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Division of Metabolism, Endocrinology, and Nutrition, University of Washington School of Medicine and Harborview Medical Center, Seattle, WA 98104 and * Division of Metabolism, Endocrinology, and Nutrition, University of Washington and Veteran Affairs Puget Sound Health Care System, Seattle, WA 98108
2To whom correspondence should be addressed. E-mail: dianalw{at}u.washington.edu.
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ABSTRACT |
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 TOP ABSTRACT SUMMARY AND CONCLUSIONSLITERATURE CITED |
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KEY WORDS: • ghrelin • food intake • obesity
Ghrelin, a ligand for the growth hormone secretagogue receptor, is a peptide produced primarily by endocrine cells in the gastrointestinal tract (1–3). Initially, ghrelin was known as a potent stimulus for growth hormone secretion, but it soon became clear that this hormone has robust effects on food intake and metabolism (4–6). Pharmacological administration of ghrelin increases feeding in multiple species, including humans (4–10), conferring upon it a unique status as the only known orexigenic hormone. We and our colleagues (11) have conducted a detailed behavioral analysis of ghrelin effects on feeding in rats, and we report that central ghrelin administration increases food intake primarily by reducing the time between meals. In other words, rats begin feeding sooner after ghrelin injection than after vehicle treatment, lending credence to the idea that endogenous ghrelin is a "hunger hormone" that signals animals to take a meal. Although it is not yet clear whether endogenously produced ghrelin affects food intake by acting directly in the central nervous system or by acting in the periphery to alter vagal afferent firing (12,13), it appears likely that fluctuations in plasma levels of this hormone reflect fluctuations in its secretion. Thus, the measurement of circulating ghrelin levels is informative regardless of the relevant target. Daily fluctuations in plasma ghrelin levels are consistent with the hypothesis that ghrelin is a meal-initiating hormone. In humans and other mammals, ghrelin levels rise before meals and fall rapidly after ingestion (4,14–16). If circulating ghrelin does, in fact, play 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. In addition to short-term fluctuations in ghrelin levels over the course of a day, longer-term regulation of circulating ghrelin appears to occur in relation to body weight change. Ghrelin levels correlate inversely with adiposity at baseline (17,18). Moreover, circulating ghrelin increases in response to weight loss resulting from multiple causes (19–22). These findings raise the possibility that ghrelin functions as an adiposity signal, a potential counterpart to leptin and insulin. Here, we discuss the factors that regulate plasma ghrelin levels acutely in relation to meals and chronically in relation to body weight.
Meal-related regulation of ghrelin
As noted above, human plasma ghrelin levels rise and fall over the course of the day in relation to food intake (Fig. 1). The premeal elevation in circulating ghrelin has often been cited as evidence supporting the hypothesis that ghrelin serves as a hunger signal in humans. The original observation was made in subjects receiving meals on a fixed schedule (14); however, a later study revealed that ghrelin levels also peak before subjects freely request a meal, in the absence of external time- or food-related cues (23). This profile is certainly consistent with a role for ghrelin as a meal initiation signal in humans, but the evidence thus far is exclusively correlative. Strong experimental support for this hypothesis would be obtained if blockade of ghrelin signaling during the premeal period delayed or prevented meal initiation. Such studies will be forthcoming when ghrelin receptor antagonists are more widely available.
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Postprandial ghrelin suppression was initially reported in rodents and humans ingesting meals of mixed macronutrient content and in rodents receiving intragastric glucose infusions. The clarification of ways in which various macronutrients affect specific components of the appetite regulation system is an especially topical research objective, in light of the focus of most popular diets on varying macronutrient distribution. Because carbohydrates, proteins, and fats differentially affect the secretion of some gastrointestinal hormones, such as CCK (26), it would be interesting to determine whether all of these macronutrients suppress ghrelin levels equally well. It appears that all 3 classes of macronutrients can suppress plasma ghrelin, but with varying efficacy. Our laboratory examined the circulating ghrelin response in rodents receiving isocaloric glucose, amino acid, or intralipid infusions into the gastrointestinal tract, and plasma ghrelin was substantially suppressed by all 3 infusions (27). Ghrelin levels were most effectively reduced by the glucose, whereas the fat infusion suppressed ghrelin least well. We have investigated the same question in humans by monitoring plasma ghrelin after subjects consumed isocaloric, isovolemic beverages consisting of 80% carbohydrate, protein, or fat, and the results were similar to those obtained in rodents (28). Plasma ghrelin was substantially suppressed after all 3 beverages, with the 80% carbohydrate beverage being most effective and the 80% fat beverage being least effective. Several other studies have confirmed that all 3 types of macronutrients suppress ghrelin in rodents and humans, but the effectiveness of the stimuli could not be compared because they were not matched for energy content (29,30).
The pattern of ghrelin suppression by food is broadly consistent with the idea that other gut hormones released in response to food may contribute to the reduction in plasma ghrelin levels. Insulin, CCK, peptide YY, and glucagon-like peptide 1 (GLP-1), for example, rise rapidly after food ingestion (24,31), and circulating ghrelin begins to fall simultaneously. The hypothesis that insulin causes the postprandial reduction in ghrelin levels has received an especially large amount of attention. Although high doses of insulin, or insulin and glucose combined, can reduce plasma ghrelin (32–36), it seems clear that an increase in insulin after ingestion is not required for meal-related ghrelin suppression. The results of macronutrient studies described above provide evidence for this argument; ingestion or infusion of fat did not increase plasma insulin, but did substantially reduce plasma ghrelin levels. Perhaps more compelling are the results of experiments with type-1 diabetic subjects (37). In the absence of any insulin treatment, these diabetics did not manifest a postprandial ghrelin response to a standard breakfast meal. However, when these subjects were given only a low basal dose of insulin, sufficient to maintain euglycemia during the hours before the meal, the ingestion of nutrients did substantially reduce circulating ghrelin. Similarly, rats treated with the ß-cell toxin streptozotocin show a partial ghrelin reduction after gavage feeding, with no increase in insulin (38). Thus, ingestion-related elevation of insulin is not required for the ghrelin response to nutrients. These data provide strong support for the idea that the nutrient-related ghrelin suppression does require the presence of insulin, but the postprandial rise in insulin does not directly mediate this reduction of ghrelin levels.
Regardless of whether postprandial ghrelin suppression is mediated by direct nutrient sensing in ghrelin-producing cells or by intermediate hormonal or neural signals, it seems clear that some form of nutrient detection must occur. Our group has attempted to identify the anatomic location of the "nutrient sensor" that is relevant to the ghrelin response to food. Because most ghrelin-producing cells are located in the stomach, one logical hypothesis is that nutrients are detected either by those cells or by other intermediaries in the stomach lumen, which then suppress ghrelin levels. We examined this possibility in rats using a pyloric cuff preparation, in which an inflatable cuff is implanted around the pyloric valve (39). When this cuff is left uninflated, gastric emptying proceeds normally, but inflation of the cuff prevents emptying and restricts ingested food or fluid to the stomach. When glucose was infused into rats’ stomachs and allowed to empty normally, ghrelin levels were substantially suppressed. When emptying of glucose into the intestine was prevented by inflation of the pyloric cuff, however, ghrelin levels were not reduced by the infusion. Therefore, neither gastric nutrient detection nor gastric distention is sufficient for the postprandial ghrelin response, which must require feedback from intestinal or postabsorptive sites. In another study, we investigated the role of the small intestine in the postprandial ghrelin response by measuring plasma ghrelin levels before and after nutrients were infused directly into the duodenum or jejunum of rats (27). Duodenal nutrient sensation is known to be a particularly important stimulus for some hormones, such as CCK and GLP-1 (24,31), so it is reasonable to suggest that postprandial ghrelin suppression requires the presence of energy in the duodenum. However, nutrient infusions into either the duodenum or the jejunum reduced circulating ghrelin equally well. We can conclude that although duodenal nutrient sensing may contribute to postprandial ghrelin suppression under normal feeding conditions, detection of energy in the duodenum is not required for the prandial ghrelin response.
Ghrelin and body weight
Although ghrelin has become widely known for its potential role as a short-term hunger signal, chronic administration increases body weight, and endogenous ghrelin levels fluctuate with changes in body weight. Weight loss substantially elevates ghrelin levels in humans and other animals (Fig. 1) (22,40). This effect is observed with weight loss achieved though a variety of means, including food restriction or deprivation and illness-induced anorexia (19,20,40,41). One may wonder whether the elevation in ghrelin levels under these circumstances is merely a reflection of the reduced feeding; circulating ghrelin may be high because less energy is entering the gut and suppressing this hormone. It appears, however, that baseline (premeal) ghrelin levels do correspond with body weight independent of food intake. In a study by Leidy and colleagues (42), healthy women took part in a chronic exercise program while fed a diet designed to maintain body weight. Some subjects remained weight stable whereas others lost weight. Over time, ghrelin levels increased only in the weight loss group. Another study conducted by our laboratory affirms this result (43). Sedentary postmenopausal women were randomized to either a chronic aerobic exercise group or a passive stretching control group for 1 y and were asked to maintain their typical diet. At the end of the intervention, the chronic exercise group had lost a small but substantial amount of weight compared with the control group, and ghrelin levels increased in relation to the amount of weight lost. Taken together, these results demonstrate that in the absence of reduced food intake, plasma ghrelin increases in response to a loss of body weight per se.
Downregulation of ghrelin in response to weight gain has been less well investigated than upregulation with weight loss, but it does appear that ghrelin levels respond in a compensatory manner to bidirectional alterations of body weight. The finding that obese subjects have relatively low ghrelin levels compared with lean individuals is suggestive, but only correlative (18). The first study to examine a ghrelin response to weight gain showed only a nonsignificant trend toward decreased ghrelin with overfeeding-induced weight gain; however, this small study also failed to replicate the elevation in ghrelin levels commonly observed with weight loss (44). More recently, this issue has been examined with rodents. Moesgaard and colleagues (45) showed that in female mice, obesity induced by 10 wk of high-fat feeding substantially reduced plasma ghrelin levels and ghrelin mRNA expression in the gastrointestinal tract, suggesting that the feeding regimen and/or weight gain suppressed ghrelin production. It is difficult to say whether the changes in plasma ghrelin observed here are a response to weight gain or to increased fat in the diet, because the nonobese control mice were maintained on a low-fat diet. One human study suggests that diet composition does influence ghrelin levels in the absence of weight change. Healthy males were overfed a high-fat diet for 3 weeks, during which time they gained only a small and nonsignificant amount of weight. Despite body mass index stability, their plasma ghrelin levels were substantially reduced by the additional dietary fat (46). We have attempted to clarify these issues by examining plasma ghrelin levels in rats that are maintained on the same diet during a weight-stable phase and an overfeeding phase, ruling out macronutrient composition of the diet as a confounding factor. With involuntary overfeeding (by intragastric gavage) there was a 20% weight gain and a substantial 25% reduction in fasting ghrelin levels (Williams, D. L., Grill, H. J., Cummings, D. E., Kaplan, J. M., unpublished results). Taken together, the extant data suggest that ghrelin levels are affected by diet composition as well as by body weight. These two factors are both at play in human obesity, where low ghrelin levels are observed.
Given that circulating ghrelin appears to track body weight and may contribute to body weight regulation, it would be of great interest to discern the means through which the ghrelin regulatory system detects changes in weight. One obvious possibility is that changes in established adiposity signals, leptin and insulin, are involved. The interplay between leptin and ghrelin is the focus of another review in this volume and thus will not be discussed here. Regardless of leptin’s potential role in ghrelin regulation, there is evidence that insulin may mediate some of the effects of obesity on ghrelin levels. In a study done with our colleagues (47), we compared ghrelin levels in obese human subjects who were classified as either insulin-resistant or insulin-sensitive, according to steady-state plasma glucose concentrations. As expected for their high BMI, the insulin-resistant group had a low mean plasma ghrelin level. However, the equally obese insulin-sensitive subjects had substantially higher circulating ghrelin levels, falling in the range typically observed in lean subjects. These data support the hypothesis that the high levels of circulating insulin seen in insulin-resistant individuals may act at a still insulin–sensitive site (such as the central nervous system or stomach) to reduce plasma ghrelin. Alternatively, other consequences of the insulin-resistant state may mediate the ghrelin reduction. In any case, this result demonstrates that the ghrelin response to obesity is not mediated merely by detection of adiposity.
Although the ghrelin response to weight change has been observed in a variety of circumstances, there are situations in which ghrelin levels are dissociated from alterations in body weight. The most widely discussed example of this occurs with a certain type bariatric surgery for weight loss. Whereas lifestyle and behavior modification and/or pharmacological approaches to long-term weight loss are largely ineffective, Roux-en-Y gastric bypass (RYGB) surgery durably decreases body weight by 
35% and is currently the most successful treatment for obesity (48,49). This surgery creates a gastrojejunal anastamosis, such that gastric volume is severely restricted and ingested food moves from a small, proximal stomach pouch to the jejunum, bypassing the remainder of the stomach and all of the duodenum. One would expect the massive decrease of BMI achieved with RYGB to trigger an elevation of ghrelin levels; however, RYGB patients in our study had extremely low plasma ghrelin levels throughout a 24-h profile (Fig. 2) (22). Many researchers have examined this effect since the original publication, and results have varied. Several reports have replicated the finding that RYGB causes a paradoxical reduction in plasma ghrelin (50–53). Other studies have shown no change in plasma ghrelin after surgery, despite the loss of body weight (54,55), and most authors have interpreted this as an impairment of the normal ghrelin response to weight loss. Only one group has reported a rise in ghrelin levels after RYGB (56), but this was a well-designed prospective study with a large number of subjects and therefore should not be ignored. It is likely that these different outcomes depend on when the postsurgical samples were taken (i.e., whether subjects were still actively losing weight or had achieved a stable, lower BMI) and also on differences in surgical technique across centers. In any case, it is tempting to speculate that a disordered ghrelin response to weight loss after RYGB contributes to surgical success.
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The vagus nerve, which innervates most visceral and abdominal organs, relays information about nutrients and distention in the gut to the brain. In addition to its afferent fibers, vagal efferent signals influence the secretion of hormones, such as insulin. Given that ghrelin is produced in the gastrointestinal tract and is responsive to changes in metabolic state, we hypothesized that the vagus nerve plays a role in ghrelin regulation (61). First, we examined the effect of 48 h of food deprivation on ghrelin levels in rats that had received subdiaphragmatic vagotomy or a sham surgery. All subjects lost a substantial amount of body weight, but vagotomy completely prevented the significant rise in ghrelin levels observed in the control group. This observation clearly supports a role for the vagus nerve in the ghrelin response to weight loss, but does not distinguish between sensory and motor contributions. To address this issue, we examined the effect of atropine, a muscarinic receptor antagonist that blocks vagal efferent signals, on ghrelin levels after 48 h of food deprivation. Atropine significantly reduced the high plasma ghrelin levels observed in rats deprived of food, indicating that a vagal efferent signal mediates the ghrelin response to weight loss. Because the effect of RYGB to reduce plasma ghrelin has been observed within a very short time after surgery, it is tempting to speculate that this effect is related to treatment of the vagus nerve in the procedure. Moreover, severing of vagal fibers is accomplished variably during RYBG by different surgeons, potentially explaining heterogeneous results across centers regarding the effect of this procedure on ghrelin levels.
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SUMMARY AND CONCLUSIONS |
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TOPABSTRACTSUMMARY AND CONCLUSIONSLITERATURE CITED |
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FOOTNOTES |
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3 Abbreviations used: AGB, adjustable gastric banding; BPD, biliopancreatic diversion; CCK, cholecystokinin; GLP-1, glucagon-like peptide 1; RYGB, Roux-en-Y gastric bypass.
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LITERATURE CITED |
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TOPABSTRACTSUMMARY AND CONCLUSIONSLITERATURE CITED |
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