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Appetite control system

Appetite control system

Lieverse Protein intake for men Boost Metabolism After, Jansen JBMasclee AA Protein intake for men, Lamers Systej Satiety effects of a physiological dose controk cholecystokinin in humans. Appetire orexigenic and anorexigenic neuron activity ensures the homeostasis of energy balance. For many modern-day humans, the impetus to begin a meal is rarely if ever based on a biological deficit or need such as insufficient glucose. Journal of Clinical Investigation 92 —

Appetite control system -

NPY is one of the most abundant neurotransmitters in the brain Allen et al. The levels of hypothalamic NPY mRNA and NPY release increase with fasting and decrease after refeeding Sanacora et al. The ARC is the major hypothalamic site of NPY expression Morris ARC NPY neurons project to the ipsilateral paraventricular nucleus PVN Bai et al.

Central administration of NPY also reduces energy expenditure, resulting in reduced brown fat thermogenesis Billington et al. This absence of an obese phenotype may be due to the presence of compensatory mechanisms or alternative orexigenic pathways, such as those which signal via AgRP Marsh et al.

It is possible that there is evolutionary redundancy in orexigenic signalling in order to avert starvation. This redundancy may also contribute to the diffculty elucidating the receptor subtype that mediates NPY-induced feeding Raposinho et al.

NPY is part of the pancreatic polypeptide PP -fold family of peptides, including peptide YY PYY and pancreatic polypeptide PP. This family bind to seven-transmembrane-domain G-protein-coupled receptors, designated Y 1 —Y 6 Larhammar Y 1 —Y 5 receptors have been demonstrated in rat brain, but Y 6 , identified in mice, is absent in rats and inactive in primates Inui The Y 1 , Y 2 , Y 4 and Y 5 receptors, cloned in the hypothalamus, have all been postulated to mediate the orexigenic effects of NPY.

The feeding effect of NPY may indeed be mediated by a combination of receptors rather than a single one. Administration of antisense oligonucleotides to the Y 5 receptor inhibits food intake Schaffhauser et al. However, Y 5 receptor density in the hypothalamus appears to be reduced in response to fasting and upregulated in dietary-induced obesity Widdowson et al.

In addition, antagonists to the Y 5 receptor have no major feeding effects in rats Turnbull et al. It has been postulated that the Y 5 receptor may maintain the feeding response rather than initiate feeding in response to NPY, as Y 5 receptor antisense oligonucleotide decreases food intake 10 h after NPY- or PP-induced feeding, but has no effect on the initial orexigenic response Flynn et al.

NPY-induced and fast-induced feeding is prevented by antagonists to the Y 1 receptor Kanatani et al. However, like Y 5 receptors, ARC Y 1 receptor numbers, distribution and mRNA, are reduced during fasting, an effect which is attenuated by administration of glucose Cheng et al.

Y 1 receptor-deficient mice are obese, but are not hyperphagic, suggesting that the Y 1 receptor may affect energy expenditure rather than feeding Kushi et al.

The presynaptic Y 2 and Y 4 receptors have an auto-inhibitory effect on NPY neurons King et al. As expected, Y 2 receptor-knockout mice have increased food intake, weight and adiposity Naveilhan et al.

However, Y 2 receptor conditional-knockout mice perhaps with more normal development of the neuronal circuits have a temporarily reduced body weight and food intake, which returns to normal after a few weeks Sainsbury et al.

There is also evidence for a role of Y 4 receptors in the orexigenic NPY response. PP has a relative specificity for the Y 4 receptor and central administration has been shown to elicit food intake in both mice Asakawa et al.

Melanocortins, including adrenocorticotrophin and melanocyte-stimulating hormones MSHs , are peptide-cleavage products of the POMC molecule and exert their effects by binding to the melanocortin receptor family.

Levels of POMC expression reflect the energy status of the organism. POMC mRNA levels are reduced markedly in fasted animals and increased by exogenous administration of leptin, or restored by refeeding after 6 h Schwartz et al. Mutations within the POMC gene or abnormalities in the processing of the POMC gene product result in early-onset obesity, adrenal insufficiency and red hair pigmentation in humans Krude et al.

The loss of one copy of the POMC gene in mice is sufficient to render them susceptible to diet-induced obesity Challis et al. Melanocortin 3 MC3R and melanocortin 4 receptors MC4R are found in hypothalamic nuclei implicated in energy homeostasis, such as the ARC, ventromedial nucleus VMH and PVN Mountjoy et al.

Lack of the MC4R leads to hyperphagia and obesity in rodents Fan et al. Polymorphism of this receptor has also been implicated in polygenic late-onset obesity in humans Argyropoulos et al.

Although the involvement of the MC4R in feeding is established, the function of the MC3R is still unclear. A selective MC3R agonist has been found to have no efect on food intake Abbott et al. However, there is some evidence that both the MC3R and MC4R are able to influence energy homeostasis.

Mice which lack the MC3R, although not overweight on a normal diet, have increased adiposity, and seem to switch from fat to carbohydrate metabolism Butler et al. However, MC3-null mice are obese and develop increased adipose tissue when fed on high-fat chow.

MC3R mutations have been found in human subjects with morbid obesity Mencarelli et al. administration of agonists to the hypothalamic MC4R suppresses food intake, and the administration of selective antagonists results in hyper-phagia Benoit et al. In addition to its effects on feeding, α-MSH also stimulates the thyroid axis Kim et al.

The agouti mouse is hyperphagic and obese, and expresses the agouti protein ectopically, which is normally restricted to the hair follicle. The agouti protein is a competitive antagonist of α-MSH and melanocortin receptors Lu et al. The antagonist effect on the peripheral MC1R results in a yellow coat, and its effect on the hypothalamic MC4R results in obesity Lu et al.

Although the agouti protein is not normally expressed in the brain, a partially homologous peptide, AgRP, is expressed in the medial part of the ARC Shutter et al. AgRP mRNA increases during fasting Swart et al.

AgRP 83— , the C-terminal fragment, is able to block the reduction in food intake seen with the icv administration of α-MSH and increase nocturnal food intake Rossi et al. Transgenic mice with ubiquitous over-expression of AgRP are obese, but with no alteration of coat colour as AgRP is inactive at the MC1R Ollmann et al.

A polymorphism in the AgRP gene in humans is associated with lower body weight and fat mass Marks et al. Consistent with its role in energy homeostasis, AgRP and AgRP 83— administered icv result in hyperphagia which can persist for a week Hagan et al.

Although NPY mRNA levels are reduced 6 h after refeeding, AgRP levels remain elevated Swart et al. This prolonged response results in a greater cumulative effect on food intake than NPY, and probably involves more diverse signalling pathways than the melanocortin pathway alone Hagan et al.

Consistent with the role of AgRP as an orexigenic peptide, the reduction of hypothalamic AgRP RNA by RNA interference results in lower body weight, although this may partly be an effect of increased energy expenditure Makimura et al.

Independent of its orexigenic effects, chronic icv administration of AgRP suppresses thyrotropin-releasing hormone, reduces oxygen consumption and decreases the ability of brown adipose tissue to expend energy Small et al. NPY may inhibit the arcuate POMC neuron via ARC NPY Y 1 receptors Fuxe et al.

Furthermore, AgRP is absent from hypothalamic nuclei known to be involved in energy homeostasis, such as the VMH Broberger et al. This suggests there must be other signalling pathways which are capable of regulating energy homeostasis Qian et al.

CART is co-expressed with α-MSH in the ARC Elias et al. Neurons expressing CART are also found in the LHA and PVN Couceyro et al. An antiserum against CART peptide 1— and CART peptide fragment 82— , injected icv in rats, increases feeding, suggesting that it is part of the physiological control of energy homeostasis Kristensen et al.

CART 1— and CART 82— injected icv into rats inhibit both the normal and NPY-stimulated feeding response, but result in abnormal behavioural responses at high dose Kristensen et al. However, administration of CART 55— into discrete hypothalamic nuclei such as the ARC and ventromedial nucleus is able to increase food intake Abbott et al.

Thus, there may be more than one population of CART-expressing neurons which have different roles in feeding behaviour. For instance, NPY release could stimulate a population of CART neurons in the ARC which are orexigenic, producing positive orexigenic feedback Dhillo et al.

These areas contain secondary neurons which process information regarding energy homeostasis. A number of signalling molecules which are expressed in these regions have been shown to be physiologically involved in energy homeostasis see Figure 2. The PVN is highly sensitive to administration of many peptides implicated in feeding, e.

cholecystokinin CCK Hamamura et al. Administration of a melanocortin agonist directly into the PVN results in potent inhibition of food intake Giraudo et al.

GABA-ergic signalling also occurs in a subpopulation of ARC NPY neurons which release GABA locally and inhibit POMC neurons. Neuropeptides involved in appetite regulation in the PVN may also signal via AMP-activated protein kinase AMPK , a heterodimer consisting of catalytic α-subunits and regulatory β- and γ-subunits.

A pharmacologically induced increase in the level of AMPK in the PVN results in increased food intake Andersson et al. α2 AMPK activity may be regulated by the MC4R, as peripheral signals of energy status are unable to modulate α2 AMPK activity in MC4R-knockout mice Minokoshi et al. The integration of signals within the PVN intiates changes in other neuroendocrine systems.

These projections have an inhibitory effect on prothyrotropin-releasing hormone gene expression in the PVN Fekete et al. Integration of signals may also take place in the DMH, as α-MSH-positive fibres are in close proximity to NPY-expressing cells in the DMH, and melanocortin agonists attenuate DMH NPY expression and suckling-induced hyperphagia in rats Chen et al.

Indeed, the perifornical area has been found to be more sensitive to NPY-elicited feeding than the PVN Stanley et al. Fasting increases MCH mRNA, and repeated icv administration of MCH increases food intake Qu et al.

Conversely, MCH-1 receptor antagonists reduce feeding and result in a sustained reduction in body weight if administered chronically Borowsky et al. Transgenic mice over-expressing precursor MCH are hyperphagic and develop central obesity Marsh et al.

This perhaps infers that MCH acts downstream of leptin and POMC, and demonstrates that not all orexigenic peptides show redundancy. Orexin A and B or hypocretin 1 and 2 are peptide products of prepro-orexin.

Orexin neurons exert their effects via wide projections throughout the brain, for example to the PVN, ARC, NTS and dorsal motor nucleus of the vagus De Lecea et al. The orexin-1 receptor, which is highly expressed in the VMH, has a much greater affinity for orexin A, whereas the orexin-2 receptor, which is highly expressed in the PVN, has comparable affinity for both orexin A and B Sakurai et al.

The prepro-orexin mRNA level is increased in the fasting state and central administration has been found to result in both orexigenic behaviour and generalized arousal Sakurai et al.

Central administration of orexin A has a potent effect on feeding Haynes et al. However, although icv administration of orexin A results in increased daytime feeding, there is no overall change in h food intake Haynes et al.

Furthermore, chronic administration of orexin A alone does not increase body weight Yamanaka et al. Orexin neurons project to areas associated with arousal and attention as well as feeding, and orexin-knockout mice are thought to be a model of human narcolepsy Chemelli et al.

In circumstances of starvation, the orexin neuropeptides may mediate both an arousal response and a feeding response in order to initiate food-seeking behaviour. Orexin may also play a role as a peripheral hormone involved in energy homeostasis.

NPY, AgRP and α-MSH terminals are abundant in the LHA and are in contact with MCH- and orexin-expressing cells Broberger et al. Central orexin neurons also express NPY Campbell et al. Some studies have hypothesized a role for orexin neurons in sensing glucose levels within this region, and these have shown that hypogly-caemia induces c-Fos expression in orexin neurons Moriguchi et al.

Glucose signalling also occurs in other hypothalamic nuclei such as the VMH Dunn-Meynell et al. The mechanism by which the MCH and orexin neurons exert their effects on energy homeostasis has not been fully elucidated.

However, it is clear that major targets are the endocrine and autonomic nervous system, the cranial nerve motor nuclei and cortical structures Saper et al. The VMH has long been known to play a role in energy homeostasis. Bilateral VMH lesions produce hyperphagia and obesity.

The VMH receives projections from arcuate NPY-, AgRP- and POMC-immunoreactive neurons and in turn VMH neurons project to other hypothalamic nuclei e.

DMH and to brain stem regions such as the NTS. NPY expression is altered in the VMH of obese mice Guan et al. Recent work has demonstrated that brain-derived neurotrophic factor BDNF is highly expressed within the VMH, where its expression is reduced markedly by food deprivation Xu et al.

Mice with reduced BDNF receptor expression or reduced BDNF signalling have significantly increased food intake and body weight Rios et al. Thus, VMH BDNF neurons may form another downstream pathway through which the melanocortin system regulates appetite and body weight.

In addition to interacting with hypothalamic circuits, the brainstem also plays a principal role in the regulation of energy homeostasis.

The NTS has a high density of NPY-binding sites Harfstrand et al. Extracellular NPY levels within the NTS fluctuate with feeding Yoshihara et al.

There is also evidence for a melanocortin system in the NTS, separate from that of the ARC Kawai et al. POMC-derived peptides are synthesized in the NTS of the rat Kawai et al.

The MC4R is present in the NTS Mountjoy et al. The rewarding nature of food may act as a stimulus to feeding, even in the absence of an energy deficit. The sensation of reward is, however, influenced by energy status, as the subjective palatability of food is altered in the fed, compared with the fasting, states Berridge Thus, signals of energy status, such as leptin, are able to influence the reward pathways Fulton et al.

The reward circuitry is complex and involves interactions between several signalling systems. Opioids play an important role, as a lack of either enkephalin or β-endorphin in mice abolishes the reinforcing property of food, regardless of the palatability of the food tested.

This reinforcing effect is lost in the fasted state, indicating that homeostatic mechanisms can override the hedonistic mechanisms Hayward et al. In man, opiate antagonists are found to reduce food palatability without reducing subjective hunger Yeomans et al.

The dopaminergic system is integral to reward-induced feeding behaviour. The influence of central dopamine signalling on feeding is thought to be mediated by the D 1 and D 2 receptors Schneider , Kuo Mice which lack dopamine, due to the absence of the tyrosine hydroxylase gene, have fatal hypophagia.

Dopamine replacement, by gene therapy, into the caudate putamen restores feeding, whereas replacement into the caudate putamen or nucleus accumbens restores preference for a palatable diet Szczypka et al.

The nucleus accumbens is an important component of reward circuitry. Conversely, opioid receptor antagonists injected into the nucleus accumbens reduce the ingestion of sucrose rather than less palatable substances Zhang et al. The MCH neurons in the LHA may reciprocally influence the reward circuitry, as the nucleus accumbens is a site which expresses MCH receptors Saito et al.

Other systems, including those mediated by endocan-nabinoids and serotonin, may also be able to modulate both reward circuitry and homeostatic mechanisms controlling feeding. Endocannabinoids in the hypothalamus may maintain food intake via CB1 receptors, which co-localize with CART, MCH and orexin peptides Cota et al.

Defective leptin signalling is associated with high hypothalamic endocannabinoid levels in animal models Di et al. CB1 receptors are also present on adipocytes where they appear to act directly in order to increase lipogenesis Cota et al.

CB1 receptor antagonists are currently in phase III clinical trials, and have been found to reduce appetite and body weight in humans for a review see Black Serotonin may directly influence the melanocortin pathway in the ARC via 5-hydroxytryptamine receptors Heisler et al.

See Figure 3. Leptin Greek: thin is a peptide hormone, secreted from adipose tissue, which influences energy homeostasis, immune and neuroendocrine function. Restriction of food intake, over a period of days, results in a suppression of leptin levels, which can be reversed by refeeding Frederich et al.

Production of leptin correlates positively with adipose tissue mass Maffei et al. Circulating leptin levels thus reflect both energy stores and food intake. Exogenous leptin replacement decreases fast-induced hyperphagia Ahima et al. In addition to its effects on appetite, circulating leptin levels also affect energy expenditure in rodents Halaas et al.

A replacement dose of leptin is able to reverse the starvation-induced changes of the neuroendocrine axes in both rodents Ahima et al. Leptin is a product of the ob gene expressed predominantly by adipocytes Zhang et al.

Similarly, mutations resulting in the absence of leptin in humans cause severe obesity and hypogonadism Montague et al. There is a higher prevalence of obesity than expected in humans with heterozygous leptin deficiency, compared with controls.

These subjects also have a greater percentage of body fat, but a lower than expected leptin level Farooqi et al. Studies from animal models also demonstrate that one deficient copy of the leptin gene can affect body weight Chung et al.

The leptin receptor has a single transmembrane domain and is a member of the cytokine receptor family Tartaglia et al. The leptin receptor Ob-R has multiple isoforms which result from alternative mRNA splicing and post-translational processing Chua et al.

The different splice forms of the receptor can be divided into three classes: long, short and secreted Tartaglia , Ge et al.

The long - form Ob-Rb receptor differs from the other forms of the receptor by having a long intracellular domain, which is necessary for the action of leptin on appetite Lee et al. This intracellular domain binds to Janus kinases JAK Lee et al.

Similarly, mutations within the human leptin receptor result in early-onset morbid obesity, though less severe than that seen with leptin deficiency, and a failure to undergo puberty Clement et al. Circulating leptin is transported across the blood—brain barrier via a saturable process Banks et al.

Regulation of transport may be an important modulator of the effects of leptin on food intake. The short forms of the receptor have been proposed to have a role in the transport of leptin across the blood—brain barrier El Haschimi et al.

The Ob-Rb receptor is expressed within the hypothalamus particularly ARC, VMH, DMH and LHA Fei et al. The anorexic response of leptin is attenuated by administration of an MC4R antagonist, demonstrating that the melanocortin pathway is perhaps an important downstream mediator of leptin signalling Seeley et al.

Mice lacking leptin signalling in POMC neurons are mildly obese and hyperlepti-naemic, but less so than mice with a complete deletion of the leptin receptor Balthasar et al. This suggests that POMC are important, but not essential, for leptin signalling in vitro. The PVN, LHA VMH and medial preoptic area may be direct targets for leptin signalling as leptin receptors are found in these nuclei Hakansson et al.

Chronic hypothalamic over-expression of the leptin gene, using a recombinant adeno-associated virus vector, has demonstrated distinct actions of leptin in different hypothalamic nuclei. Leptin over-expression in the ARC, PVN and VMH results in a reduction of food intake and energy expenditure, whereas leptin over-expression in the medial preoptic area results in reduced energy expenditure alone Bagnasco et al.

The NTS, like the ARC, contains leptin receptors Mercer et al. Peripheral administration of leptin also results in neuronal activation within the NTS Elmquist et al.

Thus leptin appears to exert its effect on appetite via both the hypothalamus and brainstem. Although a small subset of obese human subjects have a relative leptin deficiency, the majority of obese animals and humans have a proportionally high circulating leptin Maffei et al.

Indeed, recombinant leptin administered subcutaneously to obese human subjects has only shown a modest effect on body weight Heymsfield et al.

Administration of peripheral leptin to rodents with diet-induced obesity fails to result in a reduction in food intake, although these rodents retain the capacity to respond to icv leptin Van Heek et al.

Exogenous leptin in mice is transported across the blood—brain barrier less rapidly in obese animals Banks et al. Leptin resistance may be the result of a signalling defect in leptin-responsive hypothalamic neurons, as well as impaired transport into the brain.

Resistance to the effects of leptin has been shown to develop in NPY neurons following chronic central leptin exposure Sahu Furthermore, the magnitude of hypothalamic STAT3 activation in response to icv leptin is reduced in rodents with diet-induced obesity El Haschimi et al.

Leptin upregulates expression of SOCS-3 in hypothalamic nuclei expressing the Ob-Rb receptor. SOCS-3 acts as a negative regulator of leptin signalling. Therefore, increased or excessive SOCS-3 expression may be an important mechanism for obesity-related leptin resistance.

Consistent with this, neuron-specific conditional SOCSknockout mice are resistant to diet-induced obesity Mori et al. Mice with heterozygous SOCS-3 deficiency are also resistant to obesity and demonstrate both enhanced weight loss and increased hypothalamic leptin receptor signalling in response to exogenous leptin administration Howard et al.

Although as yet untested, SOCS-3 suppression may be a potential target for the treatment of leptin-resistant obesity. Leptin resistance seems to occur as a result of obesity, but a lack of sensitivity to circulating leptin may also contribute to the aetiology of obesity.

Furthermore, it may be that the high-fat diet itself induces leptin resistance prior to any change in body composition, as rodents on a high-fat diet rapidly demonstrate an attenuated response to leptin administration before they gain weight Lin et al.

Although leptin deficiency has profound effects on body weight, the effect of high leptin levels seen in obesity are much less potent at restoring body weight. Thus, leptin may be primarily important in periods of starvation, and have a lesser role in times of plenty.

Insulin is a major metabolic hormone produced by the pancreas and the first adiposity signal to be described Schwartz et al. Like leptin, levels of plasma insulin vary directly with changes in adiposity Bagdade et al. Levels of insulin are determined to a great extent by peripheral insulin sensitivity, and this is related to total body fat stores and fat distribution, with visceral fat being a key determinant of insulin sensitivity Porte et al.

However, unlike leptin, insulin secretion increases rapidly after a meal, whereas leptin levels are relatively insensitive to meal ingestion Polonsky et al. Insulin penetrates the blood—brain barrier via a saturable, receptor-mediated process, at levels which are proportional to the circulating insulin Baura et al.

Recent findings suggest that little or no insulin is produced in the brain itself Woods et al. Once insulin enters the brain, it acts as an anorexigenic signal, decreasing intake and body weight.

An infusion of insulin into the lateral cerebral ventricles in primates Woods et al. Thus, the VMH and PVN seem therefore to play an important part in the ability of centrally administered insulin to reduce food intake.

Male mice with neuron-specific deletion of the insulin receptor in the CNS are obese and dyslipidaemic with increased peripheral levels of insulin Bruning et al.

Reduction of insulin receptor proteins in the medial ARC, by administration of an antisense RNA directed against the insulin receptor precursor protein, results in hyperphagia and increased fat mass Obici et al. administration of an insulin mimetic dose-dependently reduces food intake and body weight in rats, and alters the expression of hypothalamic genes known to regulate food intake and body weight Air et al.

Treatment of mice with orally available insulin mimetics decreases the weight gain produced by a high-fat diet as well as adiposity and insulin resistance Air et al. If insulin elicits changes in feeding behaviour at the level of the hypothalamus, then levels of circulating insulin should reflect the effect of centrally administered insulin.

Studies of systemic insulin administration have been complicated by the fact that increasing circulating insulin causes hypoglycaemia which in itself potently stimulates food intake. Thus peripheral and central data are consistent with the insulin system acting as an endogenous controller of appetite.

The insulin receptor is composed of an extracellular α-subunit which binds insulin, and an intracellular β-subunit which tranduces the signal and has intrinsic tyrosine kinase activity.

The insulin receptor exists as two splice variants resulting in subtype A, with higher affinity for insulin and more widespread expression, and subtype B with lower affinity and expression in classical insulin-responsive tissues such as fat, muscle and liver. There are several insulin receptor substrates IRSs including IRS-1 and IRS-2, both identified in neurons Baskin et al.

The phenotype of IRSknockout mice does not show differences in food intake or body weight Araki et al. IRS-2 mRNA is highly expressed in the ARC, suggesting that neuronal insulin may be coupled to IRS-2 Burks et al.

There is also evidence to suggest that insulin and leptin, along with other cytokines, share common intracellular signalling pathways via IRS and the enzyme phoshoinositide 3-kinase, resulting in downstream signal transduction Niswender et al.

Insulin receptors are widely distributed in the brain, with highest concentrations found in the olfactory bulbs and the hypothalamus Marks et al. Within the hypothalamus, there is particularly high expression of insulin receptors in the ARC; they are also present in the DMH, PVN, and suprachiasmatic and periventricular regions Corp et al.

This is consistent with the hypothesis that peripheral insulin acts on hypothalamic nuclei to control energy homeostasis.

The mechanisms by which insulin acts as an adiposity signal remain to be fully elucidated. Earlier studies pointed to hypothalamic NPY as a potential mediator of the regulatory effects of insulin. administration of insulin during food deprivation in rats prevents the fasting-induced increase in hypothalamic levels of both NPY in the PVN and NPY mRNA in the ARC Schwartz et al.

NPY expression is increased in insulin-deficient, streptozocin-induced diabetic rats and this effect is reversed with insulin therapy Williams et al. Insulin receptors have been found on POMC neurons in the ARC Benoit et al.

Administration of insulin into the third ventricle of fasted rats increases POMC mRNA expression and the reduction of food intake caused by i. injection of insulin is blocked by a POMC antagonist Benoit et al. Taken together, these experiments suggest that both the NPY and melanocortin systems are important downstream targets for the effects of insulin on food intake and body weight.

Adiponectin is a complement-like protein, secreted from adipose tissue, which is postulated to regulate energy homeostasis Scherer et al. The plasma concentration of adiponectin is inversely correlated with adiposity in rodents, primates and humans Hu et al.

Adiponectin is significantly increased after food restriction in rodents Berg et al. Peripheral administration of adiponectin to rodents has been shown to attenuate body-weight gain, by increased oxygen consumption, without affecting food intake Berg et al. The effect of peripheral adiponectin on energy expenditure seems to be mediated by the hypothalamus, since adiponectin induced expression of the early gene c- fos in the PVN, and may involve the melanocortin system Qi et al.

It is perhaps counterintuitive for a factor that increases energy expenditure to increase following weight loss; however, reduced adiponectin could perhaps contribute to the pathogenesis of obesity.

Studies show that plasma adiponectin levels correlate negatively with insulin resistance Hotta et al. Adiponectin-knockout mice demonstrate severe diet-induced insulin resistance Maeda et al. Thus adiponectin, as well as increasing energy expenditure, may also provide protection against insulin resistance and atherogenesis.

In addition to leptin and adiponectin, adipose tissue produces a number of factors which may influence adiposity. Resistin is an adipocyte-derived peptide which appears to act on adipose tissue to decrease insulin resistance.

Circulating resistin levels are increased in rodent models of obesity Steppan et al. Although resistin may be a mechanism through which obesity contributes to the development of diabetes Steppan et al. Ghrelin is an orexigenic factor released primarily from the oxyntic cells of the stomach, but also from duodenum, ileum, caecum and colon Date et al.

It is a amino-acid peptide with an acyl side chain, n -octanoic acid, which is essential for its actions on appetite Kojima et al. In humans on a fixed feeding schedule, circulating ghrelin levels are high during a period of fasting, fall after eating Ariyasu et al.

Ghrelin levels fall in response to the ingestion of food or glucose, but not following ingestion of water, suggesting that gastric distension is not a regulator Tschop et al.

In rats, ghrelin shows a bimodal peak, which occurs at the end of the light and dark periods Murakami et al. In humans, ghrelin levels vary diurnally in phase with leptin, which is high in the morning and low at night Cummings et al.

An increase in circulating ghrelin levels may occur as a consequence of the anticipation of food, or may have a physiological role in initiating feeding. Administration of ghrelin, either centrally or peripherally, increases food intake and body weight and decreases fat utilization in rodents Tschop et al.

Furthermore, central infusion of anti-ghrelin antibodies in rodents inhibits the normal feeding response after a period of fasting, suggesting that ghrelin is an endogenous regulator of food intake Nakazato et al. The severe hyperphagia seen in Prader—Willi syndrome is associated with elevated ghrelin levels Cummings et al.

However, one study has failed to show a correlation between the ghrelin level and the spontaneous initiation of a meal in humans Callahan et al. Thus ghrelin secretion may be a conditioned response which occurs to prepare the metabolism for an influx of calories.

Whatever the precise physiological role of ghrelin, it appears not to be an essential regulator of food intake, as ghrelin-null animals do not have significantly altered body weight or food intake on a normal diet Sun et al. Plasma ghrelin levels are inversely correlated with body mass index.

Anorexic individuals have high circulating ghrelin which falls to normal levels after weight gain Otto et al. Obese subjects have a suppression of plasma ghrelin levels which normalize after diet-induced weight loss Cummings et al.

Unlike lean individuals, obese subjects do not demonstrate the same rapid post-prandial drop in ghrelin levels English et al.

The second category includes hormones such as insulin and leptin that are secreted in proportion to the amount of fat in the body. Satiation and adiposity signals interact with other factors in the hypothalamus and elsewhere in the brain to control appetite and body weight, and they are the topic of this review.

Body weight adiposity is a homeostatically regulated variable, and its long-term maintenance can only occur via a close linkage of energy intake to energy expenditure.

This means that over long intervals, the amount of food consumed must provide energy equivalent to the amount of energy expended. Humans and most mammals acquire energy in discrete episodes or meals. For many modern-day humans, the impetus to begin a meal is rarely if ever based on a biological deficit or need such as insufficient glucose.

Arguably, this has been the case throughout human evolution as well, with the initiation of feeding governed by nonhomeostatic factors such as food availability or having a safe haven to eat. Thus, the homeostatic influence over food intake is often left to the control over how many calories are consumed once a meal begins; i.

on meal size. Consistent with this, many of the secretions of the gastrointestinal GI tract during a meal, such as CCK, are proportional to the number of calories consumed, and some of these secretions function as satiation signals to the CNS to help limit meal size see reviews in Refs.

In contrast to satiation signals that are phasically secreted during meals, adiposity signals are more tonically active, providing an ongoing message to the brain proportional to total body fat. Insulin is tonically secreted in basal amounts, with phasic increments occurring during meals, and both components of total insulin secretion i.

basal and meal-stimulated are directly proportional to body fat Leptin is secreted in direct proportion to body adiposity, following a diurnal pattern with less direct connection to meals than insulin As an individual changes body weight through caloric restriction or overeating, the amounts of insulin and leptin secreted into the blood change in parallel, and this in turn is reflected as an altered signal of body fatness, tantamount to body energy stores, reaching the brain 1 — 3.

These adiposity signals interact with anabolic and catabolic neural circuits, causing a change in sensitivity of the brain to satiation signals. As a consequence, the homeostatic setting is geared for the intake of larger meals because more food must be consumed before a sufficient satiation signal is generated to stop eating.

A major dilemma facing clinicians and others involved in public health is the slippage in the latter limb of this homeostatic system that permits excessive energy storage, obesity, and the associated diseases of nutritional excess; e.

diabetes, cardiovascular disease, and some cancers. Model summarizing different levels of control over energy homeostasis. During meals, signals such as CCK, GLP-1, and distension of the stomach that arise from the gut stomach and intestine trigger nerve impulses in sensory nerves traveling to the hindbrain.

These satiation signals synapse with neurons in the nucleus of the solitary tract NTS where they influence meal size. Ghrelin from the stomach both acts on the vagus nerve and stimulates neurons in the ARC directly. Signals related to body fat content such as leptin and insulin, collectively called adiposity signals, circulate in the blood to the brain.

They pass through the blood-brain barrier in the region of the ARC and interact with neurons that synthesize POMC or NPY and AgRP. ARC neurons in turn project to other hypothalamic areas including the PVN and the LHA. The net output of the PVN is catabolic and enhances the potency of satiation signals in the hindbrain.

The net output of the LHA, on the other hand, is anabolic, suppressing the activity of the satiation signals. In this way body fat content tends to remain relatively constant over long intervals by means of changes of meal size. By definition, satiation factors, when administered to humans or animals at the start of a meal, result in a smaller-than-normal meal being consumed.

Exogenously administered satiation factors, or endogenous secretion of these compounds, activates specific receptors that cause premature cessation of eating. There are several excellent reviews of satiation signals such that only the salient points need to be reviewed here 7 — 9 , 12 — It is generally accepted that for an endogenous compound to be considered a satiation signal, it is secreted in response to food ingestion, acts within the time frame of a single meal, reduces meal size without creating malaise or incapacitation, and is effective at physiological doses, and removing or antagonizing its endogenous activity increases meal size 7 , The best-established satiation signals are secreted from specialized enteroendocrine cells in the wall of the GI tract in response to the digestion and absorption of meals.

In the classic model of satiation, local sensory nerves express receptors for these gut peptides as they are secreted such that the brain is immediately informed about the nutritional content of the meal by monitoring the level of hormones secreted to cope with it.

As a complex meal is consumed, the mix of macronutrients carbohydrates, fats, and proteins stimulates a proportional blend of satiation peptides, and an overall message indicating meal content is integrated in the hindbrain where it activates appropriate responses, including ultimately cessation of the meal.

In humans, this is associated with a sensation of fullness. Although not all intestinal hormones double as satiation signals, they all presumably contribute to the assimilation of nutrients; i.

by stimulating the secretion of appropriate enzymes, water, and other compounds into the lumen of the gut and regulating GI motility. CCK was the compound first identified to fit the criteria for a satiation factor, so that much is known about its actions. Consequently, CCK has become the model for the larger class of satiation factors.

When food containing fat or protein is consumed and enters the duodenum, CCK is secreted from I cells. CCK enters the blood and has hormonal influences on gut motility, contraction of the gallbladder, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion 16 — However, CCK also diffuses locally to provide a paracrine stimulus to CCK-1 receptors on nearby branches of vagal sensory nerves 20 — Satiation signals arising in the GI system converge on the dorsal hindbrain D where they are integrated with taste and other inputs.

The dorsal hindbrain makes direct connections with the ventral hindbrain V where neural circuits direct the autonomic nervous system to influence blood glucose and where the motor control over eating behavior is located.

The dorsal hindbrain also conveys information on satiation and other factors anteriorly to the hypothalamus and other brain areas. These areas in turn integrate satiation and adiposity signals as well as available nutrients with experience, the social situation and stressors, and with time of day and other factors.

The integrated information is then conveyed posteriorly back to the ventral hindbrain as well as to the pituitary to influence all aspects of energy homeostasis.

Animals lacking neural connections between the hindbrain and the hypothalamus reduce the intake of individual bouts of eating when the stomach is distended or they are administered CCK. However, those animals cannot regulate their body weight and are not sensitive to past experience, time of day, or social factors The decrease of meal size elicited by exogenous CCK is dose-dependent, with higher doses causing greater reductions of meal size.

However, CCK does not prevent meals from occurring; rather, it decreases the size of the meal once it has begun, reducing hunger and increasing fullness without concomitant sensations of illness or malaise. When a CCK-1 receptor antagonist is administered before the presentation of food to animals or humans, larger-than-normal meals are consumed 29 — 31 , providing compelling evidence that endogenous CCK normally acts to suppress intake during meals.

However, the effect of exogenous CCK is short-lived; the meal-reducing signal does not carry over to a second meal. Moreover, the effect of repeated or chronic administration of CCK 32 , 33 has no effect on body weight because the short-term regulation of meal size is overridden by overall energy balance.

That is, in the context of lower adiposity, leptin and insulin signals to the brain are reduced and satiation factors like CCK have a reduced effect to restrict meal size. There is strong experimental evidence supporting a role for CCK as a satiation factor in humans. CCK levels increase after meals, and infusion of an exogenous CCK-1 receptor agonist, CCK, to postprandial levels suppresses food intake 34 , Furthermore, infusion of a CCK-1 receptor antagonist to healthy humans causes an increase in caloric intake, strongly implicating endogenous CCK as a brake on meal size 29 , The effects of CCK-1 agonism and antagonism are similar in lean and obese humans and are associated with appropriate changes in hunger and fullness.

Interestingly, blockade of CCK-1 receptors affects the postprandial responses of other GI hormones, attenuating the usual rise in peptide YY PYY and abolishing the suppression of ghrelin This latter finding suggests that beyond directly inhibiting food intake, CCK acts as a proximal mediator of the broader satiation process.

Two minor single nucleotide polymorphisms in the CCK-1 receptor gene promoter have been associated with increased body fatness, but the mechanism of this association has not been explained Glucagon-like peptide-1 GLP-1 is derived from proglucagon in intestinal L cells that are most prevalent in the ileum and colon GLP-1 secretion is elicited by nutrients, but the mechanism whereby the distal L cells are stimulated early within meals may require neurohumoral signals initiated in the proximal regions of the small intestine GLP-1 has a broad range of actions on glucose metabolism 41 , most prominently stimulation of insulin secretion, but also inhibition of glucagon release.

It has generally been assumed that GLP-1 mediates these various actions through an endocrine mechanism, by binding directly to key target tissues like pancreatic islet cells. However, this mechanism has recently been called into question, in large part because GLP-1 is rapidly metabolized in the circulation by the protease dipeptidyl peptidase IV DPP-IV Indeed, the half-life of GLP-1 in human plasma is only 1—2 min, and the product of DPP-IV action, a truncated GLP-1, is inactive with regard to glucose metabolism Because the GLP-1 receptor GLP-1r is expressed by peripheral and CNS neurons as well as by cells in the pancreatic islets and the GI tract, recent attention has focused on neural mechanisms of GLP-1 action 46 — GLP-1 administration reduces food intake in animals and humans 49 — 54 , and these anorectic actions are thought to be mediated through both peripheral and central mechanisms.

A population of neurons that synthesize GLP-1 is located in the brain stem and projects to hypothalamic and brain stem areas important in the control of energy homeostasis 55 , Centrally administered GLP-1 reduces food intake through at least two mechanisms. GLP-1r in the hypothalamus appear to reduce intake by acting on caloric homeostatic circuits 57 — 60 , whereas GLP-1r in the amygdala reduce food intake by eliciting symptoms of stress or malaise 61 , Systemically administered GLP-1 elicits satiation in healthy 53 , obese 63 , and diabetic 64 , 65 humans.

Because the half-life of active GLP-1 is less than 2 min, any direct effects are likely transient, and the reduction of food intake may result from inhibitory effects of GLP-1 on GI transit and reduced gastric emptying However, peripherally administered GLP-1 does cross the blood-brain barrier 67 , perhaps enabling circulating GLP-1 to interact with the brain GLP-1r.

Because it both reduces food intake and stimulates insulin secretion, the GLP-1 system has been adapted to the treatment of type 2 diabetes 68 , DPP-IV-resistant, long-acting GLP-1r agonists are effective at reducing blood glucose in persons with type 2 diabetes and also cause weight loss In addition, inhibitors of DPP-IV, which elevate endogenous GLP-1 levels, are also effective at improving glycemic control in diabetic patients 71 , The effect of chronic GLP-1r agonists to cause weight loss is not consistent with the general principle that satiation peptides are subservient to long-term regulators of energy balance, such as leptin 3.

One potential explanation is that because GLP-1 can activate nonhomeostatic pathways that suppress food intake and otherwise reduce body weight, the effects of chronic administration of GLP-1r agonists work around the homeostatic systems controlling body weight.

Indeed, nausea, a hallmark feature of nonhomeostatic anorexia, is very common with GLP-1r agonist treatment 73 , although this response wanes with continued treatment and is not present in all persons who lose weight.

Another possible explanation for why patients treated with indictable GLP-1r agonists lose weight is that repeated pharmacological doses of a satiation signal can overcome homeostatic restraints. Consistent with this hypothesis is the failure of DPP-IV inhibitor treatment, which has a smaller effect to raise circulating concentrations of GLP-1r agonist activity than do injectable GLP-1 mimetics to cause weight loss.

Although it is not yet clear how GLP-1r agonists cause weight loss, the fact that they do challenges the current model of the interaction of satiation factors with overall energy homeostasis. Other peptides derived from the processing of proglucagon include glicentin, GLP-2, and oxyntomodulin, as well as glucagon itself Glicentin inhibits gastric acid secretion 74 , but at least in rats, does not affect food intake In contrast, oxyntomodulin, a C-terminally extended congener of glucagon, does reduce food intake in animals when given centrally or peripherally 75 , Although a unique receptor for oxyntomodulin has yet to be identified, oxyntomodulin may exert its anorectic effect through the GLP-1r because subthreshold doses of the GLP-1r antagonist, exendin 9—39 , block both GLP-1 and oxyntomodulin-induced reductions in food intake Oxyntomodulin is thought to cross the blood-brain barrier and stimulate neurons in the arcuate nucleus ARC that express GLP-1r and control energy homeostasis 77 , Long-term treatment with oxyntomodulin causes a persistent decrease in food intake and attenuated weight gain in rats Interestingly, weight loss in animals given oxyntomodulin chronically is greater than what would be anticipated from reduced caloric intake 78 , suggesting additional effects on energy expenditure.

Short-term treatment with iv oxyntomodulin decreases hunger, reduces consumption of an ad libitum meal, and has an anorectic action that persists for 12 h after cessation of treatment in lean humans Moreover, in obese subjects randomized to injections of oxyntomodulin or placebo before each meal for 4 wk, there was a significant loss of weight associated with active treatment.

Oxyntomodulin caused an approximately 0. These findings suggest that at least two proglucagon products may have a role in the regulation of food intake.

Distinguishing between the effects of GLP-1 and oxyntomodulin, in particular the relative in vivo actions on the GLP-1r, is an important next step in applying these compounds to clinical medicine. GLP-2 acts through a specific GLP-2 receptor to stimulate intestinal mucosal growth and has become the focus of research on short-bowel syndrome 81 , Intracranial administration of GLP-2 reduces food intake in rats, and the effect can be blocked with a specific GLP-1r antagonist More recent studies in humans found no effect of iv GLP-2 on food intake Glucagon is the most widely studied hormone cleaved from preproglucagon It is secreted from both pancreatic A cells and probably also in small amounts from the distal intestine.

The best known action of glucagon is to increase hepatic glucose production by stimulating glycogenolysis and gluconeogenesis. Glucagon also reduces meal size when administered systemically 86 , 87 , but not centrally 88 , the signal being detected in the liver and relayed to the brain A role for glucagon in the normal control of meal size was demonstrated by the observation that blocking endogenous glucagon action in rats increases food intake 90 , There is little convincing evidence that glucagon plays a role in food intake in healthy humans.

PYY is a member of a family of homologous peptides that also includes pancreatic polypeptide and neuropeptide-Y NPY. Like proglucagon-derived peptides, PYY is synthesized and secreted by L cells in the distal ileum and colon PYY is secreted as PYY 1—36 and is metabolized to PYY 3—36 by DPP-IV 93 , Receptors that mediate the effects of PYY, including reduction of food intake, belong to the NPY receptor family and include Y1, Y2, Y4, and Y5 However, PYY 3—36 is a highly selective agonist activity for the Y2 receptor, and it also reduces food intake in humans and animals 96 , Like GLP-1, PYY has been implicated in GI motility and is considered a major component of the ileal brake 98 , Secretion of PYY is stimulated by food intake and also by the presence of nutrients within the ileum itself ; lipid seems to be a particularly effective stimulus.

Similar to the case with GLP-1, it is not clear whether PYY release requires direct nutrient contact with L cells, or if neurohumoral signals originating from the more proximal GI tract mediate the response.

There is evidence that PYY influences food intake through its interaction with Y2 receptors in the ARC because it freely crosses the blood-brain barrier and because systemic PYY 3—36 is ineffective in reducing food intake in the Y2-deficient mouse Studies in humans have demonstrated that PYY signaling reduces food intake and that abnormalities in this system are present in obese subjects.

PYY secretion is proportional to the caloric content of meals, with larger meals eliciting a significantly larger response , Fasting and postprandial levels of PYY are lower in obese adults compared with lean controls , The attenuated rise in PYY after eating has also been observed in obese adolescents Infusion of PYY 3—36 into lean and obese humans reduced food consumption measured during test meals — , although there remains some question as to whether this effect of PYY 3—36 is pharmacological or occurs at circulating levels seen after eating.

Obese subjects did not differ in their sensitivity to PYY, and there was no difference in the relative PYY 1—36 and PYY 3—36 levels after exogenous administration. Taken together, these findings suggest that abnormal PYY production, rather than anorectic action of metabolism, could contribute to obesity.

Interestingly, there is evidence that genetic variations in the PYY and Y2 sequences are associated with body weight. A common gene polymorphism in the Y2 receptor has been associated with a reduced likelihood of obesity in a cohort study of men with a broad range of BMI Additionally, in a survey of lean and very obese men, a polymorphism in the PYY allele was found to segregate with increased body weight; this genetic variant of PYY was also found to have reduced binding to its receptor and an attenuated anorectic effect in mice In total, the data collected in human studies support a role for PYY in the regulation of food intake and build the strongest case for any of the satiation factors in the pathogenesis of obesity.

Apolipoprotein A-IV apo A-IV is synthesized by intestinal mucosal cells during the packaging of digested lipids into chylomicrons that subsequently enter the blood via the lymphatic system Apo A-IV is also synthesized in the ARC Systemic or central administration of apo A-IV reduces food intake and body weight of rats , and administration of apo A-IV antibodies increases food intake Apo A-IV appears to work by interacting with the CCK signal Because both intestinal and hypothalamic apo A-IV are regulated by absorption of lipid but not carbohydrate , this peptide may be an important link between short- and long-term regulators of body fat see review by Tso and Liu in Ref.

A second digestion-related peptide, enterostatin, is also closely tied to intestinal processing of lipid. The exocrine pancreas secretes lipase and colipase to aid in the digestion of fat, and enterostatin, a pentapeptide, is cleaved from colipase in the intestinal lumen and enters the circulation.

Administration of exogenous enterostatin either systemically , or directly into the brain reduces food intake, and, when rats are given a choice of foods, the reduction is specific for fats; that is, enterostatin does not decrease the intake of carbohydrate or protein Therefore, two peptides that are secreted from the gut during the digestion and absorption of lipids, apo A-IV and enterostatin, act as signals that decrease food intake, and at least one of them selectively reduces the intake of fat.

Macronutrient specificity has not been assessed with apo A-IV. There are no data from human studies to confirm the findings with apo A-IV and enterostatin on food intake.

Members of the bombesin family of peptides including bombesin itself an amphibian peptide and its mammalian analogs, gastrin-releasing peptide GRP and neuromedin B NMB , reduce food intake when administered systemically in humans and animals or into the CNS of animals — Consistent with the possibility that these peptides act endogenously to reduce food intake, mice deficient for the GRP receptor eat significantly larger meals and develop late-onset obesity Whereas most satiation factors act by reducing the size of an ongoing meal 4 , bombesin peptides are an interesting exception in that when they are administered between meals, they increase the amount of time until the subsequent meal begins; i.

they increase satiety as well as satiation , Both bombesin and GRP reduce food intake when infused into human subjects , Antagonism of endogenous bombesin receptors has demonstrable effects on gastric, intestinal, and gallbladder function but has not been studied with regard to food intake , Therefore the case for GRP as a physiological mediator of satiation in humans is not as strong as for CCK.

Amylin also called islet amyloid polypeptide is a peptide hormone secreted by pancreatic B cells in tandem with insulin secretion, which inhibits gastric emptying and gastric acid secretion, lowers glucagon concentrations, and reduces food intake Amylin causes a dose-dependent reduction of meal size when administered systemically or directly into the brain — , and antagonism of amylin action in the CNS causes increased food intake and body weight Consistent with this, targeted deletion of the amylin gene causes increased body weight in mice.

Amylin signals through the calcitonin receptor when it has been modified by receptor activity modifying proteins , , and in contrast to many satiation peptides that reduce food intake by stimulating the visceral afferent nerves, amylin seems to act as a hormone, directly stimulating neurons in the area postrema in the hindbrain , In fact, the anorectic action of amylin shares features with both satiation signals phasic, meal-induced secretion and adiposity signals chronic interruption of action in rodents causes increased body fatness.

Amylin seems to interact with both types of regulation in that the ability of amylin to reduce meal size is augmented when brain insulin action is elevated and the effects of CCK and bombesin are muted in the absence of amylin signaling Amylin has been developed as a therapeutic, with the synthetic analog pramlintide now available for the treatment of type 1 and type 2 diabetes and clinical trials under way to determine the efficacy in treating obesity.

In diabetic patients treated with pramlintide for 1 yr, weight loss averaged approximately 2 kg relative to placebo-treated controls , Similar to treatment with the GLP-1r agonist exendin-4, pramlintide presents supraphysiological levels of amylin-like activity to patients, and the primary side effect is nausea.

Nonetheless, the clinical experience with pramlintide supports the idea that chronic activity of a satiating compound can cause weight loss. Ghrelin, a product of specific endocrine cells in the stomach and duodenum, actually stimulates food intake and is the most potent known circulating orexigen Ghrelin is secreted from the fundic region of the stomach and has been identified as the endogenous ligand for the GH secretagogue receptor.

Fasting increases plasma ghrelin , and exogenous ghrelin increases food intake when administered peripherally or centrally — Ghrelin has also been linked to the anticipatory aspects of meal ingestion because levels peak shortly before scheduled meals in humans and rats and fall shortly after meals end.

Moreover, elevated ghrelin has been linked to the hyperphagia and obesity of individuals with the Prader-Willi syndrome Ghrelin is also unique among the GI signals in that its message appears to be conveyed directly to receptors in the hypothalamus — , although, as is the case for CCK, GLP-1, and other GI signals, there are ghrelin receptors on vagal sensory nerves but they do not appear to signal satiation Satiation appears to be a complex phenomenon, mediated by a number of GI peptides.

Although it is clear that the different satiation factors respond to specific nutrient stimuli e. CCK to protein and fat, GLP-1 to carbohydrate and fat, PYY primarily to fat, and so on , it has not been proven that mixed meals of differing macronutrient content elicit the release of distinct cocktails of GI hormones.

However, given the wide range of specific factors that seem to mediate satiation, it is logical to presume that this process is subject to highly refined regulation. Especially important is the modulation of the action of satiation by factors such as leptin and insulin that are responsive to body adiposity.

This interaction is the critical site of endocrine regulation of eating and energy homeostasis. A key feature of the system regulating food intake is that most if not all of the peptides that are made in the GI tract and influence satiation are also synthesized in the brain.

This includes CCK, GLP-1, GLP-2, oxyntomodulin, apo A-IV, GRP, NMB, PYY, and ghrelin. Exceptions are the pancreatic hormones that influence energy homeostasis i.

The fact that so many peripheral signals that influence food intake are also synthesized locally in the brain raises the question of whether and how the same signals secreted from different places in the body interact.

A simple generalization is that, if a peptide reduces or increases food intake when administered systemically, it probably has the same action when administered centrally. With regard to changes of food intake, this is true of CCK, GLP-1, apo A-IV, GRP, NMB, PYY, and ghrelin.

Interestingly, it is also generally true that peptide signals that are not synthesized in the brain nonetheless have the same effect on food intake when administered directly into the brain.

This is true of leptin, insulin, and amylin, but not glucagon. It is worth contemplating why there is such a large imbalance among GI hormones that suppress and stimulate food intake; i.

whereas numerous peptides secreted from the stomach and intestines decrease food intake, only one known factor, ghrelin, increases it. One possibility relates to the phenomenon of satiation itself and the benefits of meal termination. Meals end long before any physical limit of the stomach is reached.

This is easily demonstrated when food is diluted with noncaloric bulk and animals increase the volume of food consumed to attain their normal caloric load , It has therefore been argued that a primary function of satiation signals is to prevent the consumption of too many calories at one time, lest the influx of nutrients and substrates overwhelm the capacity of the animal to maintain homeostasis 5 , That is, an important role of the GI tract is to analyze and respond to the incoming macronutrients while a meal is being eaten, helping to preempt excessive challenges to biochemical homeostasis.

A corollary to this role for satiation signals is that adequate food intake does not require much specific stimulation, only the absence of inhibitory signals for food intake combined with the presence of food.

Until recently there was some question as to whether manipulation of meal size by factors activating the satiation system could have therapeutic efficacy for weight reduction. One possibility was that because the effects of satiation peptides are dependent on body adiposity, their action would become muted as food intake decreased due to homeostatic regulation of body energy stores.

Evidence for this was demonstrated for the satiating action of CCK in genetically obese Zucker rats , , but not for rats rendered obese by lesions of the ventromedial hypothalamus Furthermore, rats genetically prone to becoming obese when fed a high-fat diet diet-induced obesity rats are actually more sensitive to the satiating action of CCK both before and after becoming obese Some strains of genetically obese mice are comparably as sensitive as lean controls , and CCK works well in obese humans when administered iv Hence, there is no general principle with regard to sensitivity in obesity, at least with regard to CCK.

There is evidence that the satiating action of GLP-1 is leptin-dependent All of these observations were made with animals having relatively free access to their diets so that they could vary their meal patterns in the service of maintaining body fat; i.

when individuals are constrained to eating only small meals, they compensate by eating more often, thereby maintaining daily caloric intake and body weight. This has been observed when CCK is administered before every meal in experimental animals; animals receiving this treatment eat smaller and more frequent meals while keeping body weight constant 33 , In contrast, if animals are constrained to eating only three meals a day and receive a satiating peptide at each mealtime, they cannot compensate and consequently lose weight The advent of long-acting formulations of GLP-1 and amylin, peptides that seem to have a role in satiation , , has resulted in weight loss , However, at present it is not clear that the chronic effects of GLP-1 and amylin receptor agonists are entirely due to continued hypophagia as opposed to other, nonbehavioral actions of the compounds.

Understanding how a chronic pharmacological stimulus to the satiation system lowers body weight is important for refining the models for normal energy homeostasis. Insulin from the pancreatic B cells and leptin from white adipocytes as well as the stomach and other tissues are each secreted in direct proportion to body fat.

Both hormones are transported through the blood-brain barrier , and gain access to neurons in the hypothalamus and elsewhere in the brain to influence energy homeostasis.

Consistent with this, if exogenous insulin or leptin is added locally into the brain, the individual responds as if excess fat exists in the body; i. food intake is reduced and body weight is lost. Analogously, if either the leptin or the insulin signal is reduced locally in the brain, the individual responds as if insufficient fat is present in the body, more food is eaten, and the individual gains weight.

There are many reviews of these phenomena 1 , 2 , 87 , — An important distinction is that whereas satiation signals primarily influence how many calories are eaten during individual meals, adiposity signals are more directly related to how much fat the body carries and maintains. Developing novel compounds that interact directly with the normal detection of and response to adiposity signals would therefore seem a more promising therapeutic approach for obesity.

One obstacle is that to be effective, any compound would have to gain access to key receptors in the brain, yet any such compound would most likely have to be administered systemically.

Administering insulin systemically elicits hypoglycemia and other side effects, and hypoglycemia per se increases food intake — , thus working against the therapeutic intent.

Systemically administered insulin does result in reduced food intake when plasma glucose is prevented from decreasing in animal models , , but this would be difficult to achieve therapeutically. Alternatively, there are reports that some formulations of nasally administered insulin elicit reduced food intake and body weight in humans without altering plasma glucose , Leptin does not have the same counterproductive systemic effects as insulin, and in fact improves insulin sensitivity and circulating lipoprotein concentrations in subjects with metabolic abnormalities associated with anti-HIV treatment Moreover, chronic leptin treatment of patients with generalized lipodystrophy causes significant improvements of insulin resistance, hypertriglyceridemia, hepatic steatosis, and glucose metabolism , responses found across the spectrum of lipodystrophies.

However, the results of clinical trials using leptin in healthy obese subjects have been variable, with significant weight loss, but not of a remarkable magnitude, and some bothersome side effects related to peptide administration.

Insulin and leptin resistance characterize the obese state, meaning that more of each hormone is required to achieve a particular physiological effect than occurs in lean individuals.

Individuals with diabetes cannot achieve a maximum insulin response because of defects in insulin secretion and insulin action. The insulin and leptin resistance that characterizes peripheral tissues in obesity is also manifested in the brain.

For one thing, the transport of both hormones from the blood to the brain is compromised in obesity such that less signal reaches critical neurons — , and the ability of those neurons to respond is also compromised. When insulin is administered locally into the brain near the hypothalamus, both genetically obese and dietary obese individuals have a reduced or absent reduction of food intake, and this is the case for leptin as well An insulin mimetic that interacts with the insulin receptor and is efficacious when given orally or directly into the brain has been reported to reduce food intake and body weight in obese rodents , , but it evidently has problematic side effects.

Although receptors for insulin and leptin are found in several discrete areas throughout the brain, many that are especially important for controlling energy homeostasis are localized in the ARC of the hypothalamus Fig.

The ARC is ideally suited as a receptor site for body adiposity as well as for integration of diverse hormonal and neural signals because there is evidence that blood-borne molecules have relatively greater access to receptors there than to other brain areas, and this is thought to be due in part to a relatively leaky blood-brain barrier in the ARC , Two categories of ARC neurons are particularly important.

One synthesizes the prepropeptide, proopiomelanocortin POMC , and in the ARC POMC is cleaved to α-melanocyte-stimulating hormone αMSH as a neurotransmitter. The second group of ARC neurons synthesizes and secretes two neuropeptides important in energy homeostasis, and their axons project to many of the same brain areas as POMC neurons.

Agouti-related peptide AgRP is an antagonist at MC3R and MC4R such that one action of these neurons is to counter the activity of POMC neurons. NPY acts at Y receptors to stimulate food intake — When either AgRP or NPY is administered chronically into the brain, body weight increases , — In fact, when a single dose of AgRP is administered into the brain near the ARC, food intake is increased for 1 wk or more , Each is the origin of tracts projecting to other hypothalamic and brain areas, the two tracts often occurring in parallel.

The POMC-originating tract has an overall catabolic effect such that when it is more active food intake is reduced, energy expenditure is increased, and if prolonged, body fat is lost.

Under normal conditions, both circuits are active such that a change of input that is either stimulatory or inhibitory to either type of neuron elicits rapid changes of many energetic parameters.

In the acute situation, both food intake and plasma glucose are altered because the ARC influences circuits projecting to behavioral sites as well as autonomic circuits influencing hepatic glucose secretion and pancreatic insulin secretion — Another important aspect of the area including the ARC and nearby hypothalamic nuclei is that receptors for many of the satiation signals discussed above are expressed there; i.

circulating ghrelin is thought to interact directly with ARC neurons , which are also directly or indirectly sensitive to changes of CCK, GLP-1, NMB, and apo A-IV. Because most of these peptides are made within the brain, the origin of molecules altering ARC activity may not be directly from the plasma as occurs with insulin, leptin, and ghrelin.

Numerous circuits from the hindbrain satiation area and elsewhere in the brain project to the region of the ARC 25 , 27 , Finally, ARC neurons are also sensitive to local levels of energy-rich nutrients, including glucose , some long-chain fatty acids [ e.

oleic acid , ], and some amino acids [ e. leucine ]. Thus, the ARC is situated to be sensitive to a wide array of signals important in energy regulation , — It is directly sensitive to hormones whose secretion is proportional to body fat insulin and leptin ; it receives information on ongoing meals either directly or indirectly; and it is sensitive to local levels of nutrients.

Importantly, numerous neuronal circuits interconnect the ARC and nearby hypothalamic areas with the nucleus of the solitary tract, enabling the hypothalamic homeostatic network to be constantly aware of ongoing GI activity while at the same time influencing brain stem autonomic areas projecting to the GI tract, liver, pancreas, and other tissues 25 , 27 , — The ARC can therefore be considered as a key afferent as well as efferent area for the regulation of energy homeostasis.

Although ARC neurons project throughout the brain, two nearby target areas are thought to be especially important. Administration of exogenous CRH or oxytocin into the brain reduces food intake.

Hence, a catabolic circuit exists in which an increase of body fat is associated with increased insulin and leptin, increased αMSH, and decreased NPY and AgRP activity, and consequently increased activity of CRH, oxytocin, and other catabolic signals; all of these lead in turn to reduced food intake and increased energy expenditure.

The lateral hypothalamic area LHA has a contrasting profile from the PVN It also receives direct inputs from the ARC, and it contains neurons that synthesize and secrete anabolic peptides, including melanin-concentrating hormone and the orexins. Administration of melanin-concentrating hormone , or orexin agonists increases food intake and body weight gain.

The architecture and functioning of these opposing hypothalamic circuits therefore enables rapid and fine-tuned control over energy homeostasis because the brain can simultaneously turn up one system e.

catabolic or anabolic while turning down the other. Total food intake each day is the sum of the intake in individual meals including snacks. As discussed above, the time that meals are initiated is often under the control of nonhomeostatic influences 4 , 5 , , Hence, whatever regulatory control exists for body weight must be exerted on how much is eaten in individual meals, and meal termination is consequently under the influence of satiation signals.

The efficacy of satiation signals to terminate a meal varies with the amount of fat in the body as signaled to the brain by leptin and insulin. When an individual has been food restricted or been on a diet and loses weight, leptin and insulin secretion both decline, and a reduced adiposity signal reaches the ARC.

This in turn lowers sensitivity to satiation signals such as CCK, and the consequence is that more food is eaten during meals before satiation or feeling full occurs. Conversely, individuals who have overeaten and gained weight have elevated levels of adiposity signals and enhanced sensitivity to satiation signals, reducing the trajectory of weight gain or even promoting weight loss.

When low doses of leptin or insulin are infused directly into the brain near the ARC, they greatly enhance the ability of satiation signals to reduce food intake [ e. much less CCK or other satiation signals is required to terminate a meal — ], and when the adiposity signal in the brain is reduced, satiation signals are less efficacious The brain receives and integrates diverse information pertinent to the maintenance of energy homeostasis.

Adiposity signals such as insulin and leptin act in the arcuate nuclei to provide a background tone, and this tone in turn determines the sensitivity of the brain to satiation signals influencing how much food is eaten at any one time. This is because social factors, palatability, habits, the presence of predators, stress, and many other factors are also always at work, influencing not only when meals occur but how much food is consumed as well.

Only when extraneous factors are tightly controlled in laboratory animal experiments, or else when ingestion is precisely monitored and quantified over periods of days or weeks in free-feeding humans, do the effects of these homeostatic signals become apparent.

This work was supported by National Institutes of Health Awards DK and DK Disclosure Summary: S. received lecture fees from Sanofi-Aventis and from Merck.

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In: Stricker EM, Woods SC, eds. Handbook of behavioral neurobiology. Neurobiology of food and fluid intake. Leptin deficiency can also be found in conditions and syndromes where there is significant lipodystrophy. The effects of leptin deficiency can be reversed with the use of exogenous leptin.

PYY full name - peptide tyrosine tyrosine is a short peptide hormone released by cells in the ileum and colon in response to feeding. Once you've finished editing, click 'Submit for Review', and your changes will be reviewed by our team before publishing on the site.

We use cookies to improve your experience on our site and to show you relevant advertising. To find out more, read our privacy policy. Appetite Home Gastrointestinal The Stomach Appetite. star star star star star. Appetite Control Centre The appetite control centre is located in the hypothalamus.

The neurotransmitters released by excitatory and inhibitory neurones are: Excitatory: Neuropeptide Y NPY and Agouti-related peptide AgRP.

These promote hunger. Inhibitory: POMC and CART. POMC can be cleaved into other neurotransmitters such as α-MSH and β-endorphin. These suppress hunger.

Hormonal Signals From the Gut Ghrelin is a peptide hormone produced in the pancreas and released from the stomach wall when the stomach is empty. From the Body Leptin is a peptide hormone released into the blood by adipocytes fat cells. Clinical Relevance — Leptin Deficiency Leptin deficiency may arise from deletion of the leptin gene causing severe obesity, hyperphagia excessive eating and a reduced metabolic rate.

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Our understanding of the physiological systems that Appetitee food intake and body weight has increased immensely over the past decade. Brain centres, including the hypothalamus, brainstem and controp centres, signal via neuropeptides Artisanal breads regulate energy Protein intake for men. Insulin and hormones synthesized Apletite adipose Appetife reflect the long-term nutritional status of the body and are able to influence these circuits. Circulating gut hormones modulate these pathways acutely and result in appetite stimulation or satiety effects. This review discusses central neuronal networks and peripheral signals which contribute energy homeostasis, and how a loss of the homeostatic process may result in obesity. It also considers future therapeutic targets for the treatment of obesity. In most adults, adiposity and body weight are remarkably constant despite huge variations in daily food intake and energy expended. Body Hydration Electrolytes Natural weight loss shakes mainly Contro by your systfm the desire to eat and satiety the sensation of sustem. Many signaling molecules and hormones control appetite and satiety in the cellular, peripheral Appetitr central nervous systems. Contrrol genetic variants involved in overweight and obesity are often associated with increased appetite or diminished satiety. Body weight is determined by energy balance. The calories you get from food and beverages are called your energy intake while the calories you expend to support your life and daily activities are called your energy expenditure. When energy intake equals energy expenditure, your body weight remains the same but when energy intake exceeds your energy expenditure then you have an energy surplus. Appetite control system

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