Abstract: No truly effective drugs exist to treat obesity, which is reaching pandemic proportions. The search for new treatments has led to an interest into the homeostatic system of central appetite regulation. Key components of this system include the hypothalamus and brainstem, the gut, and adipose tissue. It is now recognized that food intake leads to the release of various gut hormones. There are several anorectic (appetite suppressing) gut hormones released, including cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine, and pancreatic polypeptide. To date, only one example is known of an orexigenic (appetite stimulating) hormone, ghrelin. These hormones circulate in the blood and signal via vagal nerve afferents to communicate with the hypothalamus and brainstem. This information is integrated and processed in key hypothalamic nuclei. The arcuate nucleus appears to be a central controller of the appetite circuit, integrating both peripheral and central signals. This information is translated into downstream signals affecting body metabolism and food intake. Increased understanding and successful manipulation of this system should enable the design of a successful and much needed anti-obesity treatment.
The body’s weight is maintained through a homeostatic system regulating food consumption and energy expenditure. Crucially, cross-talk between gut and brain is central to this homeostasis. The consumption of food leads to the release of gut hormones and the activation of neuronal pathways. These signals are integrated within the hypothalamus where they lead to changes in metabolic rate, regulation of gut motility and appetite. Unfortunately, this homeostatic system is subject to dysregulation, and the most notable sign of this dysregulation is the global trend towards increasing obesity, literally fueled by the modern availability of practically unlimited amounts of food, combined with reduced opportunities to expend energy. The traditional “eat less, play more” advice is no longer adequate in tackling this global pandemic. Our rapidly emerging understanding of the appetite circuits involving the gut, adipose tissue, and brain signaling pathways may allow the development of anti-obesity drugs to supplement diet and exercise. This review first describes the central appetite circuit, and neuropeptides of interest within this circuit, and then the various peripheral gut hormones, and the mechanism by which they regulate appetite.
The Historical Understanding of Appetite Regulation
It has been known since the 19th century that obesity can be associated with pituitary tumors (Bramwell, 1888). Experiments conducted in rats demonstrated that ablation of the hypothalamus, specifically the ventromedial nucleus led to obesity (Hetherington and Ranson, 1939). In contrast, destruction of the lateral hypothalamus reduced feeding (Anand and Brobeck, 1951). A dual center model of feeding was proposed with a feeding center in the lateral hypothalamus and a satiety center in the ventromedial nucleus (Stellar, 1954). The modern picture, however, is more complex involving multiple nuclei and signaling pathways within the hypothalamus, brainstem, and cortex.
The Hypothalamus and Appetite Circuit
The hypothalamus regulates appetite and metabolism by detecting peripheral signals, e.g., hormones from the gut and adipose tissue and nutrients within the blood (Figure 1). The blood brain barrier (BBB) separates cerebrospinal fluid from blood and prevents circulating gut derived peptide hormones from entering the brain. Peptide hormones must therefore cross at areas where the BBB is incomplete or via specific transport mechanisms. The hypothalamus lies adjacent to three circumventricular organs (CVO) which are areas lacking a BBB: the median eminence, subfornical organ (SFO), and organum vasculosum of the lamina terminalis (OVLT). The SFO and OVLT contain neuronal cell bodies and are known as sensory CVOs (Johnson and Gross, 1993). These CVOs are uniquely placed to “taste” the blood and transmit this information to the brain by axonal projections. Therefore, it is likely that peptide hormones communicate with the hypothalamus via these CVOs.
Within the hypothalamus the arcuate (ARC) nucleus is a key area involved in appetite regulation. The ARC is found at the base of the hypothalamus above the median eminence, and possibly detects peripheral signals due to its close proximity to this CVO (Broadwell and Brightman, 1976; Shaver et al., 1992). Within the ARC are two distinct neuronal populations. One co-expresses orexigenic (appetite stimulating) neuropeptides: agouti related peptide (AgRP) and neuropeptide Y (NPY). The other expresses anorectic (appetite suppressing) peptides, pro-opiomelanocortin (POMC) and cocaine- and amphetamine regulated transcript (CART) (Broberger et al., 1998; Hahn et al., 1998; Elias et al., 1998). These opposing centers are linked to regulate appetite. For example, following a meal AgRP and NPY are inhibited and POMC and CART stimulated. From the ARC, signals are relayed to various downstream effector neurons. The ARC receives neuronal information from the paraventricular nucleus (PVN) and there is reciprocal signaling between these two nuclei (Ricardo and Koh, 1978). This connection between the ARC and PVN is important in the appetite regulatory circuit.
The PVN is located at the border of the third ventricle. It is divided into a medial parvocellular division and a lateral magnocellular division. The medial division expresses thyrotropin releasing hormone, corticotrophin releasing hormone, enkephalin, somatostatin, and vasoactive intestinal peptide (VIP). The lateral division expresses vasopressin and oxytocin which project to the posterior pituitary (Swanson and Sawchenko, 1980). The PVN is therefore important for energy balance as it regulates the thyroid and adrenal neuroendocrine axes, as well as modulating sympathetic activity. It is a critical site of integration between the ARC and the nucleus of the tractus solitarius (NTS) within the brainstem (discussed in the following section).
The transfer of information between the ARC and PVN is one of the key mechanisms by which the input of nutritional information arriving in the hypothalamus is transformed into output effector signals affecting metabolism. As well as the PVN, the ARC relays information to other second-order hypothalamic sites including the lateral hypothalamic area (LHA), dorsomedial nucleus (DMN), and the ventromedial nucleus (VMN). The DMN may play an important role coordinating circadian rhythm with feeding and energy expenditure (Gooley et al., 2006). The VMN, previously known as the satiety center, contains neurons that express brain derived neurotrophic factor (BDNF). This neuropeptide is also regulated by nutritional status, leptin, and melanocortin signaling. BDNF appears to have an inhibitory role on appetite as reduced BDNF receptor expression or signaling leads to increased food intake and weight gain (Rios et al., 2001; Xu et al., 2003).
The LHA was previously designated the feeding center. Although its role is not quite that simple, it is the nucleus most sensitive to the effects of the orexigenic neuropeptide NPY (Stanley et al., 1993). In addition, it contains neurons releasing the orexigenic peptides, orexin A and B, as well as melanin concentrating hormone (MCH) (Bittencourt et al., 1992; Sakurai et al., 1998). In addition to their orexigenic properties, the orexins appear to increase arousal and may initiate food seeking behavior in starvation (Chemelli et al., 1999). These neurons project widely within the hypothalamus and also connect to the hippocampus, amygdala, basal ganglia, and thalamus, areas involved in memory, motivation, behavior, and learning.
The Brainstem and Appetite Circuit
The brainstem, consisting of the midbrain, pons, and medulla, contains key cranial nerve nuclei. The dorsal vagal complex, comprising the tractus solitarius (NTS), the area postrema (another sensory CVO), and the dorsal motor nucleus of the vagus is located within the medulla oblongata. Vagal nerve afferents within the gastrointestinal tract and hepatoportal regions are stimulated by mechanical distension, chemical stimulation, and local production of gut hormones (Schwartz, 2000). These signals terminate in the NTS, where signals from the parasympathetic nervous system are integrated, and from here information is relayed to the ARC. Therefore, peptide hormones have two main mechanisms of communicating with the central appetite circuit. The first is through the CVOs to the hypothalamic nuclei and the second is via stimulation of vagal afferents and subsequent transfer of information between the NTS and ARC. In addition, some peptide hormones are actually expressed within the brain; however, it is currently unknown how these centrally expressed peptides differ from peripheral ones.
Neuropeptides and Neurotransmitters Involved in Appetite Regulation
NPY and AgRP are orexigenic neuropeptides and act to stimulate appetite whereas POMC and CART are anorectic neuropeptides and reduce appetite. Further inputs to the appetite system include dopamine, serotonin, and the endocannabinoid signaling system.
NPY is the most abundant peptide in the central nervous system (CNS), and the most orexigenic neuropeptide in the hypothalamus (Allen et al., 1983). NPY induces food intake with a preference for carbohydrate rich foods. It also decreases energy expenditure, reduces thermogenesis, has an anticonvulsant effect, inhibits sedation, affects mood and memory, and stimulates luteinizing hormone release (Wettstein et al., 1995). In the hypothalamus, NPY neurons are found in the ARC with projections throughout the hypothalamus (Morris, 1989). Hypothalamic NPY levels correlate with food intake; expression levels increase with fasting and decrease with food intake (Sahu et al., 1988). Hormones involved in the control of energy balance, such as insulin and leptin, have a negative feedback effect on NPY expression in the hypothalamus (Stephens et al., 1995).
NPY is the endogenous ligand for four known receptors in humans: Y1R, Y2R, Y4R, and Y5R (Michel et al., 1998). Y1R and Y5R appear to mediate the orexigenic actions of NPY, whereas Y2R and Y4R mediate anorectic effects. Y1R and Y5R are co-expressed in several hypothalamic areas including the PVN. However, Y2R, an autoinhibitory presynaptic receptor, is the predominant NPY receptor in the brain (Berglund et al., 2003).
The melanocortin system
POMC is processed by prohormone convertases 1 and 2 (PC1) and (PC2) into α-melanocyte stimulating hormone (αMSH) which acts as an agonist at the melanocortin receptors, MC3R and MC4R (Fan et al., 1997). These receptors are abundant in the ARC, PVN, and VMN. While common human obesity is rarely due to single gene mutations, MC4R mutations appear to be the commonest single gene cause of human obesity and have also been implicated in polygenic obesity (Yeo et al., 2000). MC4R agonists inhibit food intake whereas antagonists stimulate food intake. Therefore, melanocortin neurons within the ARC exert a tonic inhibitory effect on feeding.
Agouti mice AY have bright yellow fur and are a model of obesity. This is due to dominant alleles at the agouti locus (A) leading to ectopic expression of agouti peptide, which is an MC1R and MC4R antagonist. Antagonism at MC1R leads to the bright yellow color whereas MC4R antagonism leads to obesity. AgRP is an endogenous melanocortin antagonist and is co-expressed by many NPY neurons in the ARC .
CART neurons are found throughout the CNS, and CART is expressed abundantly in the hypothalamus, almost exclusively co-localizing with POMC. Intracerebral CART administration either inhibits or stimulates feeding depending on the exact location of injection. To date, the CART receptor and downstream signaling pathways have not been fully elucidated.
There is currently an incomplete view of how the hypothalamus regulates appetite. The reward pathways involving the limbic system, cortex, hippocampus, and amygdala play an important role in appetite regulation, and it is likely that these systems are responsible for over-riding the homeostatic weight regulation system, leading to over-eating and obesity (Berthoud, 2004). Novel neuropeptides and hormones are being identified and how these fit into the picture is yet to be established. Since the discovery of the first gut hormone, secretin, over 100 years ago, many more gut hormones have been discovered (Bayliss and Starling, 1902). The next section describes various peripheral adipose tissue and gut hormones and the mechanism by which they exert their effects on the central appetite circuit.
Peripheral Adiposity Hormones Involved in Appetite Regulation
The idea that adipose tissue stores are sensed and signaled to the hypothalamus to regulate food intake and metabolism was proposed over fifty years ago (Kennedy, 1953). Insulin was the first hormone proposed to enter the brain via the circulation to reduce food intake (Woods et al., 1979). Although insulin is not released from adipose tissue, its levels correlate with body adipose tissue mass and it is considered an adipostat hormone. Within the brain, peptides that lead to reduced appetite and body weight have also been described as catabolic and peptides that lead to increased food intake and energy storage known as anabolic. Thus insulin has contrasting central and peripheral roles. In the periphery, insulin acts as an anabolic hormone, promoting energy storage, glucose uptake, protein synthesis, and lipogenesis. In contrast, central insulin administration is catabolic. In addition to the impracticality of using insulin as an anti-obesity treatment due to its blood glucose lowering effects, patients with diabetes on exogenous insulin often gain weight, possibly demonstrating central insulin resistance.
The discovery of leptin in 1994 has since overshadowed insulin. Leptin is an adipocyte derived hormone secreted in proportion to total body fat content (Zhang et al., 1994). A reduction in body fat leads to reduced leptin levels which stimulates food intake and reduces energy expenditure. In the absence of leptin or in leptin receptor deficiency (ob/ob or db/db mice) animals increase food intake and become obese. These mice live in a state of perceived starvation as the hypothalamus does not recognize increased adipose tissue stores. These animals also have abnormal reproduction, hypothermia, and stunted linear growth (Friedman, 1997).
The orexigenic NPY and AgRP neurons as well as the anorexic CART and POMC neurons within the ARC express both insulin and leptin receptors (Marks et al., 1990; Schwartz et al., 1996; Mercer et al., 1996). Activation of insulin and leptin receptors leads to common downstream pathways and there appears to be crosstalk between these signaling pathways. Insulin and leptin inhibit NPY/AgRP neurons and stimulate POMC/CART neurons. Leptin also reduces the inhibitory GABA release onto the POMC cells. Insulin and leptin receptor activation leads to JAK/STAT3 pathway activation which in turn modulates gene expression; NPY gene expression is inhibited and POMC gene expression increased. As well as affecting the hypothalamus and brainstem, insulin and leptin receptors are present in other areas of the brain including the cerebellum, NTS, and thalamus. In addition, adiposity signals appear to regulate certain reward aspects of foods. Overall, the actions of leptin and insulin appear to suppress appetite. In the syndrome of “diabetic hyperphagia” where levels of both leptin and insulin are low, reduced signaling to the brain may lead to increased food intake.
Leptin was initially considered to be an anorectic hormone. However, in common human obesity, elevated leptin levels do not suppress appetite. This may be due to leptin resistance; alternatively, the role of leptin may be to signal to the brain that energy stores are adequate, i.e., acts as a permissive hormone allowing energy requiring processes, such as reproduction, to occur. Obesity due to defects in leptin signaling appears to be relatively rare (Farooqi and O’Rahilly, 2006).
Peripheral Gut Hormones Involved in Appetite Regulation
There is a vast array of hormones secreted from the gastrointestinal tract that have anorectic effects. These include: cholecystokinin, glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), pancreatic polypeptide (PP), peptide tyrosine tyrosine (PYY), and islet amyloid peptide (IAP). Ghrelin is the only example of a peripheral hormone that is orexigenic. These hormones are secreted from various entero-endocrine cells located throughout the gut.
CCK was the first gut hormone discovered to reduce food intake. It is widely distributed in the gut, secreted mainly by entero-endocrine I cells in the duodenum and jejunum (Gibbs et al., 1973). It is released rapidly post-prandially in response to fat and protein. Its actions include: inhibition of food intake, delayed gastric emptying, stimulation of pancreatic enzyme secretion, and stimulation of gall bladder contraction. These effects are mediated via binding to CCK receptors on the vagus nerve. CCK administration to humans and animals inhibits food intake by reducing meal size and duration. However, the reduction in meal size is offset by an increase in feeding frequency (West et al., 1984). At high dose, nausea and taste aversion have been detected making CCK an unlikely candidate for an anti-obesity treatment.
Glucagon-like peptide-1 (GLP-1)
Pre-proglucagon is a 180-residue peptide expressed by the alpha cells of the pancreas (Mojsov et al., 1986), entero-endocrine L cells of the intestine (Orskov et al., 1987), and in the nucleus of the tractus solitarius (NTS) in the brainstem (Tager et al., 1980). Pre-proglucagon is an example of a polyprotein, a protein from which biologically important fragments are released following post translational processing. In the L cells and in the brain, pre-proglucagon undergoes post-translational modification by PC1/3 to produce active GLP-1. There are two bioactive forms of GLP-1: GLP-17-36 amide and GLP-17-37; however, the majority of circulating GLP-1 is GLP-17-36 amide (Orskov et al., 1994). GLP-1 binds to the GLP-1 receptor. These have been found in the pancreas, stomach, gut, kidney, lung, and heart and in several areas in the brain including the ARC, PVN, and the supraoptic nucleus (SON) (Kieffer and Habener, 1999).
GLP-1 is most well recognized for its incretin effects. Incretins are gut derived hormones responsible for the increased secretion of insulin when glucose is given orally compared to intravenously (Elrick et al., 1964; La Barre and Still, 2009). GLP-1 stimulates insulin and inhibits glucagon release. GLP-1 is partly responsible for the “ileal brake.” It inhibits upper gastrointestinal motility and reduces gastric emptying, gastric acid secretion, and pancreatic exocrine activity. This increases absorption of nutrients in the lower intestine (Schirra and Goke, 2005).
GLP-1 also fulfils several criteria in order to be considered a satiety signal. Circulating levels of GLP-1 rise following food intake and are low in the fasted state. In addition, GLP-1 has a rapid onset and a short half life, and is able to reduce food intake at physiological doses. As described, GLP-1 receptors are located in areas in the brain involved in appetite control. The actions of GLP-1 on ARC neurons are not totally clear although GLP-1 receptors have been found on POMC neurons (Sandoval et al., 2008). The action of GLP-1 in satiety may also be through signaling via the vagus nerve to the NTS and then to the ARC (Abbott et al., 2005). In addition, leptin may signal through central GLP-1 neurons in the brainstem (Goldstone et al., 1997). In rodent and human studies, peripheral GLP-1 administration leads to a reduction in food intake (Turton et al., 1996; Flint et al., 1998).
GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (DPP IV) and is cleared by the kidney (Hansen et al., 1999; Knudsen and Pridal, 1996). For many years, the short half life of GLP-1 limited its therapeutic effectiveness. In 1991, a GLP-1 receptor agonist peptide, exendin 4, was discovered in the venom of Heloderma suspectum, the Gila monster lizard (Eng et al., 1992). This peptide has 53% sequence homology to GLP-1 and is resistant to cleavage by DPP IV (Holst et al., 2008). The use of exendin 4 for the treatment of people with type 2 diabetes mellitus has the additional benefit of causing a reduction in weight by approximately 3 kg after 30 weeks of treatment (De Block and Van Gaal, 2009). Exendin and other GLP-1 analogues such as liraglutide are now used routinely for the treatment of diabetes.
Oxyntomodulin (OXM) was originally isolated from porcine jejuno-ileal cells (Bataille et al., 1982). It is a 37 amino acid peptide containing the entire sequence of glucagon and a C terminal extension. OXM binds to the GLP-1 receptor but with reduced affinity compared to GLP-1 or exendin 4 (Schepp et al., 1996; Fehmann et al., 1994). It is released into the circulation following the ingestion of food (Le et al., 1992) and it inhibits both gastric acid and pancreatic secretion (Anini et al., 2000) and delays gastric emptying (Schjoldager et al., 1988). OXM levels are also increased after gastric bypass surgery and tropical sprue (Besterman et al., 1979). OXM is co-secreted postprandially along with GLP-1 and PYY from the entero-endocrine L cells and shares the anorectic effects of its co-secreted hormones. In 2001, Dakin et al. were the first to demonstrate the effects of OXM as a satiety signal (Dakin et al., 2001; Dakin et al., 2004). These results have since been confirmed using peripherally administered OXM in human volunteers (Cohen et al., 2003). In a four-week study, subjects administered OXM lost weight due to a combined reduction in energy intake as well as an increase in energy expenditure (Wynne et al., 2006).
Pancreatic polypeptide (PP)
NPY, PYY, and PP all share a common tertiary structure characterized by a hairpin structure known as the PP fold (Blundell et al., 1981). PP, a 36 amino acid peptide, was the first member of the family to be identified. It is secreted principally from PP cells in the pancreas with a small amount released from the distal gut. PP is released post-prandially via vagal cholinergic dependent mechanisms. High levels of PP binding sites, now known to be Y4R, are found in the area postrema, NTS, dorsal motor nucleus of the vagus, and the interpeduncular nucleus (Whitcomb et al., 1990). PP is involved in a number of physiological functions including inhibition of pancreatic secretion, gallbladder secretion and activity, intestinal mobility, and ileal contractions.
Peptide tyrosine kinase (PYY)
Peptide tyrosine tyrosine (PYY) is a 36 amino acid peptide originally isolated from porcine intestine (Tatemoto and Mutt, 1980; Lundberg et al., 1982). Its name originates from the fact that it has a tyrosine at both ends of the peptide. PYY is found in the pancreas and in L cells in the lower small intestine with higher concentrations found distally in the gut (Adrian et al., 1985). PYY3-36 exerts its effects through the NPY family of receptors. It binds preferentially to the Y2R found on NPY neurons in the ARC (Keire et al., 2000). As previously mentioned, this is an autoinhibitory presynaptic receptor, and may therefore reduce NPY signaling within the ARC leading to reduced appetite. PYY3-36 may also exert its effects through the vagus nerve signaling through the NTS to the hypothalamus.
PYY is released into the circulation post-prandially and is reduced by fasting, therefore it is likely to be a satiety factor (Ghatei et al., 1983). In lean and obese humans exogenous PYY3-36 has been shown to reduce food intake (Batterham et al., 2002; Le Roux et al., 2006). The release of PYY seems to be proportional to dietary intake and it is preferentially secreted in response to fats compared to either carbohydrates or proteins (Wynne and Bloom, 2006). Some reports suggest that PYY levels are lower in obese subjects and the PYY response to nutrient ingestion is reduced in obesity. While this is a promising anti-obesity drug candidate, its half life is short due to enzymatic cleavage and renal clearance and it has a narrow therapeutic window - excess levels can lead to nausea and vomiting.
Ghrelin is the only known peripheral orexigenic hormone. It is a 28 amino acid peptide, octanoylated at the serine 3 residue, which is principally secreted from the X/A- like endocrine cells in the stomach oxyntic glands (Kojima et al., 1999). Lower levels of ghrelin secreting cells are found in the small intestine and even fewer in the colon. Ghrelin is an endogenous ligand at the growth hormone secretagogue receptor 1a (GHS-R1a), and indeed it was originally characterized due to its ability to stimulate growth hormone release (Date et al., 2000). This receptor has been identified in hypothalamic neurons and in the brainstem (Howard et al., 1996). The majority of circulating ghrelin is not octanoylated (Hosoda et al., 2000); however, the octanoyl group is necessary for activation of the GHS-1a receptor (Bednarek et al., 2000).
Circulating ghrelin levels rise with fasting and fall after food intake, suggesting a role in meal initiation (Tschop et al., 2000; Cummings et al., 2001). The downstream effects of ghrelin are via activation of NPY and AgRP neurons in the ARC (Chen et al., 2004). NPY and AgRP appear to function as mediators of the orexigenic actions of ghrelin to the central melanocortin circuit. Ghrelin administration has been found to be a potent stimulus of feeding in rodents and humans (Wren et al., 2001). Ghrelin levels are highest in cachectic subjects, reduced in lean subjects, and the lowest in obese subjects (Tschop et al., 2001). This may be an adaptive response, an attempt to stimulate or suppress appetite according to the energy imbalance. Obese subjects are, however, more sensitive to the effects of ghrelin. Ghrelin infusions increased energy intake by 20% in lean individuals compared to 70% in obese individuals (Druce et al., 2005). Therefore, antagonizing ghrelin may prove to be a useful obesity treatment. Conversely, ghrelin treatment may be a useful appetite stimulant, for example, in patients with cachexia due to end stage renal failure or cancer.
The management of the body’s energy balance is necessarily a highly complex process, involving the integration of signals from the gut, the adipose tissue, and parts of the brain (notably reward pathways) at the level of the hypothalamus. In turn, the hypothalamus is able to orchestrate food-seeking behavior, basal metabolism, and elective energy expenditure to maintain and defend the body’s weight against starvation, with a bias towards gaining weight. This has led, in the modern world, to the overall increase in obesity with time. Our increasing understanding of these complex circuits has led to the design of new drugs which are hoped, in time, to be the answer to obesity.
S. Zac-Varghese and T. Tan declared that they have no competing interests. S. R. Bloom has a residual interest in an oxyntomodulin analogue which was developed by the Thiakis company, bought by Wyeth in 2008.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 10(55):543-552, December 2010.]