as well as dopamine signalling (Small et al., 2003). Repeated intake of foods that are high in sugar is associated with increased D1
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receptor binding (in the shell and core of the NA) and increased μ-opioid receptor binding in
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the cingulate cortex, hippocampus, accumbens shell and locus coeruleus; changes which are similar to those associated with a number of drugs of abuse (Colantuoni et al., 2001). A
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down-regulation of post-synaptic D2 receptors in the nucleus accumbens shell and dorsal striatum (as seen in drug addicts) had also been reported in animals that were fed high-
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fat/sugar foods (Johnson and Kenny, 2010; Bello et al., 2002; Stice et al., 2010a). The exposure of obese subjects to palatable food cues has also been associated with hyper-
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responsiveness in the reward-related brain regions (Stoeckel et al., 2008; Stice et al., 2010b). From the aforegoing, dopamine is linked to the reinforcing effects of food, and studies have demonstrated that food consumption results in striatal (dorsal) dopamine release with the degree of pleasure derived from eating correlating positively with the quantity of dopamine released (Small et al., 2003). Administration of dopamine antagonists has also been
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associated with increased food intake and weight gain, while dopamine agonists cause a reduction in food intake and an ensuing weight loss (Epstein et al., 2007). Neuropeptides (orexigenic and anorexigenic) which are involved in the regulation of food consumption and metabolism have also been evaluated for their roles in the neurobiological responses of drug and alcohol-dependence (Thiele et al., 2003; Barson and Leibowitz, 2016).
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The brain expression of these neuropeptides has been reported to be altered following bingelike consumption of palatable foods (Alcaraz-Iborra et al., 2014) or drugs (Navarro et al.,
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2008; Carvajal et al., 2015). Central administration of Agouti-related peptide (a melanocortin
receptor antagonist) activates midbrain dopamine neurons and induces consumption of fat
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and sugar-enriched foods (Davis et al., 2011). Ghrelin, leptin and insulin are homeostatic
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regulators of food intake and via their influences on the dopaminergic systems, they mediate
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between the homeostatic and hedonic mechanisms of food intake (Kenny, 2011; Egecioglu et
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al., 2011; Hebebrand et al., 2014).With the discovery of leptin receptors expression on midbrain dopamine neurons (Elmquist et al., 1998), there have been suggestions that
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mesolimbic dopamine pathways could also mediate the effect of leptin on food intake (Lerma-Cabrera, et al., 2016).
Anatomy of the brain reward system
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1.2
The brain reward system is made up of a group of neurons, nerve cells and brain
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nuclei that are involved in the modulation and control of associative learning, pleasure and incentive salience (Berridge, 2012; Berridge and Kringelbach, 2015; Schultz, 2015). Reward
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is the ability of an object to stimulate appetitive or approach behaviour, choices and emotional behaviour (Schultz, 2015). The association between a feeling of reward and substance use has been linked to the reason why humans use these substances, or why laboratory animals self-administer them (Wise, 2009). The rewarding effects of substances have been linked to their ability to increase dopamine (DA) secretion in the brain regions that
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mediate reward (especially in the nucleus accumbens) (Di Chiara and Imperato, 1988; Nestler et al., 2004); although studies have also demonstrated that DA’s role in reward does not usually equate with hedonic responses which are mediated partly by endogenous opioids and cannabinoids. The neural circuitry tasked with the mediation of reward and/or addiction involves a network of brain regions that continues to evolve in number and/or complexity
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(Wise and Koob, 2014).
Brain regions that constitute the reward system are located primarily within a cortico-basal
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ganglia-thalamo-cortical loop (Yager et al., 2015), which modulates the development and
maintenance of addiction (Nestler, 2013, van Huijstee and Mansvelder, 2014). DA neurons in
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the ventral tegmental area (VTA) of the midbrain are very important (Lammel et al. 2012),
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because they form strong reciprocal connections with several other brain regions like the
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nucleus accumbens, lateral hypothalamus, and prefrontal cortex (Calabresi et al. 2007; Luo et
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al., 2015). The striatum (dorsal striatum and nucleus accumbens) is also very important in the reward pathway, as it serves as the main integration site for the cortico-basal ganglia-thalamic
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circuitry by receiving a variety of inputs. It receives GABAergic inputs from striatal interneurons (Dautan et al., 2014), cholinergic inputs from the interneurons of the striatum
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and brainstem (Yager et al., 2015), as well as dopaminergic inputs from the VTA (Swanson, 1982) and the substantia nigra (Yager et al., 2015). It also receives glutamatergic inputs from
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the prefrontal cortex, amygdala, hippocampus and thalamus (Finch, 1996, Britt et al., 2012). For a detailed discussion on the brain reward system, see Berridge and Kringelbach (2015)
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and Schultz (2015). 1.3
The food reward system Intrinsically, eating has rewarding and reinforcing effects, and studies have
demonstrated that food consumption activates the regions associated with reward in the brain (Hebebrand et al., 2014). However, food consumption is regulated by a neural circuitry that
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includes the dorsolateral prefrontal cortex, striatum, amygdala, midbrain and the hypothalamus (Berthoud, 2011). Together, these systems regulate all aspects of feeding behaviour, including both homeostatic and hedonic food consumption (Hebebrand et al., 2014). The food reward system consists of at least of two parts, a sensory and/or a postingestive component (Avena et al., 2008a, 2008b). Gustatory information (usually
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perceived by the taste receptors) send signals that ascend through the thalamus, terminating in the orbitofrontal cortex and anterior insula/frontal operculum (Kobayakawa et al.,1999;
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Small, 2006); while the amygdala makes reciprocal connections at all levels of the gustatory
pathway (Yang, 2010). Mesolimbic DA system also aids the hedonic recognition of the
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stimulus and satiation that follow consumption of palatable foods (Goldstein and Volkow,
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2002; Haltia et al., 2007; Stice et al., 2008).
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Imaging studies have revealed an increased activation in the lateral orbitofrontal cortex,
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insula, amygdala, frontal operculum and striatum in anticipation of palatable food (Stice et al., 2008) and in response to pictures of palatable foods (Rothmund et al., 2007; Stoeckel et
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al., 2008) in obese compared to control subjects. In humans (unlike laboratory animals), the influence of cognition and executive functioning influences behavioural drives for palatable
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food. This executive functioning support self-regulation of eating and have been mapped to brain regions which include the dorsolateral prefrontal cortex, the dorsal anterior cingulate,
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and the parietal cortex (Alonso-Alonso et al., 2015). 1.4
Food, food constituents and food consumption
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Foods and/or food constituents have been shown to have varying abilities for
induction of satiation. Studies have reported that foods that are high in dietary protein tend to increase the perception of satiety (Labayen et al., 2004; Schoeller and Buchholz, 2005; Luhovyy et al., 2008; Thomas and Chapman, 2008). Several studies have also reported that foods that are high in protein are less liked than low-protein foods (Johnson and Vickers,
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1992; Vanderwater and Vickers, 1994). High-protein foods have also been shown to produce an increase in sensory-specific satiety, compared to low-protein foods (Johnson and Vickers, 1992; Vanderwater and Vickers, 1994; Sivertsen et al., 2010). Sugar- and fat-rich foods are highly palatable, and studies have shown that foods rich in sugar and/or fat can promote overeating (Berthoud, 2011; Egecioglu et al., 2011; Ryan et al., 2012).
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The ability of sweet taste and fatty flavour to activate the brain reward systems and promote
food consumption has been demonstrated by a number of animal studies (Hajnal and
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Norgren, 2008; Liang et al., 2006). Also, the ability of these foods to cause obesity in rodents
has been observed (Sclafani, 1993; Speakman et al., 2008). It is now generally accepted that
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food can be made more palatable by: the addition of biopolymers like transglutaminase
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(which improves food texture), adding soy protein sauce or carrageenan mix, varying the fat
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content (Muguruma et al., 2003; Pietrasik and Duda, 2000), addition of flavour enhancers
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{like monosodium glutamate, inosine-5-monophosphate (IMP-5) (Bellisle, 1999; Yamaguchi and Ninomiya, 2000) and sodium guanoate}, or food sweeteners like non-nutritive
1.4.1
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sweeteners.
How do high-fat/high-sugar diets promote overeating and/or food addiction?
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There have been reports showing that foods that are rich in sugar and/or fats can stimulate segments of the reward system (including taste receptors, postingestive signals and
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neuropeptide systems) enough to result in overeating or binge eating. A number of rodent studies have also demonstrated that foods that are rich in both sugar and fat stimulate
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excessive eating. Consumption of foods that are high in sugar has been associated with increased secretion of DA and acetylcholine (ACH) in the nucleus accumbens (Avena et al., 2012b). Increasing palatability of food or food constituents (as it occurs with high-sugar or high-fat diets) has also been associated with a reduction in the effectiveness with which intestinal and post-absorptive satiation signals suppress food intake (Sclafani, 2013). Johnson
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and Kelly (2010) also demonstrated that excessive intake of highly-palatable food results in a down-regulation of the expression of striatal D2 receptors. The body controls food intake and energy expenditure by a series of impulses which include satiation. Satiation represents a cumulation of the inhibitory signals that are induced by the ingestion of food substances. These signals may be cognitive, digestive, sensory or hormonal.
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Satiation results in a feeling of being full and ultimately signals the end of a meal (Woods and D'Alessio, 2008). The duration or intensity of satiety that follows a meal and persists
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until hunger pangs begin is also modulated by various signals which form part of the satiety cascade (Blundell et al., 1993). Studies have shown that sensory and cognitive processes
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interact with post ingestive and post absorptive peripheral and central mechanisms that help
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to maintain satiety. Satiation signals generally reflect the nutrient and caloric content of a
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meal. The gut peptides involved in the induction of satiation include cholecystokinin,
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enterostatin, amylin, glucagon-like peptide, peptide tyrosine-tyrosine, apolipoprotein A-IV, glucagon, oxyntomodulin and members of the bombesin family of peptides (Moran, 2004;
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Woods and D’Alessio, 2008).
In addition to satiation signals, there are also adiposity signals which in conjunction with
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satiation signals modulate food intake and metabolism. Adiposity signals reflect the amount of stored body fat, insulin which is secreted by the pancreatic β-cells and leptin secreted from
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adipocytes; with both insulin and leptin correlating with the body’s total adiposity and energy store (Polonsky et al., 1988; Frederich et al., 1995; Schwartz et al., 1996). Increased flux of
A
insulin or leptin stimulates receptors in the hypothalamus and other brain regions to reduce food intake (Woods et al., 1979; Brief and Davis, 1984; Seeley et al., 1996); while a reduction of adiposity-signalling in the brain (in experimental animals) has been associated with hyperphagia (Cohen et al., 2001; Obici et al., 2002). Adiposity signals (unlike satiation signals) exert long-lasting effects spanning several meals or days, and stabilising adipose
12
stores (Ryan et al., 2012). Studies have shown that chronic exposure to foods that are high in fat raises the body’s adiposity and satiation threshold, such that higher levels of signals are required to suppress feeding (Ryan et al., 2012). Apart from the direct effects of palatable flavours of high-sugar and high-fat foods in preventing satiation, studies have also revealed that sugar and fat can induce post-oral
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processes which stimulate food intake and food-preference (Sclafani and Ackroff, 2012). In
the central nervous system, molecular lipid sensors have been discovered, which link high fat
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diets to over-eating and/or food addiction. The peroxisome proliferator activated receptors
(PPARs) are nuclear receptors which are usually activated by intracellular lipids and regulate
U
gene expression. An isoform of this molecule (PPARγ) which has been located in key regions
N
of the hypothalamus that are associated with the regulation of energy balance (Sarruf et al.,
A
2009) is also expressed in adipocytes, where it acts as a master regulator of adipogenesis
M
(Tontonoz et al.,1994; Patel et al., 2003) and lipogenesis (Patel et al., 2003; Lehrke and Lazar, 2005). From the results of some studies (Lu et al., 2011; Ryan et al., 2011),
ED
researchers have deduced that central activation of PPARγ (most likely hypothalamic) result in increased food intake and the accumulation of body fat, whilst the effects of local
PT
administration of antagonist (Ryan et al., 2011) or neuron- specific gene deletion (Lu et al., 2011) resulted in a decrease in the consumption of diets that are high in fat. So from the fore-
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going, for any food or food constituent to stimulate or induce food addiction, it must influence at least one or more of the different peripheral or central signals that the body uses
A
to maintain food and energy balance. 1.5
Flavour, taste and food preference The flavour of food which is perceived by smell, texture and/or taste is a sensation
that provides individuals with information relating to the nutritional quality of food. This sensation may also stimulate cephalic phase digestive responses which facilitate food
13
utilisation, as well as induce a hedonic response that either stimulate likeness or distaste for the food, regardless of the presence (or not) of a homeostatic need for food (Smeets et al., 2010; Berthoud et al., 2011). Studies have revealed that taste stimulation acts directly on the brain reward system to drive eating behaviours, while in addition to taste cues, smell and/or texture stimuli provide conditioned reward signals (Hajnal and Norgren, 2008; Yamamoto
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and Shimura, 2008). Three basic tastes have been described with regards to food preferences;
the sweet taste of sugar, the taste for fat or lipids in some species (Khan and Besnard, 2009),
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and umami, which is the taste of glutamate and certain nucleotides that add a savoury flavour
to food (Yamaguchi and Ninomiya, 2000). While there may exist an innate preference for
U
sweet, fatty and umami tastes, generally, most flavour preferences are learned (Yamamoto
N
and Ueji, 2011; Sclafani and Ackroff, 2012) and can be enhanced by the postoral actions of
A
sugars (Myers and Sclafani, 2001) or other nutrients. The hedonic response to the
M
consumption of fat derives from an innate preference modulated by orosensory factors and learned preferences that can be modulated by postoral factors (Ackroff and Sclafani, 2010).
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Studies have revealed that in humans (Drewnowski et al., 1992) and rodents (Takeda et al., 2000; Yoneda et al., 2007a. Yoneda et al., 2007b), a conditioned flavour, taste or place-
PT
preference for fat exists. This preference also increases with higher concentrations of fat (Figlewicz and Benoit, 2009; Manabe et al., 2010). Some fats have also demonstrated the
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presence of a concentration-dependent conditioned place-preference (Figlewicz, 2004; Imaizumi et al., 2000) and reinforcing effect in an operant task in rodents.
A
1.6
Is food addiction a disease, or the consequence of disease? Several scientists and researchers have questioned the validity of the term ‘food
addiction’, with scientific literature for and against the validity of the construct, as well as a large body of work examining the clinical presentations and neuroscience of food addiction (Randolph, 1956; Gearhardt et al., 2009, 2011a, 2011b; Davis et al., 2011; Ziauddeen and
14
Fletcher, 2013; Brownell and Gold, 2013; Hebebrand et al., 2014; Pursey et al., 2015; LermaCabrera et al., 2016). While evidences for its existence and implications in humans are still evolving, the possibility of food addiction being a cause, co-morbidity or possibly a consequence of obesity is still being debated. Its relationship to the development of compulsive eating and/or obesity has also been queried (Ziauddeen and Fletcher, 2013). A
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number of researchers have suggested that while arguments and evidences showing that
obesity may indeed result from an addictive tendency to consume food (Davis and Carter,
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2009; Gearhardt et al., 2009), caution against solely attributing the development and
neurobiology of obesity to food addiction should be exercised (Volkow et al., 2012). There
U
have also been suggestions that food addiction may correlate more with binge eating-
N
disorder (Davis et al., 2011; Avena et al., 2012a; Gearhardt et al., 2012) which is
A
characterised by excessive consumption of highly palatable food within short periods of time,
M
followed by loss of control over eating (Velázquez-Sánchez et al., 2015). Rats exposed to an operant limited access to a sucrose diet have an escalation in their response to the diet and
ED
show excessive food intake within a short period of time (Blasio et al., 2013; Cottone et al., 2012; Velazquez-Sanchez et al., 2014).
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The conditioned place or flavour-preference paradigm has been applied widely to study the reward value of a number of drugs of abuse (Tzschentke 1998, 2007). One of the advantages
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of the paradigm is that it allows the assessment of the reward value of substances over a relatively brief exposure period, thereby rapidly offering insights into their additive
A
potentials. The conditioned place preference (CPP) utilises the pairing of a conditioned stimulus (chamber) with an unconditioned stimulus (administered drug or flavour) to unmask the behavioural response to stimulation (or otherwise) of the brain reward system (Watanabe, 2013). This paradigm usually involves a two-choice test that ascertains the flavour preference for two flavours; one (the conditioned stimulus) which is paired with a nutrient that is orally
15
consumed or infused via a post-oral route such as the intragastric infusion and a second flavour (the unconditioned stimulus) which is paired with a nonnutritive source ((Sclafani and Ackroff, 2012). In a rat model of binge-eating, an increased conditioned place preference, heightening of food-seeking behaviour and inflexible response to palatable food were observed (Velázquez-Sánchez et al., 2015).Presently, there is no sufficient scientific evidence
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to support the classification of food addiction as a disease entity; neither can a conclusion be reached on its precise relationship with other eating disorders. However, research into this
2.0
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area continues to unfold.
Food additives and the stimulation of the brain reward system
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The development of the food industry in the 21st century has allowed the creation and
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modification of food and food additives, resulting in the production of large quantities of
A
highly-palatable foods that may have the ability to stimulate the reward centres of the brain.
M
An obvious up-side to the development and use of food additives is their inherent ability to enhance food-palatability and increase the consumption of low calorie foods that on their
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own are not palatable. This has become important to food scientists and researchers who have suggested that it may be possible (through food-reformulation) to produce foods that not only
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suppress appetite, but are also desirable to eat; in a bid to influence behavioural change and facilitate the consumption of healthier low-energy foods. The possible down-side to the use
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of food additives may have been reiterated by food critics and a number of other scientists (Yang, 2010; Cargil, 2017) who are of the opinion that the inclusion of food additives (which
A
have the tendency to stimulate the reward centres and/or increase DA secretion, especially in brain regions that modulate the reward system) in foods would result in overeating and/or compulsive eating (which occur with food addiction), ultimately predisposing to obesity or binge eating disorder. However, there is a dearth of scientific literature on the possible addiction-like potential of the commonly-available food additives (when administered alone
16
or especially when added to foods) either in humans or animals. Hence, the debates for and against food additives continue. In the remaining sections of this review, we examine available scientific literature for and against the possible addictive potential of some common food additives (flavour enhancers and food sweeteners), and the implications (if any) for human health and well-being. Flavour enhancers
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2.1
Flavour is the sensory impression or biological perception of food or food substances,
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which is determined primarily by perceptions from the chemical senses of taste. The
perception of flavours depends on structure, texture and oral manipulation of food. The
U
flavour of the food can be modified with the use of flavours or flavour enhancers. Flavourants
N
or flavouring agents include all types of natural or synthetic mixtures used for impacting a
agents
are
now
available
to
the
modern
food
industry,
M
flavouring
A
defined flavour or enhancing an inherent flavour. A wide range of natural and synthetic
with monosodium glutamate and inosine monophosphate being common examples of
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culinary flavour enhancers. 2.1.1 Monosodium glutamate
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Monosodium glutamate (MSG), a sodium salt of glutamate, is found in various concentrations in numerous food products. Glutamate (either in the non-protein or protein-
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bound forms) has been a part of culinary flavour component of human diets for many years. MSG’s effect in humans (Geha et al., 2000; He et al., 2008) and rodents have been evaluated
A
by a number of studies (Falalieieva et al., 2010; Leshchenko et al., 2012; Onaolapo OJ et al., 2011, 2015, 2016a, 2016b; Onaolapo AY et al., 2013). MSG is a widely-available culinary flavour enhancer approved by food-regulating agencies all over the world for use in improving the palatability of foods and food substances. In recent times, there have been suggestions of a possible addictive potential associated with its use; and this has continued to
17
be the focus of health and nutrition debates, and the central theme in a number of nutrition and health-related blogs (Moskin, 2008; Blaylock, 2014). MSG is the prototype of the umami taste sensation (Hayakawa and Kawai, 2003), the fifth basic taste, which evokes the taste of glutamate and similar nucleotides present in animal protein, vegetables and cured foods like cheese. Its savoury flavour (McCabe and Rolls,
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2007) has been used to improve the palatability and acceptability of a wide variety of foods
and food substances (Yamaguchi and Kumiko, 2000; Prescot, 2004) worldwide. The
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consumption of MSG has been reported to be in excess of 2.5 million tons per year, with
suggestions that this widespread use may be due to its role as a flavour enhancer as well as its
U
possible physiological and nutritional role in metabolism (Torii, 2013). The flavourenhancing property (Mathey et al., 2001) and possible low satiety value (Rogers and
A
N
Blundell, 1990) have been suggested as important factors in MSG’s potential for sustaining
M
higher energy intake (Masic and Yeoman, 2013). There have also been reports suggesting that MSG, possibly through its effects at the umami taste receptors may cause the detection of
ED
certain nutrients and therefore enhance their consumption (Bachmanov et al., 2009). Studies have however revealed that diets supplemented with MSG are associated with a long-term
PT
maintenance of stable energy intake (Schiffman et al., 1994; Essed et al., 2007), and that MSG, by its interaction with macronutrients like proteins has the potential to enhance satiety
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over time (Viarouge et al., 1992). MSG has been reported to increase hedonic stimulation, hence, it may have the potential to stimulate appetite and/or food intake, and it may also help
A
to maintain stable energy levels (Yeomans, 1996; Masic and Yeomans, 2013). Debates regarding the ability of MSG to cause overeating or induce compulsive eating in predisposed individuals have continued till date, with a consensus that individuals differ in their perception of the umami or glutamate taste (Lugaz et al., 2002; Raliou et al., 2009). These variations, which may be genetic (Chen et al., 2009; Shigemura et al., 2009; Raliou et al.,
18
2009) has also been demonstrated in rodents (Ninomiya et al., 1992). However, the possible effects MSG on induction of satiety and satiation are yet to be determined (Masic and Yeomans, 2013). It is also not known if the variations in taste perception of glutamate induces or modulates glutamate preference or intake (Bachmanov et al., 2009). Also, there have been suggestions that variations in umami taste responsiveness may be associated with
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postingestive effects (Bachmanov et al., 2009) that may be mediated by different
mechanisms. Such mechanisms include nutritive value (which is dependent on the energy
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generated from its catabolism), stimulation of vagus activity, the release of hormones and
changes in gastrointestinal secretion of peptides (Niijima, 1991; Wu, 1998; Brosnan, 2000;
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Kondoh et al., 2000).
N
While examining the influence of MSG on appetite (by studying the effects of consuming
A
soups of varying concentrations of MSG and macronutrient content) in 24 non-obese males,
M
Masic and Yeomans (2013) reported that: a) food-added MSG significantly increased palatability which was associated with a smaller decrease in hunger immediately after
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ingestion of soup b) there was a reduction in the feeling of fullness immediately after ingestion of the high-protein soup c) the MSG added to protein soup resulted in a lower
PT
increase in satiety compared to MSG added to carbohydrate, and no MSG added soups conditions d) the increase in hunger and the decrease in the feeling of satiety that were
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observed in the subsequent 2 hour period were significantly lower in the individuals that had MSG conditioned with the protein than the groups with no MSG added to protein soup within
A
30 and 60 min post-ingestion. They concluded that MSG may have a bi-phasic effect on appetite, a hedonic satisfaction (Yeomans, 1996, Masic and Yeomans, 2013) that reduces satiation and stimulates appetite and intake, and a potential for enhancing post-ingestive satiety, particularly in relation to protein ingestion (Masic and Yeomans, 2013).
19
MSG’s role as a flavour-enhancer ordinarily suggests that its presence in foods will enhance consumption, which may result in weight gain. However, inspite of MSG’s ability to enhance preference for itself and other flavours related to it (or elicit a conditioned preference), the reports of its effects on body weight remain conflicting. There have been studies suggesting an increase (Oleksandra et al., 2014), a decrease (Kondoh et al., 2008; Onaolapo OJ et al,
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2015, 2016a), or no effect (Onaolapo AY et al., 2012; Tordoff, et al., 2012). Studies in which MSG was administered to neonatal rats reported weight gain (Oleksandra et al., 2014). In
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studies using adult rodents, no change in body weight was observed when MSG is added to
food or water (Tordoff, et al., 2012). However, when administered by gavage, a dose-related
U
weight loss has been observed (Onaolapo OJ et al, 2015, 2016a).
N
Other issues that have been raised include the possibility of MSG inducing reward or
A
addiction (Onaolapo et al., 2017), and till date, studies continue to examine the possible
M
rewarding or addiction-like effects of oral MSG in rodents (Bachmanov et al. 2000, 2009, Ackroff et al. 2012; Ackroff and Sclafani, 2013, 2016; Onaolapo OJ et al., 2017). It has been
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shown that MSG has a post-oral reward component, evidenced by low MSG intakes and the lack of expression of preference for MSG, relative to water (in MSG-naïve C57BL/6J mice)
PT
on exposure to ascending concentrations of MSG. An increase in intake and preference across a range of MSG concentrations was also observed in MSG-conditioned C57BL/6J mice
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(Bachmanov et al. 2000; Ackroff et al. 2012). The enhancement of MSG preference (with experience) has led to suggestions that a flavour-conditioning process may be involved,
A
which could be related to the post-oral effects of MSG, which increases flavour preference due to its association with rewarding effects that are detected in the gut (Ackroff et al. 2012; Sclafani and Ackroff 2012). There are also studies that have revealed that MSG reinforces (through conditioning) preferences for its own flavour and flavours related to it (Ackroff and Sclafani, 2013). MSG (at increasing concentrations) was associated with the induction of
20
conditioned taste preference for either MSG itself or MSG-paired flavours (Bachmanov et al. 2000, 2009, Ackroff et al. 2012; Ackroff and Sclafani, 2013, 2016). Also observed in a number of these studies were the strain differences in MSG intake, preference and flavourconditioning (Ackroff and Sclafani, 2013, 2016). In a recent study, Onaolapo et al. (2017) examined the effects of oral MSG in MSG-naïve (no prior MSG exposure) and MSG-
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pretreated (administered increasing doses of MSG daily for 21 days via an oral cannula, prior
to conditioning) mice exposed to the conditioned place preference paradigm (CPP paradigm).
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The results obtained suggested that the administration of MSG was rewarding, and an
association was learnt, as both MSG-naïve and MSG-pretreated mice showed ‘MSG-paired’
U
chamber preference. However, pre-treatment with MSG potentiated MSG’s ability to induce
A
2.1.1.i Glutamate and the brain reward system
N
CPP (Onaolapo OJ et al., 2017).
M
There have been reports (Tzschentke and Schmidt, 2003; Kawasaki et al., 2005; He et al., 2014) that suggest that endogenous brain glutamate plays a role in the development and
ED
maintenance of drug addiction. This could possibly be related to its effects on processes such as reinforcement, sensitisation, reinforcement learning and habit learning (Tzschentke and
PT
Schmidt, 2003). The dopaminergic projections that link the different brain regions (VTA to the NAc, and the VTA to the PFC) are crucial pathways of the reward system, through which
CC E
many drugs of addiction act. The glutamate system is believed to have a modulatory role on the activities of the dopaminergic system in the evolution and sustenance of drug addiction
A
(Tzschentke and Schmidt, 2000). However, this does not mean that exogenous glutamate would have similar effects on the brain reward system. Researchers examining the mechanisms involved in glutamate consumption or its effect on appetite have suggested that it may be related to the chemosensory perception of its taste and/or its postingestive effects (Bachmanov et al., 2009). Consumption of MSG has been linked to a direct or indirect
21
increase in brain stimulation. Kondoh et al. (2009) demonstrated that a luminal presence of glutamate results in the stimulation of gut L-glutamate receptors that activates vagal afferent nerve fibres, which via vagal inputs then go on to stimulate brain regions (like the habenular nucleus) which exerts an influence on other regions of the brain. Functional magnetic resonance imaging and blood oxygen level dependent (BOLD) signals have shown that an
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intragastric load of MSG results in the activation of brain regions such as amygdala, insular cortex, lateral hypothalamus, medial preoptic area and the dorsomedial hypothalamus
SC R
(Tsurugizawa et al., 2009; Uematsu et al., 2009; 2010; Tsurugizawa and Torii, 2010).
Hence, the luminal presence of glutamate is linked to its ability to influence the brain regions
U
that modulate reward. However, despite the fact that some studies may have demonstrated
N
that MSG has the potential to stimulate the brain reward system, its ability to ultimately
A
induce addiction (or potentiate the addictive potential of other food macronutrients) still
M
needs further evaluation.
2.1.2 Purine nucleotides: inosine monophosphate
ED
Purine nucleotides like inosine monophosphate and guanosine monophosphate have both health and economic benefits in the food and biotechnology industries, where they have
PT
found value as food flavouring agents that also have nutritional and pharmaceutical properties (Ledesma-Amaro et al., 2013). The umami taste sensation is also the taste quality of inosine
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monophosphate (IMP), guanosine monophosphate (GMP) and a few other L-amino acids. IMP and GMP have flavour enhancing capabilities via exerting synergistic effects in
A
enhancing the umami flavour when combined with MSG (Jinap and Hajeb, 2010). Studies have also revealed that these purine nucleotides (inosine and guanosine) have health benefits that are related to their antioxidant, cardiotonic, immunomodulatory and neuroprotective properties (Aviado, 1983; Hasko et al., 2004; Shen et al., 2005; Tsuda, 2005).
22
IMP was discovered in 1913 when it was found that the active ingredient in dried bonito (which is traditionally used amongst the Japanese to make dashi, a soup stock) was 5′inosinate (salt of 5′-inosinic acid) (Kodama, 1913; Kurihara, 2015). IMP and GMP are synthesised industrially by microbial fermentation, using either RNA extraction with subsequent breakdown into free nucleotides; or by improved metabolic biosynthesis with
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excretion of the nucleosides into the culture medium, and subsequent enzymatic or chemical
phosphorylation (Ledesma-Amaro et al., 2013; 2015). In vivo, IMP is the first nucleotide to
SC R
be formed during purine synthesis and is present in nucleic acids and adenosine triphosphate, which are the body’s chemical energy store in muscles and other tissues (Watterson et al.
U
2007).
N
IMP is a colourless, odourless, white crystalline compound that is usually marketed alongside
A
MSG. IMP (like MSG) elicits the umami taste sensation in humans and rodents, via its ability
M
to stimulate gustatory cells in taste buds and interact with taste receptors like T1R1 and T1R3 heterodimers (Ninomiya et al., 2000; Nelson et al., 2002). IMP and MSG are marketed
ED
together because studies have shown that compounds that elicit umami display synergism (Kumazawa and Kurihara, 1990; Yamaguchi and Ninomiya, 2000). There is scientific
PT
evidence demonstrating that the addition of 0.5 mM IMP to MSG resulted in an increase in preference scores without significantly affecting detection thresholds in food (Schiffman et
CC E
al., 1994). Zhang et al. (2008) reported that the combination of MSG and IMP augmented the umami taste sensation via stimulation of the T1R1 and T1R3 receptors in the oral cavity. de
A
Araujo et al. (2003) showed that both compounds are recognised in the brain as the same taste. Tsurugizawa et al. (2011) reported that the gastrointestinal stimulation resulting from an intragastric load of MSG and IMP induced BOLD signals in the same brain regions, but with differences in the time course of the BOLD response. They also reported that while MSG and IMP induced BOLD signals in the lateral hypothalamus, nucleus of the solitary
23
tract and insular cortex, only MSG increased the BOLD signals in the amygdala. This observation led to the suggestion that the mechanism of perception of MSG and IMP in the gastrointestinal tract differed from that of the taste-sensing system of the oral cavity (Tsurugizawa et al., 2011). Questions regarding the possible effects of the MSG/IMP synergism on appetite and satiety
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have been raised, with only a few studies examining this effect. Masic and Yeomans (2014)
concluded that in addition to increasing the flavour pleasantness of foods, a combination of
SC R
MSG/IMP (when added to a low-energy preload like a high protein diet) elicited a biphasic
effect. First, by stimulating appetite during ingestion (an appetiser effect), and secondly, by
U
enhancing postingestive satiety.
N
There is a dearth of scientific literature examining the possible rewarding or addiction-like
A
effects of IMP or MSG/IMP combinations, either in humans or rodents. However, a number
M
of studies have examined the effects of dried bonito dashi (a broth that is made from dried bonito tuna, which is frequently used in Japanese cuisine) that contains IMP amongst other
ED
amino acids. The taste component of dashi per 100g stock includes about 108 mg inosinate and glutamate (Honda et al., 2006). There are suggestions that the taste preference for dashi
PT
solution in rats is not solely linked its umami-salty taste (Kawasaki et al. 2008). The results of a conditioned taste aversion experiment in mice also revealed that the dashi flavour includes
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the five recognised basic taste qualities (Delay and Kondoh 2013). There is also evidence suggesting that both olfactory and taste stimuli are needed, but not exclusive to the induction
A
of the dashi preference (Kawasaki et al. 2008) in rodents, and that post-oral nutritive feedback enhances dashi preference (Kondoh et al. 2012a, 2012b). Ackroff et al (2014) examined the effect of dashi on reward, using a series of three experiments. The first experiment showed no evidence for postoral dashi preference following an intragastric selfinfusion, while the second experiment showed an inability of the preferred dashi solution to
24
condition a preference when orally consumed. In the third experiment using taste-impaired genetically modified mice, it was observed that dashi preference in mice depended upon the Trpm5 signalling system which mediates the taste cell response to umami, sweet and bitter tastes. Although C57BL/6J mice did not acquire preferences for dashi-paired flavours, oral exposure to 0.1% inosinate enhanced subsequent dashi preference. However, the
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concentration of IMP and other umami components in dashi may not be sufficient to induce post-oral flavour conditioning (Ackroff et al., 2014). Studies using the CPP have
SC R
demonstrated that dashi is able to mediate reward only in combination with a nutritive
sweetener like dextrin (Kawasaki et al. 2011). This suggests that dashi may be an orally-
U
attractive substance without an inherent post-oral reward component. It could be deduced
N
from the foregoing that while IMP and/or MSG may be able to condition flavour or taste-
A
preference, in food, they are usually present in concentrations that are insufficient to
2.2
M
stimulate the brain reward system. However, more studies are needed to validate this theory. Food sweeteners
ED
Sweeteners are food additives which are used to impart a sweet taste in food and food substances. They elicit pleasurable sensations, in addition to providing nutritive or non-
PT
nutritive energy. Concerning their regulation, nutritive sweeteners like sucrose or sucrose substitutes (monosaccharide, disaccharide and polysaccharide polyols) are generally
CC E
recognised as safe (GRAS), or have petitions filed for GRAS. Sugar is a term that refers to sweet, soluble carbohydrates, which are food additives used to
A
sweeten food and food substances. There are different forms of sugars, with simple sugars (also known as monosaccharides) including glucose, fructose and galactose. Another type of sugar is the disaccharides, including sucrose (which is commonly available as either granulated sugar or table sugar), maltose and lactose. Oligosaccharides or polysaccharides are sugars with longer chains. Sucrose is present in all green plants, where it is an early product
25
of photosynthesis and the main agent for the translocation of carbon to the rest of the plant. In sugarcane and sugar beet, high concentrations of sugars are found which is sufficient for commercial extraction. In the last few decades, there are questions regarding the health implications of diets that are high in sugars, more especially refined sugars. Although studies examining the health impacts remain inconclusive, excessive use of sugar has been linked to
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an increased risk of cardiovascular disease (Brown et al., 2008; Stanley et al., 2009), diabetes
mellitus (Apovian, 2004; Gross et al., 2004), obesity (de Ruyter, et al., 2012), cognitive
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decline (Lakhan and Kirchgessner, 2013; Chiavaroli et al., 2014) and tooth decay (Zero et al., 2009; Jacob et al., 2016). More recently, diets that are high in sugars have been implicated in
U
the development of food addiction or specifically sugar addiction, and obesity.
N
Polyols or sugar alcohols are nutritive, low calorie, digestible carbohydrates that have been
A
associated with the addition of sweetness to foods without significantly increasing energy.
M
Polyols are obtained from the substitution of an aldehyde group with a hydroxyl (Shankar et al., 2013). Examples of polyols include hydrogenated monosaccharides (mannitol, sorbitol),
ED
hydrogenated disaccharides (isomalt, lacitol, maltitol) and hydrogenated starch hydrolysates (Shankar et al., 2013; Grembecka, 2015). There are also mixed compounds like polydextrose
PT
which is a combination of corn sugar and sorbitol. Polyols tend to occur in small quantities in animals and plants (Mäkinen, 1984). Acceptable daily intake (ADI) levels are yet to be
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specified for these polyols. However, when consumed in large quantities, they have been associated with potent laxative effects and gastrointestinal symptoms like abdominal
A
discomfort, bloating and flatulence (Grabitske and Slavin, 2008; EFSA, 2011). In addition to their ability to impart a sweet taste, polyols have been shown to improve the texture, holding moisture and cooling sensation of food products in the mouth, as well as serve as preservatives (Health Canada, 2005). Polyols also have prebiotic and anti-cariogenic effects, and help with the normalisation of intestinal function (Grabitske and Slavin, 2008; EFSA,
26
2011). They have also been associated with weight loss and reduction in energy intake, due to their lower caloric value (Grabitske and Slavin, 2008). They are recommended for use in diabetics because they induce only a small increase in blood glucose or insulin secretion (Nakamura, 2005; Grabitske and Slavin, 2008; Wheeler and Pi-Sunyer, 2008; EFSA, 2011).
from about 25 to 100 %, compared with sucrose (Grembecka, 2015).
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Erythritol and xylitol are widely used as bulk sweeteners. The sweetness of polyols varies
Six non-nutritive sweeteners (acesulfame-K, aspartame, neotame, saccharin, sucralose and
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stevia) with intense sweetening potential are approved and classified as generally recognised as safe (GRAS) for use in humans by the United states Food and Drug Administration (FDA)
U
and the European Food Safety Authority (FDA, 2015; EFSA, 2015). Siraitia Grosvenorii
N
Swingle Fruit Extract (SGFE) known as Luo Han Guo in Chinese, is a traditional Chinese
A
herbal-based sweetener which was also granted GRAS status by the FDA (FDA, 2014). Two
M
others which have been approved for use in other regions of the world, but not in the United States of America are alitame (approved for use in Australia, China, Mexico and New
ED
Zealand) (Ellis, 1995; Australia New Zealand Food Authority, 2002) and cyclamate ( used in over fifty countries). Non-nutritive sweeteners (NNS) are usually about 30–13000 times
PT
sweeter than sucrose (Shankar et al., 2013), and have established acceptable daily intake limit currently available for each of them. However, there are ongoing debates on the safety of
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(NNS), with a number of studies examining the possible effects of the different NNS in humans or rodents (Weihrauch and Diehl, 2004; Akihisa et al., 2007; Magnuson et al., 2007;
A
Lin and Curhan, 2011; Gardner et al., 2012; Pepino et al., 2013; Liu et al., 2013; Suez et al., 2014). Aspartame is made up of two amino acid isolates (phenylalanine, aspartic acid) and methanol in a ratio of 5:4:1. It also breaks down into these components on ingestion. The central effects of aspartame have been credited to alterations in the concentrations of catecholamines
27
such as epinephrine, norepinephrine and dopamine (Coulombe and Sharma, 1986). In recent studies examining the effects of increasing doses of aspartame in mice, dose-related behavioural, biochemical and morphologic changes involving different regions of the brain (Onaolapo AY et al., 2016, 2017a, 2017b) were observed. Acesulfame-potassium (acesulfame) is a white crystalline powder and a potassium salt of 6-methyl-123-axathiazine-
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4(3H)-one 2, 2-dioxide. It has a bitter after-taste when used alone as a sweetener (Horne et al.
2002), so it is usually combined other sweeteners (sucralose or aspartame) allowing the
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sweeteners mask each other’s after-taste, with an increased sweetness derived. Acesulfame is
excreted unmetabolised in humans; therefore, in addition to being a non-caloric sweetener, it
U
does not alter potassium metabolism (ADA, 2004). Sucralose is derived from a process that
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substitutes 3 chloride atoms for 3 hydroxyl groups on the sucrose molecule. The bulk of
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sucralose is not metabolised in humans and as it is excreted in the faeces unchanged, and
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while 14–20% of it is absorbed from the gastrointestinal tract, this is also excreted in the urine within 5 days (Roberts et al., 2000; John et al., 2000).
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2.2.1 Nutritive Sweeteners (Sugars and modified-sugars) and food addiction Food sweeteners have the ability to increase palatability and consumption of nutrient-
PT
dense foods or beverages, thereby promoting a healthy diet. However, questions continue to be raised over the possible effects of food sweeteners on appetite, satiety, brain reward
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system and food addiction. Studies investigating the construct ‘sugar addiction’ have been conflicting in their reports, with some researchers and food scientists asserting that
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consumption of high sugar diets or sugar stimulates the brain reward system in ways that are similar to drugs of addiction (Avena et al., 2008b).Whereas, others have suggested that sugar addiction does not occur in humans (Hedebrand et al., 2014; Westwater et al., 2015). Studies have shown that sugar is easily detected by the sweet taste receptors in the oral cavity, and it elicits a strong taste or flavour preference in many animals (Bachmanov et al., 2011). Also,
28
sugars can be detected by gut chemosensors, as well as chemosensors in post-absorptive sites (like liver, pancreas and brain), providing a possible source of the positive feedback signals of sugar-conditioned flavour preferences. In humans and rodents, the sweet taste sensation of sugar has been linked to stimulation of the heterodimeric T1R2+T1R3 sweet receptor which are located in taste buds on the tongue and palate (Bachmanov et al., 2011; Treesukosol et al.,
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2011). This activates an intracellular signalling mechanism that is coupled to the inositol 1,
4, 5-trisphosphate receptor 3, G protein α-gustducin phospholipase Cβ2 and the transient
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receptor potential cation channel Trpm5 (Chaudhari and Roper, 2010). Intragastric or intraduodenal infusion of sugars has been associated with a post-oral enhancement of the
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conditioned flavour-preference in rodents (Sclafani and Glendinning, 2005) and humans
N
(Yeomans et al., 2008). Once developed, conditioned flavour-preference for sugars has been
A
observed to persist for days, and is also resistant to extinction (Myers, 2007). This suggests
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that conditioning to sugar produces a long-lasting increase in the reward value (Sclafani and Ackroff, 2012). The mechanism by which sugars may cause or potentiate food addiction has
ED
been discussed in section 1.4.1.
In the light of studies that have demonstrated the possible deleterious metabolic effects of
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excessive consumption of sugar and its ability to increase the risk of addiction to foods; there has been an increase in the advocacy for the substitution of sugar with either nutritive low
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calorie sweeteners like polyols, or non nutritive sweeteners like aspartame. However, there are still debates on the possible effects that these sugar substitutes may exert on appetite and
A
satiety (or their ability to influence the brain reward system), since they also stimulate the same sweet taste receptors as sugars, and may therefore elicit the same postingestive and/or post-absorptive effects. While there is a dearth of scientific literature examining the ability of sugar alcohols to condition preferences or activate the brain reward circuit, studies have evaluated the effects
29
of polyols (xylitol, lacitol) and glucose polymers like polydextrose (PDX) on appetite and satiety (Gee and Johnson, 2005; King et al., 2005; Olli et al., 2011; Kumar et al., 2012; Ibarra et al., 2016). PDX has been shown to increase satiety when administered as a supplement about 60-90 minute before an ad libitum lunch (exerting no such effect when administered with breakfast) and it also reduces energy intake (Hull et al., 2012; Astbury et al., 2013;
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Ranawana et al., 2013). It has also been associated with enhanced satiety and satiation when
it replaced 30% of the other available carbohydrates in a diet (Konings et al., 2014).
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However, effects of supplementation of lower concentrations of PDX on appetite and satiety
were inconsistent (King et al., 2005; Schwab et al., 2006; Astbury et al., 2013). PDX is high
U
in fibre and this is believed to be partly responsible for its effects on appetite and satiety,
N
although other factors have also been considered. A recent study examining the effects of a
A
PDX-supplemented meal on appetite regulation in obese participants, reported that PDX-
M
supplemented diet enhanced satiety and reduced hunger after a high-fat diet (Olli et al., 2011).These effects were associated with stimulation of the postprandial secretion of
ED
glucagon-like peptide 1, a satiety hormone (Olli et al., 2011). Other studies have also associated PDX with increase in the secretion of glucagon-like peptide 1 and peptide YY, and
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lower ghrelin levels in lean men (Astbury et al., 2014). The impact of polyols on satiety and satiation has also been reported (Kumar et al., 2012). Polyols have been observed to enhance
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satiety, stimulate the secretion of glucagon-like peptide1, and increase acute postprandial concentrations of plasma peptide YY (Massimino et al., 1998; Gee and Johnson, 2005;
A
Lesniewska et al., 2006). Polyols also delay gastric emptying, which has been suggested to be partly responsible for their effects on satiety. 2.2.2 Non-Nutritive Sweeteners and food addiction There is increasing evidence to suggest that artificial sweeteners (like aspartame and saccharin) activate the food reward circuit, using pathways that differ from those used by
30
sugar and other natural sweeteners. NNS are low calorie sweeteners, so this could possibly eliminate the postingestive component (Yang, 2010) that is dependent on metabolic products of the food (Sclafani and Ackroff, 2004). Therefore, NNS activate the gustatory component of the reward pathway differently from caloric sweeteners. The ingestion of sucrose (compared to saccharin) was associated with an increased activation of higher gustatory areas
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like the orbitofrontal cortex, insula and amygdala (Haase et al., 2009). Imaging studies comparing the effects of sucrose and sucralose on central taste pathways demonstrated that
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although both sucrose and sucralose activated primary taste pathways, sucrose elicits a
stronger brain response in the anterior insula, frontal operculum, striatum and anterior
U
cingulate, compared to sucralose (Frank et al., 2008). Also, only sucrose stimulates
N
dopaminergic midbrain areas, suggesting that the brain probably distinguishes caloric from
A
non-caloric sweeteners (Frank et al., 2008). Functional imaging studies (in male subjects with
M
normal weight) following sucralose ingestion also revealed an absence of the prolonged hypothalamic signal depression that was observed with glucose ingestion (Smeets et al.,
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2005). The results obtained from a human study also suggested that habitual use of NNS was associated with alterations in reward-processing of sweet taste and modulation of
PT
consumption (Green and Murphy, 2012). Rudenga and Small (2012) also tested the hypothesis that sweet taste may produce a differential response in brain regions that signal the
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post-ingestive effects of flavours. They observed an inverse relationship between amygdala response to sucrose and artificial sweetener use, and a trend towards a similar effect in the
A
insula. These findings also support suggestions that experiencing sweet taste without calories degrades the predictive capacity of sweet sensation in the amygdala and insula (Davidson and Swithers, 2004). Studies have evaluated the effect of NNS on appetite, satiety and weight, with conflicting reports. There have been suggestions that because NNS are sweet, they could potentiate
31
sugar-craving and sugar dependence (Yang, 2010) leading to overeating and weight gain. A number of studies have suggested that acute administration of NNS in vehicles that are energy deficient (water or chewing gum) result in an increase in hunger compared to vehicle alone (Black et al., 1993; Blundell and Hill, 1986; Rogers et al., 1988; Tordoff et al., 1990). However, when administered with high energy vehicle, no alteration of hunger, relative to
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vehicle alone or vehicle sweetened with sucrose (Rolls et al., 1989; Maone et al., 1990; Drewnowski et al., 1994) was observed. Some studies have however suggested that low
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calorie NNS neither promote nor suppress appetite (Bellisle and Drewnowski 2007; Renwick and Molinary, 2010). A study evaluating the effects of NNS-containing beverages (compared
U
to sugar-sweetened beverages) on satiety, reported no difference in satiety ratings in children
N
over an 18-month intervention trial (de Ruyter et al. 2013); similar effects were observed in
A
adults in another study (Anton et al., 2010). Studies in rodents have also demonstrated
M
preference for non nutritive sweeteners like stevia compared to water (Martínez et al., 2016), and conditioned flavour preference; although preference for nutritive sweeteners exceeded
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that observed for NNS (Sclafani and Ackroff, 2017). From the foregoing it can be said that NNS do not elicit the same effects on appetite, satiety, conditioned preferences or the brain
PT
reward circuit as observed with sugars. Also, they are not likely to potentiate the effects of
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other foods or food substances. Conclusion
In conclusion, while the validity of the concept of food addiction continues to be debated,
A
studies have continued to show that deliberate alterations in the composition of foods can change the behavioural response to their consumption, due to differences in sensory perception. However, the scientific evidences in support of food addiction are not yet sufficient to categorically state that any particular food ingredient, micronutrient or standard food-additive is addictive.
32
Therefore, research needs to focus more on understanding the mechanisms by which food constituents may modulate the brain response to their consumption. Also, the probable longterm changes (in brain chemistry and structure) that may accompany the consumption of
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certain foods or food-additives need to be further investigated.
Acknowledgement
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This research did not receive any specific grant from agencies in the public, commercial, or not-for-profit sectors.
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Conflict of interest:
Onaolapo AY declares no conflict of interest related to the content of this manuscript.
A
N
Onaolapo OJ declares no conflict of interest related to the content of this manuscript.
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Ethical statement
This article does not contain any studies with human participants performed by any of the authors. All studies
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referenced in this article performed by the authors using animal were in compliance with international, national,
A
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and/or institutional guidelines for the care and use of animals.
33
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