Reward-Induced Eating: Therapeutic Approaches to Addressing Food Cravings

The homeostatic controls over eating are inextricably linked to the reward aspects of eating. The result is an integrated response that coordinates the internal milieu with the prevailing environment. Thus, appetite, which reflects a complex interaction among the external environment, behavioral profile, and subjective states as well as the storage and metabolism of energy, has an important role in the regulation of energy balance. In the prevailing food environment which offers an abundance of food choices it is likely that the motivation to consume from a wide range of delectable foods plays a greater role in contributing to overeating than in the past when the motivation to eat was largely governed by metabolic need. The response to food-related cues can promote strong desires to eat known as cravings by activating the mesocorticolimbic dopamine neurocircuitry. Cravings are associated with subsequent eating and weight-related outcomes. Being able to control food cravings is a determinant of success at adhering to an energy-restricted diet regimen. Increased understanding of the neurocircuitry of appetite regulation, especially reward-related eating behavior, has provided potential targets for therapeutic anti-obesity agents specifically directed at reward mechanisms. The naltrexone–bupropion combination and lorcaserin, which are both approved by the US Food and Drug Administration (FDA) for long-term weight management, have shown promise in addressing craving-related eating behavior. Phentermine and liraglutide are approved as monotherapies for weight management. Preliminary research suggests that liraglutide, as well as phentermine alone or in combination with lorcaserin, may be effective in targeting food cravings. Food components such as thylakoid membranes have also been shown to influence food cravings. This review explores the concepts related to appetite and reward-induced eating behavior, as well as the pharmacological options and food-derived components that may be used to address food cravings.

reflects a complex interaction among the external environment, behavioral profile, and subjective states as well as the storage and metabolism of energy, has an important role in the regulation of energy balance. In the prevailing food environment which offers an abundance of food choices it is likely that the motivation to consume from a wide range of delectable foods plays a greater role in contributing to overeating than in the past when the motivation to eat was largely governed by metabolic need. The response to food-related cues can promote strong desires to coronary heart disease and stroke [1].
Overweight and obesity are important risk factors of CVD [2][3][4], operating in part through mechanisms such as elevated levels of blood pressure, dyslipidemia, and abnormal glucose metabolism. However, interventions that address these abnormalities resolve approximately half of the excess risk for coronary heart disease that may be attributed to a high body mass index [5]. Thus, maintenance of optimum body weight through strategies that can curb or reverse adiposity is of paramount importance in reducing CVD and type 2 diabetes [5]. Current obesity guidelines suggest that sustained weight loss of just 3-5% achieved through lifestyle interventions can result in clinically significant positive metabolic outcomes [2]. Any obesity treatment involves creating a negative energy balance. Finding the optimal diet composition for achieving a negative energy balance has proven elusive. What appears to be important is not the type of diet, but adherence to a diet regimen that promotes energy restriction [6]. Lifestyle change programs can help many individuals to achieve weight loss but a large percentage will fail to do so and many of those who achieve it will regain body weight. Weight loss induces neuroendocrine changes that impinge on what is called ''willpower'', as a result of counter-regulatory mechanisms that provoke a powerful unconscious impulse to eat [7]. There are associated increases in neural activity in areas of the brain involved in processing the rewarding value of food stimuli [8,9]. Economic growth and technological developments are important for prosperity, but the trade-off to business and trade by way of less regulated global markets has led to the creation of cheap, easily available food sources [10]. The biological drive to eat is inextricably linked not only to the satiating and satiety-enhancing power of food but also to its rewarding value.
In an environment that presents a plethora of inviting food choices the consumer is often prodded to disregard dietary recommendations [11]. Obesity results from a chronic energy imbalance; hence, controlling the urge to eat assumes importance. This review explores the concepts related to appetite regulation with special emphasis on reward-induced eating and interventions that target reward mechanisms.

Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

APPETITE
Appetite reflects a complex interaction between the external environment, the behavioral profile, and subjective states as well as the storage and metabolism of energy [12]. The expression of appetite manifests the interplay of events and processes that occur at three levels: (1) psychological events such as perceptions of hunger, food cravings, or hedonic sensations, and the corresponding behavioral actions; (2) responses in the peripheral physiologic system and metabolic events which stem from nutrient absorption, metabolism, and storage; and (3) central neural processes that translate the physiologic events [13]. The hypothalamus is the cerebral appetite center, integrating peripheral humoral signals that transmit information about food intake and energy expenditure with neuronal signals from the brainstem and higher cortical center dealing with cognition, pleasure, and emotion [14]. antagonist [15,16]. Following the ingestion of food, sensory information is transmitted from the gastrointestinal tract to the central nervous system either through vagal and somatosensory afferent fibers or via bloodstream signals which may be the gut hormones [17]. The presence of an incomplete blood-brain barrier in the regions of the brain such as the area postrema permit many circulating signals, including the gut hormones, direct access to the central nervous system [18].
Thus, complex neuronal pathways with reciprocal connections between the hypothalamus, brainstem, and higher cortical areas [19] are involved in the control of appetite acting through endocrine and neuronal feedback signals from the periphery to synchronize appetite perception, food intake behavior, and energy homeostasis.
The widely accepted homeostatic view of the control of food intake is that adiposity signals such as leptin and insulin influence the sensitivity to meal-derived satiation signals to regulate meal size in response to changes in body weight [20]. Translation of the metabolic need into behavioral action is closely intertwined with reward and is orchestrated by a cognitive and emotional brain that operates on factors such as past experiences, cost, and availability [22]. The mesocorticolimbic system is involved in reward processing through dopamine release from neurons in the ventral tegmental area and their projections to the nucleus acumbens, amygdala, prefrontal complex, and other forebrain regions [23]. In the reward system, dopamine and opioid systems interact in the determination of eating behavior [24].
Dopamine signaling plays an important role in translating motivation into action [25], and increases the drive to obtain a rewarding stimulus, but it is opioid peptide transmission in the nucleus acumbens rather than dopamine that modulates the hedonic or pleasure impact of food [23,26] (Fig. 1). Specifically, opioids, particularly the l-opioids, covey the reward sensation of desirable foods whereas dopamine regulates the reward value of food and the motivation to obtain that food [27]. Thus, appetite reflects (1) physiologic hunger or a conscious sensation reflecting an urge to eat and (2) reward that can be triggered without any physiologic hunger, but is still controlled physiologically.

REWARD-INDUCED EATING BEHAVIOR
In the modern world, humans often eat in the absence of any metabolic feedback indicating a diminution of reserves [22]. This non-homeostatic eating involves perceptions of food reward. The psychological components of reward include (1) learning which includes knowledge resulting from associative and cognitive processes; (2) affect (emotion) or liking which reflects the immediate experience or eagerness to experience pleasure from the hedonic value of consuming a food; and (3) motivation to actually eat, or wanting [28].
Components of affective and motivational processes can exist objectively, without conscious awareness of them. Therefore, they can be implicit which assumes importance because individuals can react to a rewarding stimulus without conscious awareness of either the stimulus or their hedonic response to it [28]. Perceptions of food reward can occur by encountering food-related cues such as the sight, smell, and taste of the food, sensations that often initiate an intense desire to eat known as craving: a conditioned response to food that is often accompanied by increased salivation, physiologic arousal, and neural stimulation. Such craving is a form of food cue reactivity, called cue-induced craving. Another type of craving that arises independently of external cues as may occur when merely imagining a favorite food causes the individual to be consumed with the desire to eat and is known as tonic craving. Other forms of craving include state craving which is tonic or cue-related craving assessed at a particular moment in time and trait craving which is a general tendency to crave with or without the presence of cues [29]. Further, there are gender differences in cravings and the response to Fig. 1 Brain reward circuitry. a Neurons in the VTA of the midbrain project to forebrain areas including the NAc, striatum, and cortex, and assign reward value to palatable food. b Perception of pleasure associated with consumption of a palatable food involves neuronal activation in the NAc and striatum, which through activation of opiate peptide receptors disinhibits the lateral hypothalamic area and thereby stimulates feeding. Amy amygdala, GP globus pallidus, NAc nucleus accumbens, VTA ventral tegmental area. Reprinted with permission from Macmillan Publishers: Morton et al. [26] them. Men exhibit a yearning for savory foods [8,30,31], whereas women prefer high-fat sweet foods such as chocolate [8,31,32]. Women have a greater inclination than men to succumb to cue-related food cravings, and more so in the luteal phase of the menstrual cycle [29].
Both cue-related and tonic craving are associated with subsequent eating and weight-related outcomes. Moreover, reactivity to visual cues such as images of food is as related to eating behavior as real food [33]. Individuals unsuccessful at adhering to dietary energy restriction report greater food cravings that are related to loss of control over eating and plans to consume food than those who achieve success at following a diet regimen [34].
Meta-analyses of brain imaging studies suggest that major brain regions involved in cue reactivity to alcohol, drugs of abuse, sex, gambling, smoking, and food for the most part overlap, and consist of a network that processes reward responses [35,36]. These biological and behavioral parallels suggest that eating behavior is addictive. It appears that food cravings are a mediator between addictive eating behavior and increases in body weight [37].
Hypothalamic signals regulating energy intake can influence the activity of the hedonic or reward systems in the corticolimbic structures [38].  [47,48]. The Yale Food Addiction scale is a measure of addictive-like eating behaviors that has been validated to various extents across different age groups, races, and among subjects with obesity or eating disorders. However, the concept of food addiction has been criticized because of the lack of evidence for substance-based food addiction [49].
Neuroimaging using functional magnetic resonance imaging to permit measuring and mapping of brain activity that is specific to food stimuli in the reward circuitry is also a possible way to measure motivational signals [50,51].

TARGETING REWARD MECHANISMS
The term obesity was paired with each of the following terms using the operator AND: food cues, food cravings, and reward-induced eating. Bupropion, a dopamine reuptake inhibitor, is approved for the treatment of depression and seasonal affective disorder, and to aid in smoking cessation [55,56]; whereas, naltrexone, an opioid receptor antagonist, is approved for the treatment of alcohol and opioid dependence [57,58]. Bupropion is thought to stimulate secretion of a-MSH from POMC cells which produces an anorexic effect. Further, the antidepressant effects of bupropion and its effectiveness in aiding smoking cessation suggest that it mediates processes in the reward system [59]. Although bupropion stimulates POMC activity, the anorexic effects of POMC are curtailed by the melanocortin system's inherent feedback mechanism that limits sustained stimulation of POMC cells by simultaneous secretion of endogenous opioids such as b-endorphins that inhibit a-MSH secretion [27]. Naltrexone monotherapy has little efficacy for weight management. However, consistent with the established role of opiates in the reward aspects of eating and stimulation of consumption of energy dense sugar and fat-laden foods [60], naltrexone antagonism of opioid receptors reduces the subjective pleasantness or liking of certain foods [61,62].
Blockade of the l-opioid receptor with naltrexone to counteract the auto-inhibitory actions of bupropion-stimulated release of endogenous opioids forms the basis of the combination treatment of bupropion and naltrexone for obesity treatment. Moreover, naltrexone and bupropion both reduce food intake in mice when injected directly into the reward system; but the effect is synergistic when they are administered together. Results from the phase III trials showed that the combination treatment of naltrexone and bupropion consistently reduced measures of food reward assessed using the COEQ [43,44,63]. Subjects reported reduced frequency and strength of food cravings (Table 1) approved by the FDA for the long-term treatment of obesity [71]. Studies showed that lorcaserin produced weight loss without the adverse cardiac outcomes associated with non-specific serotonin receptor agonists Table 1 Therapies for reducing reward-related eating
In the Pilot Evaluation of Tolerability and Safety of Lorcaserin and phentermine (PETAL) study, conducted to evaluate if administration of the combination of lorcaserin with immediate release phentermine for 12 weeks was associated with adverse events, the effect of the drug administration on food cravings was also evaluated as a secondary endpoint. Subjects were given lorcaserin 10 mg twice daily or lorcaserin 10 mg twice ? phentermine 15 mg once daily, or lorcaserin 10 mg twice ? phentermine 15 mg twice daily.
Weight loss at 12 weeks was 3.3%, 6.7%, and 7.2% in the lorcaserin only and the combination with phentermine once or twice daily, respectively. Analysis of the food craving data evaluated using the FCI indicated that subjects in all treatment groups showed improvement in the FCI total score from baseline to week 12 as well as in the FCI subscale scores for high-fat foods, sweets, carbohydrates, and fast foods without any one particular category of foods driving the overall effect [52]. Subjects also reported improvements in control of eating in all treatment groups at week 12 compared to baseline, evaluated using the COEQ. The frequency and strength of food cravings reduced including the craving for chocolate, sweets, non-sweets, and starchy foods in a sample that comprised 85% women. The limitation of this study is that there was no placebo-treated group [53].
In the brains of humans GLP-1 receptors have been identified in the hypothalamus, medulla, and parietal cortex [82]. In human subjects, the GLP-1 receptor agonist exenatide reduced activation in response to food cues in brain areas involved in the regulation of reward, the effect of which was greatly attenuated by GLP-1 receptor blockade [83,84]. The response to GLP-1 receptor blockade was more pronounced in subjects with type 2 diabetes and obesity than in lean healthy subjects [85]. In response to treatment for 17 days with liraglutide (Saxenda TM ) a GLP-1 agonist approved by the FDA for long-treatment of obesity [86], activity in the parietal cortex decreased when subjects viewed images of highly desirable foods compared to placebo. The parietal cortex is involved in controlling the location of attention [87]; hence, it is likely that there was a reduced appeal of the food cues, especially since liraglutide treatment also increased fullness and reduced food intake [82]. However, gastric inhibitory peptide increased and serum leptin decreased in response to food cues, each of which has opposing effects in the areas of the brain involved with reward mechanisms [88]. Leptin is secreted by fat cells and binds to specific leptin receptors on dopaminergic neurons in the ventral tegmental area to inhibit dopamine signaling in the nucleus acumbens and amygdala. Unlike gastric inhibitory peptide, leptin reduces reward-related eating behavior [89]. The short-term effects of liraglutide on reward mechanisms warrant corroboration in future studies.

Food-Based Interventions
Thylakoids are compartments inside the chloroplasts of green plants such as spinach and are composed of membranes that form the internal photosynthetic membrane system of chloroplasts. By interacting with lipids and delaying fat digestion, thylakoid membranes promote the release of hormones that mediate satiety [90]. Studies investigating the effects of thylakoids (Appethyl TM ) on eating behavior have demonstrated increases in perceptions of satiety [91,92], and a reduction in body weight [93]. Additionally, two studies demonstrated a decrease in the craving for sweet foods and chocolate among women in the overweight or obese body mass index range, measured subjectively [93,94]. In another study, men tended to reduce their intake at a pizza meal; whereas, among women food intake did not change following a 5-g dose of thylakoids [91].