Introduction
With an increased obesity epidemic over the decades, people are being aware of its following health risks, including diabetes, hypertension, arthritis, hypertension and certain cancers. [1,2] The development of obesity is defined as a chronic disease where energy intake persistently exceeds energy expenditure. [1,3] Therefore, increasing interests to understand appetite control and energy homeostasis which involves sophisticated neuro-humeral networks have been developed. The central nervous system (CNS), including the hypothalamus and the brainstem, integrate numbers of peripheral endocrine signals and neural signals reciprocally to modulate energy homeostasis. [3] It is established that gut hormones, such as Cholecystokinin (CCK), Peptide Tyrosine Tyrosine (PYY), Glucagon-like Peptide-1 (GLP-1), Pancreatic polypeptide (PP), and ghrelin are short-term appetite modulators. [3,4] Adiposity factors such as leptin and insulin induce both short- and long-term regulation on appetite by sending signals to the brain, particularly the hypothalamus. [3,5] While excessive food intake can lead to obesity, however, genetic and environmental factors also influence energy balance, which further increase the complexities in the pathogenesis of obesity. [1] It is believed that the mutation in human obese (ob) gene can lead to leptin-resistance, which causes a dysfunction in energy balance, thus obesity. [5,6] Furthermore, environmental factors, such as tobacco use, exercise and stress, also play critical roles in the regulation of obesity. [7] The aim of this article is to critically appraise how appetite is controlled by our body through neuro-humeral interactions.
Central nerve system (CNS)
The brain-gut axis is considered as a central pathway to regulate food intake for decades. [8] In addition to the local and peripheral gut hormones and adipose signals released in response to meal ingestion, neural signals, from the brainstem and higher cortical centres, are integrated with those chemical messages in the hypothalamus. [3] Hypothalamus, as a key region of regulating internal homeostasis, integrate peripheral humoral signals and central neural signals to perform appetite regulation in a delicate way. [4, 8]
Arcuate nucleus (ARC) is the most crucial region in the hypothalamus, where the lack of complete blood-brain barrier (BBB) makes it susceptible to circulating factors. [9] Two discrete neuron populations are resided within the ARC. One group of neurons inhibit appetite by expressing cocaine- and amphetamine-related transcript (CART) and proopiomelanocortin (POMC); while another group of neurons stimulate appetite by expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP). [10, 11] Both groups of neurons project to the paraventricular nucleus (PVN). [12] They interact within the system, subsequently altering food intake and energy expenditure. [13]
As will be discussed later, gut hormones, such as CCK, PYY, GLP-1, PP, and ghrelin are involved in short-term appetite regulation, while adipokines such as insulin and leptin are responsible for long-term regulations.
Gut hormones
Various gut hormones are released from the gastrointestinal (GI) tract in response to meal ingestion with different appetite regulatory effects. While CCK, PYY, GLP-1 and PP have anorexigenic effects [3, 4], hormone ghrelin is the only known orexigenic gut hormone [14].
CCK
CCK is the first hormone found to influence appetite, which is predominantly synthesised by the I cell of the duodenum and jejunum. [15,16] It reduces appetite in response to meal initiation by stimulating gallbladder contracting and inhibiting gastric emptying. [17,18] Accordingly, CCK has become a novel therapeutic target for obesity intervention. [4] Besides its wide distribution in the GI tract, CCK is the most abundant neuropeptide in the CNS. [19] Experiments have suggested that centrally-administrated CCK reduced food intake in rodents [20], whereas the same effect has been found in both rodents and humans through peripheral administration [21]. Despite a dramatic decreased meal size after CCK therapy, an increase in meal frequency has been found in rodents, possibly due to its ability to increase intestine motility. [3, 22] In addition to the increased meal frequency, the development of tolerance [23] and a short half-life of CCK [24] may greatly undermine its therapeutic utility in practical. [4] Interestingly, Peneau et al have found that CCK and leptin can actually act synergistically to reduce body weight in a stronger effect (7), which call for more future research to be conducted to find out possibilities of synergistic effects of drugs. Thus, more human trials are needed in the future to investigate the effectiveness of therapeutic utility of CCK. Side-effects and tolerance should be minimized, perhaps through co-administrating with other artificial gut hormones, to fully support CCK treatment in obesity.
Peptide Tyrosine Tyrosine (PYY)
PYY is an appetite suppressing hormone which secreted from the L cells in the lower intestine along with GLP-1 and Oxyntomodulin (OXM) postprandial in proportion to calorie intake. [3, 24, 25] It is a 36-amino acid peptide with characteristic tyrosine (Y) residues at both its N- and C- terminals. [3, 4] It inhibits food intake by binding to Y2 receptor (Y2R) in the hypothalamus with a high affinity. [3, 24] PYY has reported to be involved in a negative feedback system, which is known as ‘ileal brake’, to control the rate of ingested food transiting down the GI tract. [26] Also, anorectic effects, including energy expenditure regulation, reduced acid and pancreatic exocrine secretions and inhibited gallbladder contraction were found in response to PYY release. [27, 28] A low circulatory PYY level is usually associated with obesity pathogenesis with a lower level reported in obese. [29] Notably, the anorexigenic effect of PYY by intravenous administration has been shown not only in healthy weight subjects, but also in the obese population without causing any nausea, decreased food palatability, or following compensatory hyperphagia. [29, 30] Moreover, it remains intact in obese individuals without developing any resistance, compared to CCK and leptin, suggesting a promising anti-obesity therapeutic for a longer-term weight loss. [29] However, the route of injection contributes to the complexity that central administration of PYY has been found to increase food intake. [31] The reason has been postulated based on the selectivity and accessibility of Y receptor subtypes. [30] While the circulating PYY accesses and binds to Y2R which activates orexigenic NPY/AgRP neurons, intracerebroventricular (ICV) administration of PYY increases appetite through Y5R. [31, 32] Consistently, the same anorectic effect is proved to be abolished by blocking Y2R. [30, 33] Therefore, although corroborated evidence of the anorexigenic effect of PYY has been investigated, dose, route and time of injections are vulnerable factors that should be carefully handled with when applying pharmaceutical interventions to obesity.
Glucagon-like peptide (GLT-1)
GLT-1 is one of the proglucagon-derived peptides which are expressed in the pancreas, intestine and brain. [34] It is co-secreted with PYY from the intestinal L cells postprandially in proportion to calorie intake. [24] Besides the same engagement in ileal brake function as PYY does, it also encourages pancreatic B cell growth to stimulate insulin release, and inhibits glucagon secretion. [35] Its anorexigenic effect is activated by acting on the GLP-1 receptor (GLP-1R). [36] Progressively weight loss as been shown among diabetic patients with the peripheral injection of either GLP-1 or GLP-1R agonist ‘exenatide’ for the following two years even after treatment. [37, 38] Remarkably, harmonization regarding the improved glycaemic control among other organs under these treatments was achieved. [38] Despite the ameliorated diabetic conditions, short half-life of GLP limits its therapeutic value. [39] Nevertheless, another study regarding the long-term weight loss effect of exenatide remains conservative. [40] Similar to PYY, side effects such as vomiting and nausea were reported with ICV injection of GLP-1R. [41] What’s more, C-cell carcinoma of the thyroid as well as pancreatitis have been identified in animal safety studies. [41] Therefore, despite discovered benefit role in regulating appetite, future studies are needed to confirm the long-term safety and effectiveness in weight loss with GLP-1-based therapies.
Pancreatic Polypeptide (PP)
PP is a 36-amino acid anorexigenic peptide secreted from PP cells of the pancreatic islets of Langerhans in proportion to calorie intake. [13] Similarly, physiological effects of PYY and GLT-1 were also found with peripheral PP administration in both lean and obese individuals. [42] The mechanism to reduce food intake is through its significant ability to suppress NPY neuron expression in the hypothalamic ARC, by acting on the Y4R, both peripherally and centrally. [43] However, adverse effects have been shown with central PP administration. [44] Like PYY, this disparity might result from different selectivity and accessibility to Y receptors, which central PP increases appetite through Y5R. [30, 45] On the other hand, circulating PP remained a three-fold’s higher level after intravenous infusion in healthy subjects compared to normal postprandial releasing, indicating a potential long-term effect in regulating food intake. [46] Overall, it has been confirmed that PP is effective in appetite control, with agonists to the Y4R being a promising novel obesity therapy without side effect reported.
Ghrelin
Ghrelin, a 28-amino acid peptide, is the only known orexigenic gut hormone which secreted mainly from the stomach (80%). [47] Contrary to satiation hormones, it increases appetite and food intakes, mainly by increasing meal frequency. [48] Ghrelin level rises pre-prandially and drops post-pradially. [48] However, in obese individuals, fasting ghrelin level appeared to be lower compared to healthy individuals. [49] Notably, there was attenuated post-prandial fall in circulating ghrelin level in the obese, indicating a pathogenic feature of ghrelin in obesity. [50] For example, an elevated plasma ghrelin level is usually characterized in Prader-Willi syndrome. [50] Although the mechanism of this orexigenic effect has not been fully understood yet, it is believed that ghrelin acts on NPY/AgRP neurons and inhibit the POMC neurons within the ARC region of the hypothalamus. [51] Since ghrelin receptor deficient rodents were found resistant to obesity [52], NPY/AgRP antagonist YIL-870 has been developed and shown to abolish ghrelin-induced appetite and weight gain. [53] However, whether the ghrelin system should be considered as a therapeutic target for obesity treatment is still under debate. Delicate human studies are needed to support the finding and the mechanism behind requires further investigation.
Adipose signals
Leptin
The production of leptin is regulated by human obese (OB). [54] It is predominantly secreted by the white adipose tissue with small amounts produced by the stomach, mammary epithelium, placenta and heart, signalling the status of body energy stores. [5] The release of leptin from adipocytes is proportional to the adipose fat percentage. [5] Leptin controls food intake, thus body energy stores, through a negative feedback system. When energy intake is greater than energy expenditure, the secretion of leptin is increased to inhibit orexigenic NPY/AgRP neurons and activate anorexigenic POMC/CART neurons within the hypothalamic ARC, results in decreased appetite and increased metabolic rate. [55-57] Contrarily, starvation leads to shrinking in adipocytes due to energy generation using stored fats. The decrease in size proportionally decreases the release of leptin, therefore removes the signal which normally suppresses appetite. [58] As a result, body decreases the metabolic rate and increases appetite to compensate for the body energy store. This finding suggests an adaptive role of leptin in energy deprivation.
Decreased production of leptin contributes to visceral obesity and other metabolic abnormalities. [59] People with leptin deficiency are susceptible to obese. [6] Surprisingly, instead of expected low leptin production and high ghrelin-induced appetite, obesity is often associated with disturbed leptin and ghrelin levels, where high circulating leptin levels and decreased ghrelin levels were indicated. [60, 61] However, they are not responding to leptin to generate any anorxigenic effect. [61] The disturbance is explained by the concept of ‘leptin-resistant’, which is usually caused by chronic over-eating. [62] Continuous high leptin levels in the circulation over-stimulate leptin receptors in the hypothalamus, making hypothalamus less sensitive to leptin, which further exacerbates the sustained elevation in leptin levels. [63] As such diet/lifestyle-induced leptin resistance, a low-fat diet in restricted meal size with shorter time intervals are suggested for appetite control. [5, 64] Take together the importance of size, frequency and composition of meals having on hormonal concequences, following a specifically tailored diet to regulate food intake is suggested to the obese.
Genetic mutation in the ob gene leads to the development of leptin resistance, and cause leptin deficient patients become more susceptible to obesity, which will be discussed in detail later.
Insulin
Being synthesized in the B cells of the pancreas, insulin has a similar lipostatic role to that of leptin. [65] It decreases appetite and increases satiety by inhibiting NPY/AgRP neurons. [66] Central administration of insulin results in a dose-dependent suppression of food intake. [67] However, similarly, increased adiposity can lead to insulin resistance with diminished regulation on appetite. [68] Approaches aimed at improving insulin sensitivity and insulin receptor function have been targeted. [69-71] Drugs such as metformin, berberine chloride have been proved to function as insulin-sensitizing products to upregulate insulin sensitivity in humans. [69, 70] However, challenges such as safety and effectiveness in human of these pharmacological approaches have been raised [72], which future studies are needed to further elucidate the mechanisms of these products.
Genetics and environmental factors
Like many other chronic diseases, genetic, behavioural and social-environmental factors cause obesity interactively.
Followed by the first discovered human obese (ob) gene and its subsequent product leptin [73], numerous studies have shown a significant regulatory role in appetite and energy expenditure of leptin. [55-57] Besides the hormonal reflexes of leptin, genetic evidence of leptin in human regulating energy balance was first suggested by Montague et al. [74] They confirmed that congenital leptin deficiency is caused by a homozygous frame-shift mutation in the ob gene, in which a single guanine peptide is deleted in codon 133. Those who experience ob gene mutation usually have a normal birth weight, however, hyperphagia and impaired satiety are rapidly developed during their growth, causing severe obesity. Leptin treatment turned out to be effective for leptin-deficient patients, [75] with decreased body weight and beneficial effects on metabolism parameters. Behavioral changes were observed in the trial as well. However, as they had different phenotype and responses to the treatment, studies with diverse patients recruited are needed to confirm the effectiveness of leptin treatment on different individuals. Also, the combination of physical activities in the treatment was highlighted which indicates an important role of environmental factors. [75]
Tobacco use, as the leading cause of preventable mortality worldwide, is associated with appetite control. [76] Ironically, nicotine, a major addictive component in tobacco, suppresses appetite, which lead to decreased food intake and a leaner body image. [76] Smoking cessation even results in weight gain. [77] Although not well understood, nicotine suppress appetite by increasing leptin levels and influencing the CNS. [76] Genetic factor can contribute to the inherited susceptibility to develop nicotine addiction [78], while the motivation is also influenced by family smoking. [79] While it’s usually hard to cease smoking, physical activity has been found to have protective role on youth smoking. [80] These evidences altogether emphasized the complexities in gene-environmental interactions in developing risk behaviours.
Nowadays, the prevalence of the obesogenic environment generates a direct impact on food intake on a neighbourhood level. [81] The built environment with increasingly high density convenience stores and fast-food restaurants limit people’s food choice to an unhealthier stream. [82] Visual and olfactory sensory factors can stimulate the CNS to increase food intake through reward systems. [3] While sedentary lifestyle is undermining people’s health, Exercise has been demonstrated to suppress food intake by reducing ghrelin level and corresponding appetite. [83] Other lifestyle factors such as sleep and stress can have opposite while interactive roles in hormonal adjustments to regulate appetite [84], thus maintaining a healthy body weight.
Conclusion
Human brain, particularly the hypothalamus, integrate various hormonal signals from gut with adipose signals elegantly to regulate food intake and energy balance. Disturbance of the hormones can lead to abnormal metabolic conditions such as obesity and diabetes. Leptin, one of the most important gut hormones, together with CCK, PYY, PP, GLP-1 and insulin, suppress appetite by acting on POMC/CART neurons in the ARC region of the hypothalamus; ghrelin, as the only known orexigenic hormone, stimulate appetite by activating the NPY/AgRP neurons adversely. Treatments include blockage of ghrelin receptors, improved leptin sensitivity and improved leptin receptor function. Vulnerable factors such as dose, route and time of injections should be carefully handled with when applying pharmaceutical interventions. Leptin resistance, which is usually caused by chronic over-eating, can cause obesity. A specifically tailored diet to regulate food intake is suggested to the patients. However, compared to diet-induced obesity, genetically-induced leptin resistance usually lead to uncontrollable hyperphagia and impaired satiety. Leptin treatment appeared to be effective, however, a combination of behavioral intervention is suggested. Environmental factors, such as tobacco use, exercise and stress, have impacts on appetite accordingly. The complexity between the behavioural motivations, environmental factors and genetic factors are noticeable.
In summary, appetite is controllable at hormonal level; however, genetically-induced impaired satiety can be hard to control. Future studies looking at the safety and effectiveness of novel treatments are required.