The Role of Psychobiological and Neuroendocrine Mechanisms in Appetite Regulation and Obesity

Initiation of Food Intake

The biological mechanisms involved in the initiation of each meal include stomach contractions, food taste and energy levels. In particular, although for several years stomach contractions were regarded as the main stimulus, it seems that other mechanisms are involved as well such as psychosocial factors and dieting practices [2, 5, 11].

Food taste plays a key role on food preference and food choice because of the way that a human can perceive the food but also the sensory affective response to the taste, smell, sight and texture of food [16,17]. Food taste for most of the people translates into flavour, smell and oral perception of food texture [17].

There are 'signals' in the circulation that reflect energy reserves [5], one of them being non-esterified fatty acids (NEFAs). Increased concentrations of NEFAs occur in response to lipolysis. So NEFAs are regarded as a biomarker of negative energy balance, if the supply of glucose is insufficient in order to cover energy demands. In obese individuals, NEFAs are constantly increased due to insulin resistance, thus providing a misleading signal of lack of food; as a result obese people eat more than they actually need [18]. Furthermore, there are theories which support the concept that glucose uptake and utilization play a major role in the regulation of hunger, satiety and energy balance. The glucostatic theory maintains that food consumption is activated because of a decrease in blood glucose [19-22]. The lipostatic theory specifies that body fat is the answer to regulate the feeding behaviour [22, 23]. The aminostatic theory proposes that amino acids in the blood have a significant role in defining satiety [22]. The thermostatic theory claims that temperature that develops in specific sensors in the body, such as central thermoreceptors, could act as a food intake sensor for total energy balance [24]. The hepatostatic theory concentrated on the metabolic activity of the liver [25]. The ischymetric hypothesis suggests that the process of feeding can be regulated by our metabolic rate. When the body is in the process of food absorption, the metabolic rate is faster than in fasting [26, 27]. It may well be that all these factors play a role with their contributions differing in individuals.

Meal Duration

Meal duration depends on both endogenous and exogenous mechanisms. Endogenous factors, including a variety of stimuli deriving from the mouth, pharynx, esophagus and the stomach, may cause temporal extension of the meal [28-30]. After the food enters the intestine, absorption, an important function of the small intestine, begins.

The exοgenous factors that may influence meal duration are food appearance, smell and taste as well as environmental conditions. Satiation occurs when the inhibitory mechanisms dominate over stimulants. Interestingly, the hedonistic effect of food consumption may prolong feeding. The mesolimbic dopamine pathway may be responsible for this action; tasty foods may release dopamine into the nucleus accumbens [28-31].

End of Meal

The digestion process initiates in the stomach, where pepsinogen is converted to pepsin by hydrochloric acid, and proceeds to the intestine via the pyloric sphincter. The nervous system and various digestive system hormones [e.g. glucagon and cholecystokinin (CCK)] can control the process which leads to the end of meal. The brain is “informed” about the quantity of food consumption and its nutrient content via sensory stimuli. The gastrointestinal system is equipped with specialised chemo- and mechano-receptors that monitor physiological activity and transfer information to the brain mainly via the vagus nerve [1,28]. Among the factors that influence this process during the meal are amino acid levels in the circulation (amino acids are derived from both protein catabolism and their intestinal absorption). According to the aminostatic hypothesis, amino acids act as peripheral signals to the brain in order to maintain the long-term balance between energy intake and energy expenditure as well as body fat mass over days or weeks [24, 32]. In this context, increased muscle catabolism and elevation of amino acids levels leads to feeding, whereas postprandial uptake of amino acids from the plasma into the muscles results in the cessation of feeding and a period of satiety [24, 33].

The absorption rates of amino acids are highly dependent on their protein source. Several amino acids derive from the catabolism of soy protein and milk; however specific milk proteins such as beta-lactoglobulin and casein have different digestibility [24, 33-35]. The classification of whey proteins as “fast proteins” and of caseins as “slow proteins” is consistent with their reported effect on food intake in humans. Whey has been found to reduce food intake at 90 min, whereas casein exerts a stronger effect later (at 150 min) [33,36]. Furthermore, there is considerable evidence that the effect of whey proteins on satiety and food intake is mediated via the release of certain satiety hormones such as CCK, glucagon like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY and ghrelin. Indeed, more than 20 different regulatory peptide hormones are released in the gastrointestinal system and many of them are involved in the regulation of food intake [36, 37]. Furthermore, peripheral opioid and CCK-A receptors can be activated by casein ingestion; blocking these receptors with antagonists reduces their effect on food intake [36-39].

Dietary Choices

Dietary preference is defined as an option when all kinds of food are available. Practically all types of food are never available at one time, therefore we choose the food we like best or the food that is easier to have at that time. Appetite is characterized by the preference of a particular food over another whose consumption may bring pleasure and taste.

Dietary choices are determined by both biological (genetic, hereditary factors) and environmental factors. Scientific data indicate that appetite or distaste for certain kinds of food is incorporated in our genetic code. We are born with unknown predispositions for sweet or bitter tastes, sour or salty tastes [3, 4, 7, 9, 16, 40]. Other factors responsible for dietary choices involve congenital conditions; a plurality of environmental factors determines our dietary preferences including imitation, social and emotional effects, physiological needs, industrial communication policies (i.e. advertising) and seeking new dinning experiences [4, 10, 40]. In obese people the situation is slightly different because the amount of food intake may be increased following its beneficial effect on emotional status (i.e. stress reduction and improvement of depressing feelings) [7, 41, 42]. Interestingly, there is a tendency towards the consumption of foods rich in carbohydrates whenever obese individuals are emotionally distressed [11, 41, 43]. It should also be noted that exogenous factors such as food taste, smell and hedonic effect may have a greater influence on obese people than endogenous factors such as hunger, energy needs and satiation [3, 4, 11, 41].

Leptin, Insulin and Obesity

Leptin, one of the most important adipose-tissue derived hormones, plays a major role in the regulation of energy intake and energy expenditure in terms of appetite and metabolism control [59, 60]. Leptin is a 167 amino acid protein primarily produced in white adipose tissue. Circulating leptin levels are directly proportional to the total amount of fat in the body. Leptin acts on specific hypothalamic receptors and inhibits appetite by counteracting the effects of the orexigenic neuropeptide Y (NPY) [47,61-63]. Furthermore, leptin enhances the synthesis of alpha menalocyte stimulating hormone (α-MSH), an appetite suppressant [64]. The absence of leptin or its receptor leads to uncontrolled food intake, resulting in obesity [65]. Insulin, a hormone composed of 51 amino acids, is produced by the islets of Langerhans in the pancreas; it can regulate carbohydrate and fat metabolism in the body via glucose utilization in the periphery (e.g. liver and muscles) and inhibition of glucagon release [64]. In the absence of insulin, glucose uptake from peripheral tissues is inhibited; thus hyperglycemia occurs, leading to diabetes, and fat becomes the energy source of the organism via gluconeogenesis [65]. Similarly, in cases of insulin resistance, both obesity and diabetes may arise.

Leptin and insulin were shown to proportionally increase the quantity of body fat after eating [64]. Furthermore, these hormones are able to influence meal duration, metabolic activity and energy intake for a prolonged period of time through interactions with the CNS [44, 45,59]. Certain characteristics of leptin and insulin secretion and action explain why they are regarded as regulators of food intake and energy homeostasis [47,66-68]. For example, their levels in the circulation are proportional to adipose tissue mass, they penetrate the blood-brain barrier into the CNS at rates that depend on their plasma concentrations and specific receptors for leptin and insulin have been identified in neurons that control metabolic activity [64, 66,69].

Furthermore, their administration directly into the CNS was reported to inhibit food intake in animal models [64,69]. Interestingly, both hyperinsulinemia and insulin resistance exist in obese individuals, probably as a balancing mechanism to inhibit further increases in body weight [59,62,70]. Leptin effects on food intake mechanisms seem to be stronger than those of insulin. It has been shown that the absence of leptin in the human body can cause severe obesity, even though insulin levels are high [65]. The interactions between leptin and insulin are complicated while their effects on the endocrine system differ [71-73]. Leptin acts as a negative signal for the brain and suppresses food consumption. On the other hand, insulin promotes glucose uptake from peripheral tissues in a rate proportional to serum leptin levels. Insulin secretion is adjusted in response to acute metabolic changes; insulin levels increase during meals or when glucose is elevated for another reason and decrease during stress and exercise [64, 65,73]. Leptin is secreted from adipocytes in an amount proportional to the metabolic action of fat cells; thus plasma leptin levels are a reliable marker of body fat [47, 74]. Low leptin levels indicate depleted fat stores and inhibit functions that require adequate energy stores (e.g. reproduction) [47,64,74]. Plasma insulin levels have a direct link to body weight and body adiposity; they also reflect acute changes in energy homeostasis [64, 74]. Of note, insulin secretion reflects the amount of visceral white adipose tissue, whereas leptin secretion reflects total fat mass and especially subcutaneous fat mass [64, 75]. Of note, in obesity, small quantities of food consumption may cause greater reductions in insulin and leptin levels compared with the expected in terms of the increased adipose tissue mass [64]. In response to body fat increase, leptin and insulin levels are also increased [64]. Through the bloodstream, these 2 hormones reach the hypothalamus and activate specific "catabolic" neuroendocrine circuits, which inhibit food intake and increase metabolic activity [ 47, 59, 63]. On the other hand, in cases of body fat reduction (e.g. during dietary weight loss), insulin and leptin levels are also decreased. This process results in a reverse effect of the aforementioned mechanisms, i.e. "anabolic" circuits are activated that increase food intake and meal duration, and reduce metabolic activity [59,63]. The "catabolic" neuroendocrine pathways that are stimulated by increases in body fat, leptin and insulin levels, involve activation of anorexigenic neurons and inhibition of orexigenic neurons, particularly those that express NPY. On the other hand, when the "anabolic" circuits are activated by body fat reductions, these mechanisms are completely reversed i.e. orexigenic neurons are now stimulated and anorexigenic neurons are suppresed. By these alterations, the CNS controls appetite and food intake in order to maintain energy homeostasis [62,67,76,77]. The neuroendocrine circuits that are involved in the control of food intake, are situated in the hypothalamus [47,70]. Leptin and insulin receptors are located throughout the CNS and mainly in the arcuate nucleus (ARC) of the ventral hypothalamus [47,69]. Interestingly, in obese individuals, a persistent eating behaviour (i.e. overeating) remains, although blood leptin levels are elevated [64]. The exact causes of this phenomenon are still unknown. However, 2 potential mechanisms may be involved; firstly, it has been proposed that circulating leptin may not be able to penetrate the blood-brain barrier in adequate amounts and thus cannot perform its action in the hypothalamus. Secondly, it is possible that some orexigenic receptors become resistant to leptin and therefore, they cannot be activated by leptin-dependent mechanisms [62, 67, 70, 76].

Ghrelin and Obesity

Energy balance is achieved by the synergistic action of both endocrine and neural signals from adipose tissue and the gastrointestinal tract as well as the interactions of these signals with the CNS [78-80]. These mechanisms are complicated and interrelated; none of them work independently. In this context, apart from leptin, insulin and NPY, ghrelin, a gastrointestinal hormone, also plays an important role in appetite control and energy homeostasis [72,74,78,80]. Ghrelin was first discovered in a rat stomach [81]. It is produced mainly in the dome of the stomach by a specific type of endocrine cells of the gastric mucosa (H/A neuro-secretory cells). Additionally, ghrelin is produced by the kidney, pituitary, hypothalamus and placenta [78, 81]. Of note, ghrelin secretion is rhythmic following the circadian rhythm [80] with increased hormone levels during the night. Typically, circulating ghrelin concentrations are elevated before eating and decline rapidly, soon after a meal [82].

Ghrelin effects on energy balance were studied in mice and rats [78]. Regional daily administration of ghrelin could cause weight increase due to decreased use of fat as energy source; continuous administration of the hormone, both centrally and peripherally, led to a dose-related increase in food intake and, consequently, in body weight [78]. In growth hormone (GH) deficiency, ghrelin reverses the leptin-dependent inhibition of food intake and mRNA expression of the hypothalamic NPY. Therefore, ghrelin acts as endogenous antagonist of leptin [72, 80, 83]. Ghrelin effects on food intake are thought to be mediated within the CNS. The role of the ARC is well established in food intake control [12]. There are 2 key neuronal populations in the ARC; those promoting feeding and those suppressing appetite. Ghrelin targets the neurons that co-expresses the orexigenic peptides NPY and agouti-related protein (AgRP) [80]. In detail, animal studies have demonstrated an increased mRNA expression of the hypothalamic AgRP and NPY following ghrelin administration [80]. Studies in rats showed that plasma ghrelin concentration was increased by fasting and decreased by re-feeding and administration of oral glucose but not with water intake [78].

Overall, ghrelin is a gastric peptide with orexigenic action promoting fat decomposition, informing the hypothalamus when an increase in calories is needed for energy production.[20]. Ghrelin may also exert beneficial direct cardiovascular effects via regulation of energy homeostasis and increased GH release, as well as control of autonomic nervous system and interaction with cardiovascular cells [84]. In this context, ghrelin was found to increase inducible nitric oxide synthase (iNOS) expression in rat hearts [85]. Furthermore, ghrelin was previously shown to bind to a species of high density lipoprotein (HDL) that is associated with the plasma esterase, paraoxonase, and clusterin; this interaction may alter the biostability and activity of ghrelin through conversion of ghrelin to des-acyl ghrelin as the acylated form of ghrelin is the active one [86]. It is important to consider that HDL has multiple actions in addition to reverse cholesterol transport [87]. This finding suggests a link between ghrelin and lipid profile; of note, obesity is frequently characterized by low HDL-cholesterol levels.

Interestingly, obese individuals with GH deficiency were found to have increased small low density lipoprotein (LDL) and HDL particles (i.e. more atherogenic lipids) compared with obese subjects with normal GH levels and non-obese ones [88]. The clinical importance of LDL subfractions has been discussed in a statement by a European panel on LDL subclasses [89]. Lipid-lowering drugs including statins, fibrates, ezetimibe and niacin, as well as anti-obesity agents (e.g. orlistat) were shown to reduce LDL size [90,91]. Rosuvastatin alone or combined with fenofibrate or ω-3 fatty acids not only raised LDL size but also reduced the cholesterol of HDL particles [92]. Whether GH replacement therapy could beneficially affect lipoproteins, thus reducing CVD risk, remains to be established [93].

Obese individuals have lower ghrelin levels compared with similarly aged people with normal weight [78]. In contrast, individuals who suffer from eating disorders, such as anorexia nervosa, have higher plasma ghrelin concentrations than others with normal or below normal body weight [82,94]. These findings highlight the fact that ghrelin acts inversely in relation to calorie intake.

Table 1 summarizes the metabolic effects of leptin and ghrelin, as reported in animal studies.

Leptin, Insulin and Ghrelin Interactions in Response to Dietary Status and Cardiovascular Risk Reducing Drug Treatment

Leptin, insulin and ghrelin are closely related with regard to the regulation of hunger, satiety and nutritional status. In detail, insulin decreases ghrelin production and increases leptin release [47,95,96] while leptin decreases insulin secretion [64,75]. Low levels of insulin lead to increased ghrelin concentrations, thus resulting in hunger and food intake [64]. In addition, stored fatty acids are released from fat cells and leptin production by adipose tissue is decreased as fat cells shrink in size. The reduction in leptin release causes a fall in the metabolic rate and thus fewer calories are consumed [76].

After long-term calorie excess, insulin levels are increa-sed and fatty acids enter fat cells.[64] As a consequence, leptin secretion from adipose tissue is increased. Leptin in turn increases adiponectin production [35]. Adiponectin is an adipocyte-derived peptide that beneficially affects several functions such as glucose regulation, fatty acid catabolism and atherosclerosis [97], as well as the production of new fat cells. It follows that adiponectin plays a role in the development of metabolic diseases such as obesity, non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome [15]. When leptin resistance develops, adiponectin levels are decreased despite the presence of elevated leptin concentrations [62, 98]. As fewer new fat cells are made, the already existing adipose cells, that are full of fatty acids, produce more and more leptin [64]. Eventually, fatty acids start being stored in the muscles and liver, thus impairing insulin sensitivity [64]. Interestingly, increased insulin levels also inhibit the activity of hormone sensitive lipase (HSL), an important muscle enzyme that is involved in the utilisation of stored fatty acids as energy source [64, 99]. HSL is activated in cases of energy need in response to catecholamines and adrenocorticotropic hormone (ACTH). The inhibition of HSL in the presence of hyperinsulinemia leads to the accumulation of even more fatty acids in muscles [99]. The overall result is the development of a continuous vicious cycle of hyperleptinemia, leptin resistance, hyperinsulinemia and insulin resistance, also leading to the consumption of extra calories even though obesity has already developed [64,75,99].

Obesity frequently co-exists with dyslipidemia, hypertension and insulin resistance, which are metabolic syndrome (MetS) components [100]. MetS is characterized by increased CVD morbidity and death as well as all-cause mortality [101,102] supported by meta-analyses [103-105]. Multifactorial treatment was shown to significantly reduce CVD risk in MetS patients [106-108]. In this context, several drugs (e.g. lipid-lowering, antihypertensive, hypoglycemic and weight-reducing) may also influence the levels of these regulatory peptides (i.e. leptin, insulin, ghrelin and NPY) [109]. For example, insulin treatment was shown to increase leptin and decrease NPY levels in diabetic patients; body weight was also increased in insulin-treated patients [110]. This was probably due to other mechanisms such as the anabolic effects of insulin, stimulation of lipogenesis, suppression of hepatic glucose production, reduction of basal metabolic rate and elimination of glycosuria. It is also possible that leptin resistance may be partly responsible for the observed weight increase.

With regard to antiobesity drugs, orlistat (an inhibitor of gastrointestinal lipases) and sibutramine (a selective inhibitor of central neuronal reuptake of serotonin and noradrenaline) were found to reduce leptin and increase adiponectin levels in obese patients; orlistat also raised ghrelin concentrations [109]. Similarly, rimonabant (a selective cannabinoid CB1 receptor antagonist) was reported to decrease leptin [111] and increase adiponectin concentrations [112] in obese patients with dyslipidemia. Of note, orlistat, sibutramine and rimonabant also exerted beneficial metabolic effects on waist circumference, lipids and insulin sensitivity, thus contributing to reduced CVD risk [113-116]. Both rimonabant and sibutramine were withdrawn from the market due to psychiatric and cardiovascular (raised blood pressure) side effects, respectively [117-119]. Orlistat is still available for obesity treatment with certain adverse effects and drug interactions that limit its efficacy [120]. As new weight-reducing drugs that are both effective and safe are needed, several developing agents have been evaluated in Phase II and III trials including Contrave [a combination of naltrexone sustained-release (SR) + bupropion SR] [121] Qnexa (combination of phentermine with controlled release topiramate) [122] and lorcaserin (a selective 5-hydroxytryptamine receptor 2c agonist) [123]. Apart from weight loss, these drugs also improved cardiometabolic parameters (e.g. waist circumference, lipids, fasting glucose and insulin sensitivity) [121,123, 124]. Lorcaserin was recently (27 June 2012) approved by the U.S. Food and Drugs Administration (FDA) for obesity treatment in addition to lifestyle changes (i.e. diet and exercise) [125]. The drug should not be used in combination with medicines that treat migraine and depression or other drugs that may increase serotonin release or activate serotonin receptors and should be discontinued if < 5% of initial body weight is lost within 3 months of treatment [125]. Furthermore, it should be used with caution in patients with valve abnormalities since serotonin receptors and metabolism have been implicated to drug-induced valvular heart disease as was the case with methysergide, ergotamine, fenfluramine and dexfenfluramine [126]. Of note, animal studies have reported increased incidences of mammary adenocarcinomas and brain astrocytomas in relation to lorcaserin administration [127]; the company (i.e. Arena Pharmaceuticals) defended the drug stating that lorcaserin concentrations in human brain are significantly lower than the amount used in rats [128].

Qnexa was also approved by the FDA on 17 July 2012 for treating obesity; upon its approval, the drug name was changed to Qsymia to avoid confusion with another drug [129]. The drug should not be used in patients with glaucoma, hyperthyroidism, recent (within the last 6 months) or unstable heart disease and stroke as it increases heart rate; heart rate should be monitored regularly. Furthermore, the drug should be discontinued if the achieved weight reduction is less than 5% of initial body weight after 3 months of therapy [129].

Contrave, although initially rejected by the FDA in the early 2011 due to concerns on CVD risk, has now a second chance as the FDA agreed (in September 2011) to a new cardiovascular outcomes trial design with potential approval in 2014 [130]. The effects of commonly prescribed drugs on adipokines and cardiometabolic factors should be taken into consideration in obesity prevention and treatment. Of note, hypolipidemic drugs, either as monotherapy or in combinations, were reported to reduce the residual vascular risk in obese patients, highlighting their importance in clinical practice [131].

Ghrelin effects on energy balance in humans are not entirely clear, but it was found that ghrelin levels are affected by both acute and chronic variations in nutrition [78]. Of note, the maintenance of weight loss after gastric bypass surgery was shown to be due not only to the reduced stomach volume but also to a reduction in ghrelin levels which were no longer elevated before meals [82]. In general, bariatric surgery represents a promising treatment option in morbidly obese patients, leading to reduced CVD morbidity and mortality; several co-morbidities such as hypertension, dyslipidemia, diabetes and NAFLD are also improved [132].

Apart from the aforementioned hormones, several other peptides are involved in energy homeostasis and food intake control, including resistin, visfatin and retinol binding protein-4 (RBP-4) [133,134]. In this context, these peptides have been associated with MetS and its components such as obesity and insulin resistance, thus contributing to the increased CVD risk that characterizes these metabolic abnormalities [135-138]. Furthermore, visceral and liver fat correlated with visfatin and RBP-4 levels in diabetic patients [139].