Obesity is a multifaceted condition [1
] and represents a pandemic that needs urgent attention [2
]. In Canada, over one in four adults are obese [3
], and the province of Newfoundland has one of the highest rates of obesity in the country (after the Northwest Territories and Nunavut) [3
]. Obesity is caused by multiple factors, including genetics, endocrine function, behavioral patterns and environmental determinants [5
]. It has been well documented that chronic overconsumption of calories plays a fundamental role in the development of obesity [6
]. In a previous study on the general Newfoundland population, our laboratory discovered that chronic compulsive overeating, defined as “food addiction” by the Yale Food Addiction Scale (YFAS) [7
], significantly contributes to human obesity [9
]. Additionally, the clinical symptom counts of food addiction defined by the YFAS is highly associated with the severity of obesity [9
]. Addiction is considered a psychological disorder with a definite neuro-endocrine basis; however, food addiction is still not defined as an independent disorder in Diagnostic and Statistical Manual (DSM) V [10
]. Similar to drug addiction, food addicts lose control over food consumption despite the negative consequences relevant to obesity [12
]. This suggests that they suffer from repeated failed attempts to reduce their food intake, and they are unable to abstain from certain types of food or to reduce consumption [12
In humans, the regulation of food intake is based on an intricate feedback system controlled by hunger and satiety signals [5
]. These signals are generated in the brain, peripheral tissue and/or organs through two complementary drives, including both homeostatic and hedonic pathways [5
]. The hedonic or reward-based regulation pathway is related to the mesolimbic dopamine pathway, which is stimulated in both drug abuse and the consumption of highly-palatable foods [15
]. Evidence has shown that the release of dopamine coordinates food reward, which is impaired in food addicts [15
]. Contrastingly, the homeostatic pathway primarily regulates the energy balance between the brain and peripheries (for instance, digestive tract and adipose tissue) [14
]. This means that based on energy reservation and the psychological want for food, the brain increases or decreases food intake by interpreting the neuronal and hormonal signals received form peripheries [15
]. Therefore, in both pathways, a large number of neurotransmitters (dopamine, cannabinoids, opioids, gamma-aminobutyric acid (GABA) and serotonin), neuropeptides (α-MSH, β-endorphin, cortisol, melatonin, neurotensin, orexin A, oxytocin and substance P, etc.
) and hormones (gut hormones, anterior pituitary hormones and adipokines) are involved, many of which can also be detectable in serum [17
]. Interestingly, many studies have linked these hormones and neuropeptides with the current obesity epidemic [21
]. Moreover, in our previous aforementioned study on the general Newfoundland population, we have reported that food addicts consumed a higher percentage of calories from fat and protein [9
]. However, to the best of our knowledge, there is no study available regarding the differences in appetite regulating hormonal level between being obese with and without food addiction.
Furthermore, macronutrients have been reported to play an imperative role in obesity, addiction-like behaviour and metabolic consequences [33
]. However, there is no study available on the hormonal characteristics and potential differences of macro- and micro-nutrients between being obese with and without food addiction, which will be critical to unravel how food addiction develops. Hence, the aim of the current study is to explore potential biomarkers that may differentiate being obese with and without food addiction by measuring and comparing various hormones and neuropeptides regulating appetite and metabolism and also dietary nutrient intakes in both groups.
In general, endocrine factors have an important role as appetite regulating signals. A large number of hormones play a role in feeding regulation [15
]. The abnormality in the aforementioned hormonal secretions can lead to overeating and, consequently, obesity [16
]. Interestingly, similarities in hormonal changes have been found between obesity and substance abuse addiction [10
]. According to the etiology, obesity is a complex disease and can be caused by many genetic and environmental factors. As we previously reported, food addiction may be an important factor leading to obesity with a unique etiology [9
]. To the best of our knowledge, this study is the first to attempt to prove the idea that obesity with a definite food addiction may manifest distinguished dietary intake and hormonal characteristics.
The first finding in the current study was the significantly lower serum level of TSH and the higher level of prolactin in obese food addicts as compared to obese non-food addicts. Several population-based studies have shown a significant association of BMI with TSH and prolactin levels [46
]. Findings from our current study indicate that the combined abnormality of TSH and prolactin might be one of the hormonal characteristics in obesity with food addiction rather than in general obesity. Data from a number of studies have suggested that the serum TSH level may be a marker of alcohol, opium and cocaine dependence and craving [51
]. A significant negative correlation between TSH level and alcohol craving has been reported in alcohol-dependent subjects [51
], and a significantly lower level of TSH has been found in opium users as compared to healthy controls [54
]. Taken together with our present findings, a lower level of circulating TSH is not only associated with alcohol, opium and cocaine dependence, but also with food addiction. The significant association of prolactin in obese food addicts and the data from other studies on alcoholics, heroin and cocaine addicts with elevated basal prolactin [51
] strongly suggests the involvement of circulating prolactin with food addiction, as well.
Another significant finding in the current study is the significant lower level of serum TNF-α in the obese food addiction group as compared to the obese non-food addiction group. TNF-α level is usually higher in the obese people compared to healthy controls [59
]. TNF-α is known as an anorexigenic cytokine, which reduces food intake. It is thought that the impaired actions of TNF-α may lead to obesity [32
]. It was reported that the levels of circulating TNF-α have been altered in alcoholics, cocaine abusers and opiate addicts. In addition, it has been suggested that TNF-α can be a potential diagnostic biomarker for drugs of abuse [60
]. In an animal model, TNF-α has been investigated as a potential therapeutic target to prevent drug abuse and to increase the chance of cessation. [61
]. The current findings of the association of low TNF-α with food addiction is very interesting and unique. There is more likely a specific manifestation in obese food addicts contrary to the increased level of TNF-α in obese people.
In the current study, we also measured serum neuropeptides regulating appetite. Neuropeptides are predominately synthesized and secreted in the central nervous system; however, levels of some neuropeptides can be detected in the peripheral circulation system [22
]. Abnormalities of neuropeptide levels have also been found in individuals with other addictions and obesity [66
]; however, in this study, no significant differences in the level of any of the measured neuropeptides were found between food addicted and non-food addicted obese subjects.
The third important finding in the current study was the significantly lower level of serum amylin in obese food addicts compared to the obese non-food addicts. This seems to be the first report regarding the link of amylin with food addiction or any other types of addictions. It is not clear at this stage if this low level of circulating amylin is a reflection of food addiction status or simply is just a secondary change owing to other factors. In a randomized crossover study on 10 healthy males consuming one meal high in carbohydrate or fat, it has been shown that amylin is affected by the macronutrient compositions of a meal, as the amylin level was greater after a high carbohydrate meal compared to a high fat meal [71
]. In this study, dietary fat intake was higher in obese food addicts, which may be at least partially responsible for the low level of serum amylin.
In our previous study, we found that all food addicts, regardless of obesity status, consumed a higher percentage of calories from fat [9
]; the same result was also found in an obese food addicts cohort. The high intake of dietary fat was further supported by the finding showing that obese food addicts consumed higher total calories per kilogram of body weight, higher carbohydrates per kilogram of body weight and dietary fat per kilogram of body weight (and per BMI and per percentage of trunk fat). For the first time, we also explored the potential differences of 71 micronutrients intake between food-addicted and non-food-addicted obese subjects. Corresponding to our previous discovery, we found that obese food addicts consumed a significantly higher amount of fat subcomponents: saturated, monosaturated, poly-saturated and trans fat, omega 3 and 6, vitamin D, gamma tocopherol and dihydrophylloquinone (the main source in commercially-baked snacks and fried food [72
]) compared with obese non-food addicts. In addition, obese food addicts consumed higher amounts of sodium and sugar. Therefore, taken together, the data suggest that obese food addicts may consume more hyper-palatable foods that are known to have high amounts of fat, sugar and salt (sodium).
In the present study, the YFAS and Willett Food Frequency Questionnaire (FFQ) were used as tools for the diagnosis of food addiction and measuring nutrient intake over the past 12 months. These sets of measures and the criteria on which they are based have been validated in different populations [7
]. The YFAS is the only tool available for the diagnosis of food addiction. Using this set of criteria can help to distinguish subjects who regularly indulge in hyper-palatable foods from those who have lost control over their eating behaviour [7
]. However, since the aforementioned questionnaires are self-reported, there tends to be self-reporting bias.
It needs to be indicated that food addiction is a complex disease, and numerous factors are involved in the etiology. Psychological conditions, like anxiety and depression, which may cause the fluctuation of TSH, prolactin and TNF-α, were not assessed in the current study [77
]. A related study showed that in alcohol-dependent patients, it has been shown that the hypothalamic-pituitary thyroid axis may have the ability to lead to anxious or depressed mood, which may further affect the TSH level [51
In the current study, the active form of ghrelin was measured. However, the specific inhibitor was not added during sample collection, and therefore, it cannot be excluded that part of the ghrelin may have been degraded. Since all of the samples after blood drawing were placed immediately on ice during the entire process of all experiment, we believe that any degradation would be little, because enzymes that degrade ghrelin would have little activity at this ice-cold temperature.
The correction for multiple comparisons has not been made, since this study is a pioneering study and numerous markers were measured. Moreover, the sample size is relatively small in both groups. However, each of the individuals were well matched in both groups for gender, age, BMI and physical activity level, which would reduce the heterogeneity of subjects and increase the statistical power to detect possible difference in most variables between the two groups. Nonetheless, larger cohorts in different populations are warranted to replicate our findings.