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.     

Regulation of ghrelin in physiologic and pathophysiologic states

Ghrelin, a ligand for the growth hormone secretagogue receptor, is an orexigenic hormone produced in the gastrointestinal tract. In humans and other animals, circulating ghrelin levels fluctuate over the course of the day in relation to food intake. If circulating ghrelin plays a role in determining food intake from meal to meal, it will be important to understand the factors that regulate plasma ghrelin levels in relation to feeding. Circulating ghrelin levels also appear to reflect body weight changes over the longer term, raising the possibility that ghrelin functions as an adiposity signal. This review discusses some of the factors known to affect ghrelin levels, including nutrient stimulation of the gastrointestinal tract, diet composition, and weight loss. We also consider potential hormonal and neural mediators of the effects of nutrients and weight change on ghrelin levels.     

Influence of ghrelin on food intake and energy homeostasis

PURPOSE OF REVIEW: The purpose of this review is to provide updated information on the role of ghrelin in food intake and energy homeostasis, and on its mechanism of action. Moreover, the potential of ghrelin as a target for drugs to treat cachexia and obesity will be discussed. RECENT FINDINGS: Whereas the effects of ghrelin in the regulation of appetite, food intake and energy homeostasis have been fairly well documented, the pathways responsible for the effects of ghrelin are now increasingly being understood. As a consequence, clinical applications of ghrelin are now being developed. SUMMARY: Ghrelin is an endogenous orexigenic peptide recently discovered in the stomach. Ghrelin is involved in short-term regulation of food intake since its plasma levels increase before meals and decrease strongly postprandially. Ghrelin is also involved in long-term body-weight regulation by inducing adiposity. Ghrelin might be useful for cachexia and obesity treatment.     

Brain somatic cross-talk: ghrelin, leptin and ultimate challengers of obesity

Energy balance is largely regulated by the central nervous system (CNS), which senses metabolic status from a wide range of humoral and neural signals, and controls energy intake. Accumulating evidence supports the model that stimulation of leptin- and ghrelin-responsive pathways, including the central melanocortin system, in the hypothalamus, contributes to the maintenance of body weight. Ghrelin is the brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach and acts as an afferent signal to the hypothalamus and hindbrain. Leptin, the adipocyte hormone, is believed to tonically act as an afferent signal from adipose tissue to the brain, in particular hypothalamus, as a part of negative feedback loop regulating the size of energy stores and energy balance. Dysregulation of these pathways is a marker of changes in energy balance. Ghrelin is negatively correlated with weight and obese subjects have lower ghrelin levels than lean subjects, consistent with a compensatory rather than causal role for ghrelin in obesity. On the contrary, circulating leptin levels correlate in proportion to adiposity being high in obesity suggesting that human obesity is associated with insensitivity to leptin. The leptin resistance in diet-induced obesity emphasizes that environmental factors can modulate leptin sensitivity. It is speculated that through hypothalamic/pituitary axis ghrelin and leptin operate as a metabolic switch. Ghrelin actually transfers information from the stomach to the hypothalamus in cooperation with leptin and provides calories that growth hormone (GH) needs for growth and repair. Pharmacological manipulations of circulating hormone levels may work well in "cheating" the brain regarding information from the periphery. It might also be necessary to combine two or three agents to fight obesity. A combination of drugs that decrease preprandial appetite (ghrelin antagonist) and increase post-prandial satiety (gut hormone fragment peptide YY 3-36) might have a chance of achieving sustained weight loss. The administration of exogenous satiety hormone peptide YY 3-36 (PYY) may prevent the action of appetite-stimulating hypothalamic circuits on the anorexigenic melanocortin pathways.     

Effect of food restriction on ghrelin in normal-cycling female rats and in pregnancy

OBJECTIVE: Ghrelin is a 28-amino-acid acylated peptide that was recently identified as the endogenous ligand for the growth hormone secretagogue receptor. Previous studies have shown that ghrelin potently increases growth hormone release and food intake. The aim of this study was to clarify the physiological implications of ghrelin in the regulation of energy balance, by assessing the effect of undernutrition throughout 21 days in normal-cycling and pregnant rats on ghrelin. RESEARCH METHODS AND PROCEDURES: We have determined ghrelin levels by radioimmunoassay and gastric ghrelin mRNA expression by Northern blot analysis during 21 days of chronic food restriction (30% of ad libitum available diet) in normal-cycling female rats and in pregnancy. RESULTS: Our results show that chronic food restriction led to an increase in plasmatic ghrelin levels in normal-cycling female rats. In pregnancy, ghrelin plasmatic levels were enhanced particularly during the latter part of gestation (19 and 21 days) compared with pregnant rats with free access to food. Gastric ghrelin mRNA expression showed a similar expression pattern, being higher in the food-restricted group than in the group fed ad libitum, in normal-cycling as well as in pregnant rats. DISCUSSION: These observations indicate that ghrelin plasmatic levels and ghrelin gastric mRNA are up-modulated during undernutrition in normal-cycling rats and in pregnancy. These findings suggest that increased ghrelin levels may have a role in mediating the physiological responses to undernutrition and could represent an adaptative response to prevent long-lasting alterations in energy balance and body weight homeostasis.     

Ghrelin: update 2003

Ghrelin is a recently described peptide hormone that is secreted by endocrine cells in the gastrointestinal tract. Although its initial discovery was as a novel growth hormone secretagogue, it has been found to regulate feeding behavior by modulating expression levels of orexigenic peptides in the hypothalamus. Ghrelin has been implicated in the coordination of energy balance and weight regulation, and its dysregulation may be important in obesity. Ghrelin also has several other physiologic actions besides potential regulation of food intake that are described in this brief review.     

Ghrelin--a hormone with multiple functions

The growth hormone secretagogue ghrelin is in the centre of interest since its discovery in 1999. It stimulates growth hormone, corticotropic hormone and prolactin secretion, but also plays an important role in the regulation of appetite, carbohydrate- and lipid metabolism and possibly on gastric acid secretion, gastric motility, heart function and as well as immune functions and cell proliferation. Ghrelin was originally identified from the stomach but it is also present in all tissue among others in: hypothalamus, pituitary, pancreas, lung, immune cells, placenta, ovary, testis, kidney and in different tumours including pituitary adenoma, neuroendocrine tumours, thyroid carcinomas, endocrine tumours of the pancreas and lung. The gene structure and its receptor are similar to motilin, they are both synthesized in the upper gastrointestinal tract and both have prokinetic activity on gut motility. The ghrelin receptor (growth hormone secretagogue receptor) is a member of G protein-coupled seven transmembrane domain receptor. The receptor is localised in the central nervous system, kidney, thyroid, pancreas, myocardium and spleen. Starvation and low body mass index decrease, while food intake, hyperglycaemia, elevated insulin levels and high body mass index increase the endogenous ghrelin levels. Although we know much about the ghrelin, number of questions remain unanswered, such as the effects of the locally-produced ghrelin or its role in the cell metabolism.     

Changes in serum ghrelin concentration following biliopancreatic diversion for obesity

OBJECTIVE: Ghrelin is a recently discovered hormone that is produced mainly by the stomach and that increases food intake in rodents and humans. It has been postulated that the weight loss after gastric bypass surgery for obesity might be related to changes in serum ghrelin concentration. RESEARCH METHODS AND PROCEDURES: Serum leptin and ghrelin concentrations were measured in a group of obese patients before biliopancreatic diversion (BPD) and 2 and 12 months postoperatively. Insulin sensitivity was determined from serum glucose and insulin levels according to the homeostatic model of assessment for insulin resistance (HOMA IR). RESULTS: A sharp drop was observed in body weight, in BMI values, in HOMA IR data, and in serum leptin concentration at 2 and 12 months after BPD, whereas a significant increase of serum ghrelin level was observed at 12 months, when food intake had returned to preoperative levels. A negative correlation between the postoperative changes of serum ghrelin concentration and those of HOMA IR values was observed at 2 and 12 months after BPD. DISCUSSION: No evidence upholding a relationship between serum ghrelin concentration and food intake after BPD was seen; the postoperative changes likely reflected the achievement of a new state of energy balance. The negative relationship observed between post-BPD changes in HOMA IR values and changes in serum ghrelin concentration supported the role of insulin in the modulation of ghrelin production.     

The many faces of ghrelin: new perspectives for nutrition research?

The appetite-modulating peptide ghrelin is predominantly produced and secreted by the stomach and shows a strong growth hormone-releasing activity, which is mediated by the activation of the so-called growth hormone secretagogue type 1a receptor. Ghrelin is involved in the regulation of energy balance by increasing food intake and reducing fat utilization. Additionally, it stimulates lactotroph and corticotroph function, influences the pituitary gonadal axis, inhibits pro-inflammatory cytokine expression, controls gastric motility and acid secretion and influences pancreatic exocrine and endocrine function, as well as impacting on glucose metabolism. This review summarizes the known functions of ghrelin and its role in the regulation of the gut-brain axis.     

Hypophysectomy prevents ghrelin-induced adiposity and increases gastric ghrelin secretion in rats

OBJECTIVE: The novel gastric hormone ghrelin has recently been identified as an important modulator of energy homeostasis. Leptin-responsive hypothalamic neuropeptide Y/Agouti-related protein neurons are believed to mediate afferent ghrelin signals. Little is known, however, about ghrelin-induced efferent signals. We therefore investigated if hypothalamic-pituitary axes have a role in transferring ghrelin-induced changes of energy balance to the periphery. RESEARCH METHODS AND PROCEDURES: We subcutaneously injected hypophysectomized, as well as adrenalectomized, thyroidectomized, and sham-operated control rats with GH secretagogues [ghrelin, growth hormone (GH)-releasing peptide] for 1 week. Body weight, food intake, and body composition (chemical carcass analysis) were analyzed and compared with vehicle-treated controls. In addition, we quantified circulating levels of endogenous ghrelin in hypophysectomized and GH-treated normal rats. RESULTS: GH-secretagogue treatment of sham-operated control rats dose-proportionally increased food intake, body weight, and fat mass compared with vehicle-injected controls (p < 0.01). These effects, however, were not observed in ghrelin-treated hypophysectomized, thyroidectomized, or adrenalectomized rats, indicating an essential role for the pituitary axis in ghrelin-induced adiposity. Circulating levels of endogenous ghrelin were reduced by administration of GH in normal rats and were about 3-fold higher in hypophysectomized rats (n = 20, p = 0.001), suggesting a regulatory feedback loop involving the stomach and the pituitary to regulate gastric ghrelin secretion. DISCUSSION: According to these results, the endocrine pituitary is mediating ghrelin-induced changes toward a positive energy balance and is involved in the regulation of ghrelin secretion through a gastro-hypophyseal feedback loop.     

Short-term effects of gastric bypass surgery on circulating ghrelin levels

OBJECTIVE: To prospectively evaluate the short-term effects of Roux-en-Y gastric bypass (RYGBP) on ghrelin secretion and its relevance on food intake and body weight changes. RESEARCH METHODS AND PROCEDURES: Ghrelin response to a standardized test meal was evaluated in eight obese patients (BMI, 43.5 to 59.1 kg/m2) before and 6 weeks after RYGBP. Ghrelin response was compared with that of an age-matched group of six normal weight individuals (BMI, 19.6 to 24.9 kg/m2). RESULTS: Fasting serum ghrelin levels were lower in obese subjects compared with controls (p < 0.05). Meal ingestion significantly suppressed ghrelin concentration in controls (p < 0.05) and obese subjects (p < 0.05), albeit to a lesser degree in the latter group (p < 0.05). Despite a 10.3 +/- 1.5% weight loss, fasting serum ghrelin levels were paradoxically further decreased in obese subjects 6 weeks after RYGBP (p < 0.05). Moreover, at this time-point, food intake did not elicit a significant ghrelin suppression. The changes in ghrelin secretion after RYGBP correlated with changes in insulin sensitivity (p < 0.05) and caloric intake (p < 0.05). DISCUSSION: This study showed that the adaptive response of ghrelin to body weight loss was already impaired 6 weeks after RYGBP. Our study provides circumstantial evidence for the potential role of ghrelin in the negative energy balance in RYGBP-operated patients.     

Focus on the short- and long-term effects of ghrelin on energy homeostasis

The endogenous ligand for the growth hormone secretagogue receptor, ghrelin, is a 28–amino-acid peptide acylated with an octanoyl group at the serine in position 3. Most of the circulating ghrelin results from its synthesis and secretion by the X/A-like endocrine cells from the stomach and proximal small intestine. Besides its potent growth hormone secretory action, ghrelin is a highly pleiotropic hormone, contributing significantly to the regulation of appetite and food intake control, gastrointestinal motility, gastric acid secretion, endocrine and exocrine pancreatic secretions, cell proliferation, glucose and lipid metabolism, and cardiovascular and immunologic processes. The purpose of this review is to consider the orexigenic effects of ghrelin on short-term regulation of food intake and long-term regulation of body weight, the implications of genetic ghrelin and growth hormone secretagogue receptor polymorphism, and the use of antagonists and agonists of ghrelin in pathophysiological conditions.     

Food intake and plasma ghrelin response during potato-, rice- and pasta-rich test meals

Objective Complex carbohydrates such as potato, rice and pasta are frequently consumed accompaniments of meat meals and have different effects on satiety, food intake, glucose, and insulin concentrations. The orexigenic gastric hormone ghrelin contributes to feeding regulation and as yet it is unknown whether there is any differential ghrelin response to these starchy food items corresponding to their effects on food intake. Methods In 11 subjects the effect of satiating amounts of potatoes, rice or pasta consumed together with 150g pork steak was examined on hunger/satiety ratings, food intake, plasma insulin, glucose and ghrelin concentrations. Results All meals led to comparable quantities of food intake while energy intake was significantly lower after potatoes. Satiety/hunger ratings were significantly different from basal for the entire 4 h period after rice and pasta meals, while they had returned to basal during the 4th hour after potatoes. After rice and pasta insulin rose significantly for 4 h. Ghrelin decreased during the 2nd and 3rd hour. In contrast potatoes stimulated insulin for the initial 2 h only while ghrelin rose significantly by 120 pg/ml over the 4 h period. A significant correlation was observed between ghrelin and hunger ratings while subsequent second meal food and energy intake did not differ irrespective of the preceding ghrelin concentration. Conclusion Compared to rice and pasta satiating amounts of potatoes coingested with meat result in lower energy intake and postprandial insulin concentrations, which is not counterbalanced during subsequent food intake despite higher ghrelin concentrations. The present data support the concept that ghrelin can affect hunger sensations but not necessarily food and energy intake.     

Ghrelin,an important hormone produced by the stomach

Ghrelin is a hormone produced by endocrine cells in the stomach. Ghrelin stimulates the secretion of growth hormone by the anterior pituitary. This effect is mediated by hypothalamic growth-hormone secretagogue receptors. Binding to these receptors not only stimulates growth hormone secretion, but also has vascular effects (positive inotropic effects), modifies (decreases) insulin sensitivity, affects glucose metabolism (hyperglycaemia) and stimulates gastric-acid production. Antiproliferative effects of ghrelin have been described on experimental tumour models. Ghrelin seems to play a role in stimulating the appetite as well as promoting a more effective storage of food components. Whether or not ghrelin could play any role in the induction of weight gain has yet to be established. This is also true for the role of potential ghrelin antagonists in the induction of weight loss in case of obesity.     

Hypothalamic expression of anorexigenic and orexigenic hormone receptors in obese females Neotomodon alstoni: Effect of fasting

Obesity is a world problem that requires a better understanding of its physiological and genetic basis, as well as the mechanisms by which the hypothalamus controls feeding behavior. The volcano mouse Neotomodon alstoni develops obesity in captivity when fed with regular chow diet, providing a novel model for the study of obesity. Females develop obesity more often than males; therefore, in this study, we analysed in females, in proestrous lean and obese, the differences in hypothalamus expression of receptors for leptin, ghrelin (growth hormone secretagogue receptor GHS-R), and VPAC, and correlates for plasma levels of total ghrelin. The main comparisons are between mice fed ad libitum and mice after 24 hours of fasting. Mice above 65 g body weight were considered obese, based on behavioral and physiological parameters such as food intake, plasma free fatty acids, and glucose tolerance. Hypothalamic tissue from obese and lean mice was analysed by western blot. Our results indicate that after ad libitum food access, obese mice show no significant differences in hypothalamic leptin receptors, but a significant increase of 60% in the GHS-R, and a nearly 62% decrease in VPAC2 was noted. After a 24-hour fast, plasma ghrelin increased nearly two fold in both lean and obese mice; increases of hypothalamic leptin receptors and GHS-R were also noted, while VPAC2 did not change significantly; levels of plasma free fatty acids were 50% less after fasting in obese than in lean animals. Our results indicate that in obese N. alstoni mice, the levels of orexigenic receptors in the hypothalamus correlate with overfeeding, and the fact that lean and obese females respond in different ways to a metabolic demand such as a 24-hour fast.     

Changes of body weight and plasma ghrelin levels after gastric banding and gastric bypass

OBJECTIVE: Ghrelin is an enteric peptide with strong orexigenic and adipogenic effects. Plasma ghrelin levels are decreased in obese subjects but increase after weight loss; this increase is not observed after Roux-en-Y gastric bypass (RYGB). Prospective and comparative data after adjustable silicone gastric banding (ASGB) have not been reported previously. RESEARCH METHODS AND PROCEDURES: Overnight fasting plasma ghrelin concentration was measured in morbidly obese subjects at baseline and 3, 6, 12, and 24 months after ASGB (n = 8) or RYGB (n = 5) and in nonoperated controls (n = 7). RESULTS: After RYGB, body weight (BW) decreased by 29.5 +/- 5.5 kg (mean +/- SE, p < 0.001), whereas plasma ghrelin failed to increase significantly (+167 +/- 119 pg/mL, not significant). In contrast, after ASGB, BW decreased less (by 22.8 +/- 5.9 kg; p < 0.001), and plasma ghrelin significantly increased by 377 +/- 201 pg/mL (p = 0.025). Neither BW nor plasma ghrelin changed in nonoperated controls. Plasma leptin decreased in both operated groups (similarly p < 0.05) but not in nonoperated controls. Plasma growth hormone and insulin-like growth factor 1 were not correlated with changes in plasma ghrelin concentrations. DISCUSSION: Plasma ghrelin levels failed to increase during substantial weight loss after RYGB, but did increase in response to lesser weight loss after ASGB. These findings suggest that the plasma ghrelin response after weight loss is impaired after exclusion of major parts of the stomach and the duodenum (RYGB), and the smaller long-term weight loss after ASGB compared with RYGB may be due, at least in part, to an absent increase in plasma ghrelin after RYGB.     

Role of hypothalamic AMP-kinase in food intake regulation

Adenosine monophosphate-activated protein kinase (AMPK) functions as a cellular fuel gauge that regulates metabolic pathways in nutrient metabolism. Recent studies have strongly implicated that AMPK in the hypothalamus regulates energy metabolism by integrating inputs from multiple hormones, peptides, neurotransmitters, and nutrients. Leptin is an adipocyte hormone that regulates food intake and energy expenditure in peripheral tissues. Leptin inhibits AMPK activity in the arcuate and paraventricular hypothalamus, and its inhibition is necessary for the anorexic effect of leptin. Alteration of hypothalamic AMPK activity is sufficient to change food intake and body weight. Furthermore, fasting/refeeding, glucose, and melanocortin receptor alter AMPK activity in the hypothalamus. Adiponectin has also been shown to increase food intake by activating AMPK in the arcuate hypothalamus. Recent data have shown that acetyl-coenzyme A carboxylase/malonyl-coenzyme A/carnitine palmitoyltransferase-1/fatty acid oxidation and mammalian target of rapamycin signalings are putative downstream pathways for food intake regulation in response to hypothalamic AMPK. Thus, these results suggest that food intake and nutrient metabolism are coordinately regulated by the common signaling pathway of AMPK in the hypothalamus.     

Higher habitual intake of dietary fat and carbohydrates are associated with lower leptin and higher ghrelin concentrations in overweight and obese postmenopausal women with elevated insulin levels

A highly regulated homeostatic system governs body weight; however, it is possible that this system might be impaired by the sustained intake of highly palatable foods. Short-term feeding studies suggest that the appetite-stimulating hormone ghrelin is suppressed less effectively by dietary fat intake, and diets high in sucrose decrease levels of the adipose hormone leptin. We hypothesized that higher habitual intake of dietary fat and carbohydrate (CHO) would be associated with elevated concentrations of circulating plasma ghrelin and lower circulating leptin in humans, a hormonal profile that could promote weight gain. To test our hypothesis, we examined the cross-sectional associations of ghrelin and leptin with the habitual macronutrient intake of 165 healthy overweight and obese sedentary women and tested the modifying role of insulin in these associations. We observed a significant inverse association between leptin concentrations and percentage energy from CHO independent of body mass index, percentage body fat, age, and intraabdominal fat (β = −0.11 P = .04). No significant associations were observed between ghrelin and macronutrients or their subtypes among the total cohort. Among women with insulin concentrations at or greater than the median, we found a statistically significant positive association between intake of saturated fat and ghrelin concentrations, as well as additional statistically significant associations between leptin concentrations and macronutrients not observed among the total cohort. Our results provide some evidence that diets higher in fat and CHO are associated with a hormonal profile (ie, lower leptin and higher ghrelin concentrations), which could enhance weight gain, particularly among individuals with higher circulating insulin concentrations.     

胃饥饿素维持代谢及能量稳态作用的研究进展

胃饥饿素是1999年被发现的具有28个氨基酸的多肽,由胃X/A样细胞分泌,促进生长激素的释放,同时也是一种促食欲肽。胃饥饿素通过Ghrelin-GHS-R轴发挥作用,维持机体代谢及能量稳态。本篇综述回顾了有关胃饥饿素生理、病理生理、动物实验及临床相关的系列研究及进展,介绍了胃饥饿素在维持机体代谢及能量稳态方面的作用,分析了导致具有争议的研究结果的可能原因,强调了检测方法在测定循环中酰基胃饥饿素和去酰基胃饥饿素水平和比例的重要性,提示胃饥饿素对多种疾病的预防及治疗具有积极作用。