Meal Initiation Research Articles

Peripheral ghrelin interacts with orexin neurons in glucostatic signalling

Ghrelin interactions with glycemia in appetite control as well as the potential mechanisms involving the orexin and melanin-concentrating hormone (MCH) neurons in the orexigenic ghrelin signals were investigated by using a specific anti-ghrelin antibody (AGA). Our results confirm that peripheral ghrelin is an important signal in meal initiation and appetite. Employing immunohistochemistry techniques, we found that c-fos positive neurons in the lateral hypothalamus (LH) and perifornical area (PFA) increased after insulin or 2-deoxyglucose administration. Moreover, we have also demonstrated that peripheral ghrelin blockade by the AGA, reduces the orexigenic signal induced by insulin and 2-DG administration probably partly producing a decrease of c-fos immunoreactivity in the LH and PFA as well as a lower activation of orexin neurons. In contrast, the c-fos positive MCH neurons were not apparently affected. In summary, our findings suggest that peripheral ghrelin plays an important role in regulatory “glucostatic” feeding mechanisms by means of its role as a “hunger” signal affecting the LH and PFA areas, which may contribute to energy homeostasis through orexin neurons.

Short Communication: Rate of Propionate Infusion Within Meals Does Not Influence Feeding Behavior

Propionate has been shown to depress the feed intake of ruminants, but whether the rate of propionate infusion influences this response is unknown. To test this possibility, the rate of propionate infused within meals was altered while the total amount of propionate infused was held constant. Eight multiparous Holstein cows (51±19 d in milk, 44.0±4.8 kg/d of milk; mean±SD) were randomly assigned to the treatment sequence in a crossover experiment with a 10-d diet adaptation period, 24-h treatment periods, and 3 d between treatments. Treatments were intraruminal infusion of 1.26mol of Na propionate (2.33±0.06L, 0.54 M, pH 6.0) over the course of either 5min (fast) or 15min (slow) at each spontaneous meal. The experimental diet included high-moisture corn and was formulated for 27% neutral detergent fiber, 36% starch, and 17.5% crude protein. Feeding behavior was monitored by a computerized data acquisition system that triggered infusion pumps at the initiation of meals, and consecutive infusions began at least 15min apart under both treatment protocols. Feeding behavior data were analyzed to quantify the number, size, length, and time between all meals. Compared with pretreatment intake, propionate infusions depressed feed intake by 20 and 23%, respectively, for the slow and fast treatments. However, the rate of propionate infusion did not significantly alter dry matter intake, meals/day, meal size, meal length, or intermeal interval. We found no evidence that the rate of infusion, within the range of typical meal lengths, determines the extent of hypophagia from propionate.

Détecteurs de glucose et régulation de la prise alimentaire

Based on the glucostactic and lipostastic theories, it has been proposed that two dependent phenomena could be involved in the control of food intake. At short term, the regulation of food intake is part of the of the glucoregulatory mechanism, i.e. to the mechanism of use and replenishment of the glucose stores. This mechanism which is mainly involved in meal initiation is modulated by a second mechanism linked to the use and storage of lipids i.e. fat mass. Some molecules have been proposed to play the role of signal informing some brain structures of the metabolic status of the individual, among them leptin, insulin and glucose seems to play a major role. New insights into the cellular and molecular mechanism that support the fact that the electrical activity of some neurones depends on the glucose and/or insulin concentration, have been gained recently. Making the analogy with the beta cell of the islet of Langerhans, it has been proposed that proteins such as glucose transporter 2, glucokinase and the ATP-dependent potassium channel, could assure this sensing. Alteration in this sensing system could be at the origin of some alterations in feeding behavior.

Estradiol-Dependent Decrease in the Orexigenic Potency of Ghrelin in Female Rats

Ghrelin, the only known orexigenic gut hormone, is secreted mainly from the stomach, increases with fasting and before meal initiation in humans and rats, and increases food intake after central or peripheral administration. To investigate sex differences in the action of ghrelin, we assessed the effects of exogenous ghrelin in intact male and female rats, the effects of exogenous ghrelin in ovariectomized (OVX) and estradiol (E2)-treated female rats, as well as the effects of OVX on plasma ghrelin and hypothalamic orexigneic neuropeptide expression in rats and on food intake and weight gain in transgenic mice lacking the ghrelin receptor (Ghsr(-/-) mice). Male and OVX female rats were significantly more sensitive than intact female rats to the orexigenic effects of both centrally (intra-third ventricular, i3vt, 0.01, 0.1, and 1.0 nmol) and systemically (ip, 3, 6, and 9 nmol) administered ghrelin. This difference is likely to be estradiol dependent because E2 attenuated the orexigenic action of ghrelin in OVX female and male rats. Furthermore, OVX increased food intake and body weight in wild-type mice, but not in Ghsr(-/-) mice, suggesting that OVX increases food intake by releasing ghrelin from a tonic inhibitory effect of estradiol. In addition, following OVX, there was an increase in plasma ghrelin that was temporally associated with increased food intake, body weight, and hypothalamic neuropeptide Y and Agouti-related protein mRNA expression. Collectively, these data suggest that estradiol inhibits the orexigenic action of ghrelin in females, that weight gain associated with OVX is ghrelin mediated, and that this endocrine interaction may account for an important sex differences in food intake and the regulation of body weight.

The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review

Leptin and ghrelin are two hormones that have been recognized to have a major influence on energy balance. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. As a growing number of people suffer from obesity, understanding the mechanisms by which various hormones and neurotransmitters have influence on energy balance has been a subject of intensive research. In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant. However, the manner in which both the leptin and ghrelin systems contribute to the development or maintenance of obesity is as yet not clear. The purpose of this review is to provide background information on the leptin and ghrelin hormones, their role in food intake and body weight in humans, and their mechanism of action. Possible abnormalities in the leptin and ghrelin systems that may contribute to the development of obesity will be mentioned. In addition, the potentials of leptin and ghrelin as drug targets will be discussed. Finally, the influence of the diet on leptin and ghrelin secretion and functioning will be described.

Ghrelin: a hormone regulating food intake and energy homeostasis

Regulation of energy homeostasis requires precise coordination between peripheral nutrient-sensing molecules and central regulatory networks. Ghrelin is a twenty-eight-amino acid orexigenic peptide acylated at the serine 3 position mainly with an n-octanoic acid, which is produced mainly in the stomach. It is the endogenous ligand of the growth hormone secretagogue (GHS) receptors. Since plasma ghrelin levels are strictly dependent on recent food intake, this hormone plays an essential role in appetite and meal initiation. In addition, ghrelin is involved in the regulation of energy homeostasis. The ghrelin gene is composed of four exons and three introns and renders a diversity of orexigenic peptides as well as des-acyl ghrelin and obestatin, which exhibit anorexigenic properties. Ghrelin stimulates the synthesis of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus neurons of the hypothalamus and hindbrain, which in turn enhance food intake. Ghrelin-expressing neurons modulate the action of both orexigenic NPY/AgRP and anorexigenic pro-opiomelanocortin neurons. AMP-activated protein kinase is activated by ghrelin in the hypothalamus, which contributes to lower intracellular long-chain fatty acids, and this appears to be the molecular signal for the expression of NPY and AgRP. Recent data suggest that ghrelin has an important role in the regulation of leptin and insulin secretion and vice versa. The present paper updates the effects of ghrelin on the control of energy homeostasis and reviews the molecular mechanisms of ghrelin synthesis, as well as interaction with GHS receptors and signalling. Relationships with leptin and insulin in the regulation of energy homeostasis are addressed.

Neural Ensemble Coding of Satiety States

The motivation to start or terminate a meal involves the continual updating of information on current body status by central gustatory and reward systems. Previous electrophysiological and neuroimaging investigations revealed region-specific decreases in activity as the subject's state transitions from hunger to satiety. By implanting bundles of microelectrodes in the lateral hypothalamus, orbitofrontal cortex, insular cortex, and amygdala of hungry rats that voluntarily eat to satiety, we have measured the behavior of neuronal populations through the different phases of a complete feeding cycle (hunger-satiety-hunger). Our data show that while most satiety-sensitive units preferentially responded to a unique hunger phase within a cycle, neuronal populations integrated single-unit information in order to reflect the animal's motivational state across the entire cycle, with higher activity levels during the hunger phases. This distributed population code might constitute a neural mechanism underlying meal initiation under different metabolic states.

Ghrelin and the short- and long-term regulation of appetite and body weight

Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone. Considerable evidence implicates ghrelin in mealtime hunger and meal initiation. Circulating levels decrease with feeding and increase before meals, achieving concentrations sufficient to stimulate hunger and food intake. Preprandial ghrelin surges occur before every meal on various fixed feeding schedules and also among individuals initiating meals voluntarily without time- or food-related cues. Ghrelin injections stimulate food intake rapidly and transiently, primarily by increasing appetitive feeding behaviors and the number of meals. Preprandial ghrelin surges are probably triggered by sympathetic nervous output. Postprandial suppression is not mediated by nutrients in the stomach or duodenum, where most ghrelin is produced. Rather, it results from post-ingestive increases in lower intestinal osmolarity (information probably relayed to the foregut via enteric nervous signaling), as well as from insulin surges. Consequently, ingested lipids suppress ghrelin poorly compared with other macronutrients. Beyond a probable role in meal initiation, ghrelin also fulfills established criteria for an adiposity-related hormone involved in long-term body-weight regulation. Ghrelin levels circulate in relation to energy stores and manifest compensatory changes in response to body-weight alterations. Ghrelin crosses the blood–brain barrier and stimulates food intake by acting on several classical body-weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system. Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader–Willi syndrome and low after gastric bypass surgery, possibly contributing to body-weight alterations in these settings. Extant evidence favors roles for ghrelin in both short-term meal initiation and long-term energy homeostasis, making it an attractive target for drugs to treat obesity and/or wasting disorders.

Fasting plasma peptide-YY concentrations are elevated but do not rise postprandially in type 2 diabetes

To the Editor: Weight loss appears to be particularly difficult to achieve in patients with type 2 diabetes compared to their non-diabetic counterparts [1]. The hormones peptide YY3–36 (PYY) and ghrelin are implicated in the regulation of appetite, energy balance and the pathophysiology of obesity. PYY is released from L-cells in the gut in response to food [2]. Fasting concentrations are lower and postprandial responses attenuated in obese subjects [3], and infusions of PYY to mimic the postprandial concentrations found in lean subjects reduce appetite and food intake in obese subjects [3, 4], suggesting a potential role in the pathogenesis of obesity. Peripheral administration of ghrelin increases food ingestion [5, 6], and prolonged administration leads to obesity [5, 7]. Circulating ghrelin shows preprandial peaks and postprandial troughs suggesting a role in meal initiation. Against this background, we sought to determine whether type 2 diabetes, independent of obesity status, affected the prandial regulation of PYY and ghrelin in a manner that would explain both the predisposition to increased energy intake and weight gain, and the difficulties in achieving weight loss seen in type 2 diabetes. The study was approved by the local ethics committee and subjects, who were volunteers, gave written informed consent. We studied 11 subjects with diet-controlled type 2 diabetes and 16 control subjects of similar age, sex and BMI. All subjects with diabetes were free from complications and had an HbA1c <10%. Urea, electrolytes, full blood count, thyroid function and resting electrocardiogram were normal in all subjects. Antihypertensive, lipid-lowering and aspirin treatment were not considered exclusion criteria unless they included beta-adrenoreceptor antagonists. Subjects attended at 08.30 h, having fasted from 22.00 h the previous evening and refrained from alcohol or strenuous physical activity for at least 24 h and cigarettes for at least 12 h. Anthropometric variables were measured and body fat percentage estimated using whole-body bioelectrical impedance analysis (Tanita Systems, Stokie, IL, USA). Studies were conducted at an ambient temperature of 22±1°C. Following baseline blood samples, subjects consumed a standard mixed meal of 600 kcal (63.9% carbohydrate, 13.0% protein, 23.1% fat) over 20 min. Blood was collected at 15, 30, 60, 120, 180, 240, 300 and 360 min after the meal. Samples were centrifuged, frozen immediately and stored at −80°C until assayed. Plasma PYY-like immunoreactivity (specifically PYY3–36 and PYY1–36 with no cross-reactivity with other peptides) was measured using an established radioimmunoassay [2]. Ghrelin-like immunoreactivity was measured with a specific and sensitive Diabetologia (2006) 49:2219–2221 DOI 10.1007/s00125-006-0344-y

Hunger and satiety: one brain for two?

understanding the physiological controls of eating and developing effective pharmacological tools to reduce eating has never been more important. The modern world faces an unprecedented obesity epidemic, and the current treatment strategies are rather unsuccessful. One possible solution may be a

The anorexia of aging in humans

Energy intake is reduced in older individuals, with several lines of evidence suggesting that both physiological impairment of food intake regulation and non-physiological mechanisms are important. Non-physiological causes of the anorexia of aging include social (e.g. poverty, isolation), psychological (e.g. depression, dementia), medical (e.g. edentulism, dysphagia), and pharmacological factors. Physiological factors include changes in taste and smell, diminished sensory-specific satiety, delayed gastric emptying, altered digestion-related hormone secretion and hormonal responsiveness, as well as food intake-related regulatory impairments for which specific mechanisms remain largely unknown. Studies in healthy elderly individuals have shown that men who consume diets over several weeks providing either too few or too many calories relative to dietary energy needs subsequently do not compensate for the resulting energy deficit or surplus when provided an ad libitum diet. Healthy elders have also been shown to be less hungry at meal initiation and to become more rapidly satiated during a standard meal compared to younger adults. Studies in animal models are required to investigate potential mechanisms underlying these observations, while human studies should focus on examining the potential consequences of this phenomenon and practical therapeutic strategies for the maintenance of appropriate energy intake with increasing age. In light of this need, we have recently demonstrated that low reported hunger assessed using a simple questionnaire predicts unintentional weight loss in a sample of healthy older women, and thus may provide a clinically useful tool for identifying older individuals at risk for undesirable weight change and therefore at high priority for intervention.

Energy Homeostasis and Gastric Emptying in Ghrelin Knockout Mice

To elucidate the role of endogenous ghrelin in the regulation of energy homeostasis and gastric emptying, ghrelin knockout mice (ghrelin(-/-)) were generated. Body weight, food intake, respiratory quotient, and heat production (indirect calorimetry), and gastric emptying ((14)C breath test) were compared between ghrelin(+/+) and ghrelin(-/-) mice. In both strains, the effect of exogenous ghrelin on gastric emptying and food intake was determined. Ghrelin(-/-) mice showed some subtle phenotypic changes. Body weight gain and 24-h food intake were not affected, but interruption of the normal light/dark cycle triggered additional food intake in old ghrelin(+/+) but not in ghrelin(-/-) mice. Exogenous ghrelin increased food intake in both genotypes with a bell-shaped dose-response curve that was shifted to the left in ghrelin(-/-) mice. During the dark period, young ghrelin(-/-) mice had a lower respiratory quotient, whereas their heat production was higher than that of the wild-type littermates, inferring a leaner body composition of the ghrelin(-/-) mice. Absence of ghrelin did not affect gastric emptying, and the bell-shaped dose-response curves of the acceleration of gastric emptying by exogenous ghrelin were not shifted between both strains. In conclusion, ghrelin is not an essential regulator of food intake and gastric emptying, but its loss may be compensated by other redundant inputs. In old mice, meal initiation triggered by the light/dark cue may be related to ghrelin. In young animals, ghrelin seems to be involved in the selection of energy stores and in the partitioning of metabolizable energy between storage and dissipation as heat.

Peripheral Ghrelin participates in glucostatic feeding mechanisms and in the anorexigenic signalling mediated by CART and CRF neurons

Ghrelin is upregulated under negative energy balance conditions, including starvation and hypoglycemia, while it is downregulated under situations of positive energy balance, such as feeding, hyperglycemia and obesity. The aims of this study were to assess potential ghrelin interactions with glucose levels in appetite control and to identify potential mechanisms involving orexigenic and anorexigenic ghrelin mediated signals by using a specific anti-ghrelin antibody. Our results confirm that peripheral ghrelin is an important signal in meal initiation and food intake stimulation. C-fos positive neurons in the PVN increased after insulin or 2-deoxyglucose administration. Moreover, we also demonstrate that peripheral ghrelin blockade with a specific anti-ghrelin antibody reduces, in part, the orexigenic signal induced by insulin and 2-DG administration. Furthermore, when we blocked peripheral ghrelin, c-fos positive CRF neurons and CART expression increased in the PVN, both under hypoglycemia or cytoglycopenia conditions, suggesting a neuronal activation (anorexigenic signalling) in this hypothalamic region. In summary, our findings imply that peripheral ghrelin plays an important role in regulatory “glucostatic” feeding mechanisms due to its role as a “hunger” signal affecting the PVN area, which may contribute to energy homeostasis through both orexigenic/anorexigenic pathways.

Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern

Ghrelin stimulates GH release and causes weight gain through increased food intake and reduced fat utilization. Ghrelin levels were shown to rise in the preprandial period and decrease shortly after meal consumption, suggesting a role as a possible meal initiator. However, ghrelin secretion in fasting subjects has not yet been studied in detail. 24-h ghrelin profiles were studied in six healthy volunteers (three females; 25.5 years; body mass index 22.8 kg/m(2)) and compared with GH, insulin and glucose levels. Blood samples were taken every 20 min during a 24-h fasting period and total ghrelin levels were measured by RIA using a polyclonal rabbit antibody. The circadian pattern of ghrelin secretion and pulsatility (Cluster analysis) were evaluated. An increase and spontaneous decrease in ghrelin were seen at the timepoints of customary meals. Ghrelin was secreted in a pulsatile manner with approximately 8 peaks/24 h. An overall decrease in ghrelin levels was observed during the study period. There was no correlation of ghrelin with GH, insulin or blood glucose levels. This pilot study indicates that fasting ghrelin profiles display a circadian pattern similar to that described in people eating three times per day. In a fasting condition, GH, insulin and glucose do not appear to be involved in ghrelin regulation. In addition, we found that ghrelin is secreted in a pulsatile pattern. The variation in ghrelin independently of meals in fasting subjects supports previous observations that it is the brain that is primarily involved in the regulation of meal initiation.

A new way of looking at eating

the analysis of meals, especially of spontaneous meals, has long had a problematic place in the behavioral neuroscience of eating. Only a small minority of eating researchers now, or ever, have concerned themselves with meal patterns. On first glance this seems paradoxical. After all, eating occurs

Meal size of high-fat food is reliably greater than high-carbohydrate food across externally-evoked single-meal tests and long-term spontaneous feeding in rat

A series of studies in rat using isoenergetic (kcal/ml) liquid diets differing in fat content has previously found dietary fat to dose-dependently increase daily caloric intake. In single-meal tests in which meal initiation was externally evoked in feeding-associated environments, the behavioral expression of this overeating was found to be larger meal intake. The present studies confirmed the ecological validity of this larger meal size of high-fat diet (HF) relative to high-carbohydrate diet (HC): meal size of HF>HC in home-cage testing (Experiment 1), and during undisturbed, spontaneous feeding in which ingestive behavior was continuously monitored (Experiments 2 and 3). These findings demonstrate that single-meal paradigms yield results consistent with spontaneous feeding of high-fat and high-carbohydrate liquid diets, thus supporting the use of single-meal studies to better understand the physiological bases of elevated caloric intake associated with chronic consumption of a high-fat diet.

Investigation of peptide YY and ghrelin responses to a test meal in bulimia nervosa

Gut-derived peptides, such as peptide YY (PYY) and ghrelin that regulate the initiation and termination of meals, could play a role in the altered eating behavior of patients with bulimia nervosa (BN). Therefore, we aimed to assess plasma PYY and ghrelin responses to a test meal in symptomatic bulimics. Ten healthy women and nine women with BN underwent blood sample collections before and after the ingestion of a test meal of 1300 Kcal (with 15% carbohydrates, 10% proteins, and 75% fat) at 12:00 noon. Plasma total PYY, ghrelin, insulin, and glucose were assayed. As compared with healthy women, bulimics exhibited a significantly blunted increase of circulating PYY (p < .007) and a significantly reduced suppression of plasma ghrelin (p < .0004) after the test meal. No significant differences emerged in food-induced plasma insulin and glucose changes between the two groups. Plasma ghrelin suppression after the meal was significantly correlated with plasma PYY increase. We replicated our previous findings of an altered ghrelin response to food ingestion in people with BN and showed for the first time a blunted PYY increase after food consumption in these patients. These findings support the occurrence in BN of a profound dysregulation of some peripheral regulatory mechanisms involved in the short-term regulation of feeding behavior that might be involved in the pathophysiology of their binge eating behavior.

Ghrelin and Energy Balance: Focus on Current Controversies

Ghrelin is an enteric peptide that is the only known circulating appetite stimulant. This feature of the hormone has garnered widespread attention, as reflected by more than 1000 scientific papers featuring ghrelin that have been published since the first reports of its orexigenic actions, approximately four years ago. In this review, we discuss data that support roles for ghrelin in the short-term regulation of pre-meal hunger and meal initiation, functioning as a unique orexigenic counterpart to short-acting gastrointestinal satiation factors, such as cholecystokinin (CCK). We also highlight evidence indicating that ghrelin satisfies recognized criteria to be viewed as a participant in long-term body-weight regulation--a potential anabolic counterpart to the traditional adiposity hormones, leptin and insulin. We then discuss the following controversial questions in ghrelin research and offer our opinions regarding these debates. (1) Is ghrelin synthesized within the brain? (2) How does ghrelin increase food intake? (3) Does des-acyl ghrelin have a physiologic function? (4) Are there receptors for ghrelin other than GHS-R1a? (5) Does ghrelin regulate insulin secretion? (6) Does ghrelin regulate gastrointestinal motility? (7) Can ghrelin or ghrelin-receptor agonists be used to treat wasting conditions? Finally, we offer a speculative model of ghrelin as a thrifty gene product that evolved to help animals consume and store fat well, thereby increasing their chances of survival during times of famine. We suggest that ghrelin is a "saginary" hormone, from the Latin, saginare, which means, "to fatten".

Ghrelin Suppression in Overweight Children: A Manifestation of Insulin Resistance?

Ghrelin levels increase before and decrease after meals, potentially playing a role in meal initiation and satiety in an inverse pattern to that of insulin. The role of ghrelin in childhood obesity, a state associated with hyperinsulinism and insulin resistance, is not fully understood. Therefore, the aims of the present study were to investigate the dynamics of ghrelin suppression after an oral glucose tolerance test (OGTT) in normal weight (NW) vs overweight (OW) children and the relationship of ghrelin suppression to insulin sensitivity. Thirty-seven NW (15 males and 22 females; 9.4 +/- 0.2 yr old) and 23 OW (13 males and 10 females; 9.4 +/- 0.3 yr old) prepubertal children underwent a 3-h OGTT with measurements of ghrelin, glucose, and insulin. The fasting glucose to insulin ratio and the whole body insulin sensitivity index were used to assess the relationship of insulin sensitivity to fasting ghrelin and ghrelin response to the OGTT, respectively. Fasting ghrelin levels were significantly lower in OW vs NW youth and were mainly influenced by insulin sensitivity independent of adiposity. OGTT-induced absolute suppression in ghrelin was approximately 50% less in OW vs NW children, resulting in a similar percent suppression from baseline in the two groups despite a significantly higher insulin response in OW. The suppression of ghrelin correlated positively with the whole body insulin sensitivity index (r = 0.43; P = 0.001) and negatively with the change in insulin at 30 min (r = -0.31; P = 0.02). Fasting ghrelin, the change in insulin, and the change in glucose during the OGTT were the significant independent variables contributing to the variance in absolute suppression of ghrelin (r2 = 0.42; P < 0.001). Only the change in glucose contributed significantly to the variance in the percent suppression of ghrelin (r2 = 0.14; P = 0.019). Fasting ghrelin and ghrelin suppression after OGTT are modulated by insulin sensitivity. Alterations in ghrelin suppression in OW children may be yet another manifestation of the insulin resistance of obesity. Whether this is responsible for differences in satiety in OW individuals merits additional investigation.

Roles for ghrelin in the regulation of appetite and body weight

Ghrelin, the only known circulating appetite stimulant, has garnered widespread scientific interest and is currently featured in more than 2.3 new publications per day. Antagonists and agonists of its receptor are vigorously being developed by pharmaceutical companies to treat obesity and wasting conditions respectively. Here, the authors summarize the current state of knowledge regarding ghrelin's roles in energy homeostasis. Ghrelin is an acylated peptide produced primarily by the stomach and proximal small intestine. Circulating levels sharply increase before, and decrease after, meals. These and other findings implicate ghrelin in pre-meal hunger and meal initiation. Moreover, ghrelin satisfies established criteria for an adiposity-associated hormone involved in long-term body weight regulation. Blood levels correlate with energy stores and display compensatory changes in response to alterations of those stores. Ghrelin influences neuronal activity in brain areas critical to energy homeostasis. Excessive ghrelin signaling durably increases food intake and decreases energy expenditure, thereby promoting weight gain. Conversely, acute ghrelin blockade in adult animals reduces food intake and body weight, although the effects of lifelong genetic deletions are very subtle. Overproduction of ghrelin is etiologically implicated in Prader-Willi syndrome, whereas defective secretion may contribute to weight loss after gastric bypass surgery. Ghrelin appears to participate in mealtime hunger and meal initiation, as well as in long-term energy balance. Whether these roles are sufficiently important that ghrelin blockade will prove to be an effective antiobesity modality is a pivotal question that should soon be answered as ghrelin receptor antagonists are developed. Ghrelin agonists hold promise in the treatment of wasting conditions, for which few medications currently exist.