In response to luminal food stimuli during meals, enteroendocrine cells release gastrointestinal (GI) peptides that have long been known to control secretory and motor functions of the gut, pancreas and liver. Glucagon-like peptide-1 (GLP-1) has emerged as one of the most important GI peptides because of a combination of functions not previously ascribed to any other molecule. GLP-1 potentiates glucose-induced insulin secretion, suppresses glucagon release, slows gastric emptying and may serve as a satiation signal, although the physiological status of the latter function has not been fully established yet. Here we review the available evidence for intestinal GLP-1 to fulfill a number of established empirical criteria for assessing whether a hormone inhibits eating by eliciting physiological satiation in man and rodents.
Obesity has reached epidemic proportions worldwide. According to a 2012 WHO (World Health Organization) report, the number of overweight adults exceeded 1.4 billion in 2008, with more than 200 million men and nearly 300 million women being obese (body mass index >30).1 The healthcare implications are profound as obesity represents a cluster of disordered phenotypes, including insulin resistance and type 2 diabetes mellitus (T2DM), fatty liver, hypertension, hyperlipidemia and accumulation of excess intra-abdominal adipose tissue, in association with a low-grade systemic and chronic inflammation.2 Bariatric surgery, with the Roux-en-Y gastric bypass considered the gold standard procedure, remains the most effective treatment option currently available to combat obesity, usually resulting in dramatic and sustained weight loss of 60–75% and prompt amelioration of T2DM.3, 4, 5 This unparalleled efficacy suggests that the gastrointestinal (GI) tract and alterations in the secretion of GI peptides including ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) are of much more importance in the control of eating and regulation of energy homeostasis than previously thought.
GI peptides released during meals by luminal food stimuli in the small intestine have long been known as controllers of secretory and motor functions of the gut, pancreas and liver. In a 1973 landmark paper, Gibbs, Young and Smith first hypothesized a causal link between GI peptides and eating, suggesting that CCK, and perhaps other GI peptides, serve as negative-feedback signals leading to meal termination (‘satiation signals’).6 They organized their work around a number of empirical criteria for assessing whether CCK truly inhibited eating by eliciting satiation. This approach has been paradigmatic in the study of the short-term endocrine controls of eating ever since, although the criteria have been updated to accommodate new methods, to incorporate paracrine and neurocrine as well as endocrine signaling, to assess hunger, satiation and postprandial satiety, and to apply to humans.7, 8, 9 Table 1 lists a current version of the criteria which, meanwhile, have been applied to a number of putative satiation hormones.8, 10 A hormone that is supposed to affect eating should of course be secreted in relation to eating, and its receptors should be expressed at the presumed site(s) of its action (Criteria 1 and 2), otherwise an effect of that hormone on eating can hardly be conceptualized. Likewise, mimicking the physiological secretion pattern by administration of secretagogues of the hormone or of a physiological hormone dose should be sufficient to produce satiation (Criterion 3). In other words, the inhibition of eating should not require doses of the hormone or manipulations that increase the circulating concentration high above the physiological range, otherwise the observed inhibition of eating is presumably a pharmacological rather than a physiological effect. The strongest argument for physiological relevance usually is, if antagonism of the hormone produces the opposite effect (Criterion 4). The antagonism can be accomplished pharmacologically (possible in humans and animals, but often tricky because very high doses of receptor antagonists or antibodies are necessary to produce an effect), by RNA interference (for example, to knock down the cognate receptor of the hormone—usually done in laboratory animals) or by transgenic means, that is, by inducible and often site-specific knock out of the hormone or its receptor (mostly in mice, but can be hampered by compensatory mechanisms). So far, CCK remains the only GI peptide that fulfills all these criteria, whereas the physiological status for the majority of the other candidate hormones is not yet fully established.
GLP-1 has emerged as one of the most important GI peptides because of a combination of functions not previously ascribed to any other molecule. Besides its putative satiation effect, GLP-1 potentiates glucose-induced insulin secretion, suppresses glucagon release and slows gastric emptying. The latter effect is part of the ‘ileal brake’, a mechanism that optimizes nutrient absorption in the proximal small intestine by inhibiting upper gut motility if unabsorbed nutrients reach the ileum.11, 12 More recently, GLP-1 has also been suggested to have neuroprotective effects and to modulate learning and memory as well as cardiovascular function. In response to a meal, intestinal GLP-1 is co-released with PYY from enteroendocrine proglucagon expressing cells that increase in density along the GI tract from proximal to caudal. Native GLP-1 is rapidly degraded by dipeptidyl peptidase-4, which limits its biological half life in the blood to 1–3 min. This also limits its therapeutic potential and complicates investigations towards its true physiological functions. While GLP-1’s physiological role in controlling postprandial glycemia is well accepted, it remains still unclear whether the effect of GLP-1 on eating is of physiologic or pharmacologic nature.
In the following sections we will briefly review the available evidence for intestinal GLP-1 to fulfill the criteria for a physiological satiation signal. Where appropriate we will consider the satiation hypothesis for humans and experimental rodents separately because results obtained with different techniques that are only applicable in one or the other species have led, in part, to diverging conclusions. GLP-1 is also expressed in a discrete cell group in the nucleus tractus solitarii and this central GLP-1 is implicated in the control of eating as well. We will, however, focus on intestinal GLP-1 because a comprehensive discussion of the peripheral and central GLP-1 systems and their potential interactions would be beyond the scope of this review.
The secretion pattern of GLP-1 has been studied extensively. Systemic GLP-1 plasma levels are lowest after overnight fasts, increase after food ingestion and often do not return entirely to fasting level between meals.13, 14, 15 Consistent with GLP-1’s incretin function, carbohydrates are rapid and potent secretagogues resulting in increases in systemic GLP-1 levels within 15 min after meal onset.15, 16 Protein, fat and mixed meals usually result in slower but more sustained secretory responses, with increased plasma levels for several hours.13, 16, 17, 18 The effect of fat on GLP-1 secretion depends on digestive hydrolysis and the presence of monoacylglycerols and fatty acids with a chain length ⩾C12.19, 20, 21 There is also indirect evidence that the effect of protein on GLP-1 secretion requires hydrolysis to amino acids.22, 23 Whereas the majority of studies report monophasic secretion patterns, some have found biphasic responses13, 16, 24 presumably due to differences in test meal compositions and digestibility as well as variability in the rates of gastric emptying. In obese subjects, GLP-1 responses to food ingestion are often reduced,18, 24, 25, 26 suggesting that a deficient GLP-1 response to ingestion may be involved in the pathophysiology of obesity. Of note, the meal-induced rise in plasma GLP-1 levels is increased substantially in patients after bariatric surgery (sleeve gastrectomy or Roux-en-Y gastric bypass),4, 5, 27 and plasma levels of GLP-1 correlate with weight loss and changes in appetite, suggesting that GLP-1 contributes to the substantial weight loss after surgery.28
Studies employing intraduodenal (i.d.) nutrient infusions demonstrate that the magnitude of GLP-1 secretion depends on the caloric load administered.29, 30, 31 When ad libitum test meals were served immediately following the i.d. infusions, the eating-inhibitory effect did, however, not correlate directly with increases in systemic GLP-1 when adjusted for all other parameters measured.29, 30 Similarly, in a large pooled data analysis including eight studies with similar designs only the peak number of isolated pyloric pressure waves and peak plasma CCK concentration, but not GLP-1, were associated with reductions in energy intake.32 A general limitation of studies with i.d. nutrient infusion is, however, that the stomach and gastric signals are bypassed and that test meals are served after i.d. infusions are terminated, so that eating occurs after, but not during GLP-1 release, as would be the case under physiological conditions. Also, measurements of systemic hormone concentrations do not necessarily reflect the local situation in the intestine, in the environment of the GLP-1 receptors (GLP-1R) on vagal afferents that appear to be involved in the satiating effect of endogenous GLP-1, as reviewed below. In a study in one of our labs,33 we intragastrically administered glucose, fructose or water (control) in healthy humans within 3 min and found that fructose was a much weaker GLP-1 secretagogue than glucose, but reduced hunger and increased fullness and satiety perceptions more than glucose, also suggesting that other factors than GLP-1 determined appetite perceptions. In contrast, Lemmons et al.34 compared prandial GLP-1 concentrations with the dynamics of fullness scores during oral, staggered and non-staggered, meals in normal-weight subjects and found that GLP-1 and fullness changed synchronously with a mean explained variation of 60% for fullness vs GLP-1. A relationship between GLP-1 and hunger scores in the late satiety phase after a high-fat/low-carbohydrate breakfast meal as well as between GLP-1 and energy intake at a subsequent ad libitum lunch was found recently also in overweight and obese subjects35 suggesting that GLP-1 has a determining influence on hunger and food consumption.
Taken together, despite some discrepancies, it is clear that nutrient intake induces an increase in plasma GLP-1 that, dependent on the total caloric load, is usually associated with a reduction in meal size. That correlation analyses occasionally failed to show significant relations between increases in plasma GLP-1 and reductions in meal size or changes in appetite perception may be related to the different experimental designs employed. Moreover, eating is controlled by the complex interplay of many more signals related to food ingestion than only GLP-1. Finally, if the satiating effect of endogenous GLP-1 is partly due to a paracrine effect on vagal afferents terminating in the wall of the small intestine, systemic levels measurable in humans may be of little importance for GLP-1’s satiating effect. The use of changes in circulating GLP-1 as direct biomarker for satiation and appetite perception is therefore questionable.
Increases in circulating endogenous total or active GLP-1 in laboratory animals have mainly been observed in response to intragastric (i.g.) or intraintestinal infusions of liquid diets or nutrient solutions,36, 37, 38, 39 and the results generally parallel the findings in humans. Similar to the GLP-1 release in response to carbohydrates, the GLP-1 release in response to fats appears to be primarily related to an effect of the digestive products of fat, that is, free fatty acids and monoacylglycerol, on G-protein coupled receptors on the luminal surface of enteroendocrine cells.40 In addition to this receptor-mediated mechanism, fatty acids may also stimulate GLP-1 release by uncoupling the respiratory chain (Clara, Langhans and Mansouri, personal communication).
Rodent models allow for measurements of plasma GLP-1 levels in the hepatic portal vein (HPV), that is, close to the site of its release. This is useful, but normally impossible in humans. Because first pass hepatic degradation of GLP-1 is substantial, HPV measurements in laboratory animals better reflect GLP-1 release than systemic measurements in humans. Recent parallel measurements of active GLP-1 in the HPV and vena cava of briefly food-deprived rats in response to a regular chow meal produced a short-term increase in HPV, but not vena cava, plasma concentrations within the time frame of the meal.41 This may not be surprising because rodent chow with its high content of dietary fiber and low contents of fat and readily digestible carbohydrates is not a strong stimulus for GLP-1 release. Nevertheless, the findings suggest that during a regular nocturnal chow meal in rodents, endogenous GLP-1 may have local paracrine effects or endocrine effects in the HPV and liver, but not systemic effects. One of our laboratories recently observed that isocaloric high-fat or high-carbohydrate meals taken by rats both increased intestinal lymphatic concentration of active GLP-1, but the prandial increase was more pronounced after the high-fat than after the high-carbohydrate meal.42 This finding is consistent with the potent stimulatory effect of fat on GLP-1 release and supports the hypothesis of a local paracrine effect of endogenous GLP-1 on intestinal vagal afferents. HPV infusions of GLP-1 (1 nmol kg−1 body weight) that were triggered by remote control in totally undisturbed rats produced a transient but supraphysiological increase in vena cava GLP-1 concentrations,41 indicating that the satiation response to such infusions may reflect a pharmacological rather than a physiological effect. This effect may, however, still be relevant for pharmacological treatments with GLP-1R agonists or for situations in which systemic concentrations of endogenous GLP-1 are substantially increased, such as after gastric bypass surgery.
Cognate receptors and mode of action
GLP-1R are expressed in peripheral organs such as the pancreatic islets, the lung and the entire GI tract. In the human brain, GLP-1R have been identified in several areas such as the frontal, parietal, temporal and occipital cortices, the basal ganglia and the hypothalamus.43 Whether these cerebral GLP-1R are targets for intestinal GLP-1 to produce a satiating effect is, however, still unknown. Only 25–33% of the intact peptide actually reaches the portal vein due to dipeptidyl peptidase-4 inactivation. In addition, the amount of GLP-1 reaching the systemic circulation is further reduced because of substantial hepatic extraction as suggested by studies in pigs.44 Together these findings seem to suggest a local action of endogenous GLP-1 in the GI tract rather than a systemic endocrine action. Indeed, a recent study in humans showing that the acute inhibitory effect of exogenous GLP-1 on eating is lost in subjects after a truncal vagotomy supports the hypothesis that intestinal GLP-1 may reduce eating primarily by acting on peripheral GLP-1R located on intestinal vagal afferent fibers.45 Rat experiments indicate that circulating GLP-1 can enter the brain through circumventricular organs that lack a blood–brain barrier, such as the subfornical organ and the area postrema (AP).46 This may contribute to the eating-inhibitory and weight loss effects in patients treated with GLP-1 agonists or in patients after Roux-en-Y gastric bypass who have a sustained elevation of circulating GLP-1, which could recruit central pathways that are not normally engaged by circulating GLP-1.
Functional neuroimaging methods are increasingly employed to study the neural basis of eating and energy homeostasis also in humans. In these experiments, visual food cues and food ingestion have been shown to modulate neuronal activity in brain regions that are involved in homeostatic (for example, hypothalamus) and non-homeostatic (for example, insula, thalamus, hippocampus, caudate, putamen, amygdala and orbitofrontal cortex)47, 48, 49, 50 controls of eating. Relationships between postprandial endogenous GLP-1 responses and changes in neuronal activity in some of these brain areas have been reported in a number of studies.51, 52, 53 Using functional magnetic resonance imaging, De Silva et al.53 found that a GLP-1 infusion that inhibited ad libitum eating in healthy subjects consistently reduced neuronal activities in amygdala, caudate, insula, nucleus accumbens, orbitofrontal cortex and putamen compared with a saline infusion. Co-infusion of GLP-1 and PYY3-36 reduced brain activities similar to the changes observed after a normal meal. In addition, consistent with the additive satiating effect of both hormones (as reviewed below), the summation of the individual effects of each hormone on brain activity was comparable with the reduction in brain activity observed after combined infusion of GLP-1 and PYY3-36. More recent experiments with infusions of the long-acting GLP-1 analog, exenatide, showed reduced visual food cue related activations in the amygdala, insula and orbitofrontal cortex in obese subjects and patients with T2DM, and this correlated with reductions in food intake.50 Moreover, the exenatide-induced effects were inhibited by infusion of the GLP-1 receptor antagonist exendin 9–39 (Ex-9) suggesting a GLP-1R mediated mechanism.
Taken together, the available evidence suggests that intestinal GLP-1 has specific satiating effects originating in the periphery. Whether activation of several brain areas shown by novel functional neuroimaging methods in humans results from a direct effect of circulating GLP-1 on the brain or from an action on afferent nerves (or from both) is currently unclear and requires further investigations. Moreover, these imaging data should be interpreted in light of the limitations of the current imaging techniques. First, spatial and contrast resolutions and accuracy of images make it difficult to specify in detail the structures that are responsible for the observed changes in regional brain activity. Thus, changes in brain activity in small regions, such as specific hypothalamic nuclei, are still hard to detect. Second, confounding effects of taste and swallowing can often not be completely eliminated. Third, the physiologic basis of the statistical association between gut hormone concentrations and brain activation are difficult to establish definitively. Figure 1 summarizes the possible pathways involved in the satiating effect of intestinal GLP-1.
As in humans, GLP-1R are located in several peripheral organs including the GI tract as well as in the brain, in areas that are involved in the homeostatic as well as in the hedonic control of eating. While global and permanent GLP-1R knockout mice display some disturbances in glucose metabolism, they eat normally and maintain the same body weight as wild-type mice,54 which is clearly at odds with the pharmacological data available. Such discrepancies between permanent gene knockout models and pharmacological findings from antagonist studies are common and usually ascribed to developmental compensation. Even recent studies with central or peripheral neuronal specific deletions of the GLP-1R did not significantly affect food intake or body weight.55, 56 They did, however, help to map the central nervous system pathways of the chronic effects of GLP-1R activation. There are various possible explanations for the discrepancies between the results obtained with these transgenic and pharmacologic approaches,57 and it is certainly not justified to dismiss either of them. Rather, future studies addressing this issue will hopefully unravel more details.
The available evidence from GLP-1 or GLP-1R agonist administration studies suggests that peripherally administered GLP-1 can inhibit eating by activation of at least two different pathways (Figure 1). The reduction in food intake after intraperitoneal (i.p.) administration—the most common route of administration in laboratory animals—depends on intact vagal afferents for native GLP-1.58 This is consistent with earlier findings showing that i.p., but not intracerebroventricular administration of the GLP-1R antagonist Ex-9 blocked the satiating effect of i.p. administered GLP-1.59 Interestingly, if the GLP-1R agonist exendin-4 (Ex-4) was administered instead of native GLP-1, subdiaphragmatic vagal deafferentation blocked the initial inhibition of eating (0–1 h), but not the subsequent response.60 This indicates that initially native GLP-1 and Ex-9 recruit vagal afferents to inhibit eating, whereas later Ex-9, presumably because of its longer biological half life in the circulation, is able to recruit other, non-vagal pathways, and most likely acts directly on the brain. Recent findings indicate that GLP-1R in the AP are likely candidates.41 Thus, infusion of Ex-9 into the fourth ventricle as well as lesion of the AP reliably blocked the eating-inhibitory effect of GLP-1 infused into the HPV.41 As i.p. injected Ex-4 eventually gains access to the circulation, it is reasonable to assume that it acts on hindbrain GLP-1R as well. This presumably holds for the effects of a single peripheral administration of GLP-1R agonists. It appears, however, necessary to differentiate between these effects and long-term effects after chronic administration. Thus, recent findings suggest that the chronic effect of the GLP-1R agonist liraglutide on body weight does not depend on vagal afferent GLP-1R, the AP or the paraventricular nucleus of the hypothalamus.56 In mice, peripherally injected fluorescently labeled liraglutide was found in the circumventricular organs, and in particular on neurons in the hypothalamic arcuate nucleus (Arc), where it was internalized in neurons expressing pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript.56 Also, liraglutide stimulated the pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript neurons and indirectly inhibited Arc neurons expressing neuropeptide Y and agouti-related peptide via gamma-aminobutyric acid-dependent signaling. These findings led the authors to conclude that GLP-1R on hypothalamic pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript neurons most likely mediate the chronic, weight reducing effect of liraglutide.56 For therapeutic purposes in humans it is important to know where and how GLP-1 receptor agonists act to exert their antiobesity and antidiabetic effects.
Physiological exogenous dose
Several studies have shown that i.v. infusion of GLP-1 significantly and dose-dependently reduces meal size with effects on subjective appetite and in the absence of malaise in healthy subjects and patients with T2DM and obesity.61, 62, 63, 64, 65, 66 Although physiological GLP-1 doses were sufficient to inhibit eating,62, 63, 64, 65, 66 the overall effect was rather small and did not occur under all test conditions.67, 68, 69 In the only meta-analysis70 available so far, pooling 147 observations, an average GLP-1 dose of 0.89 pmol kg−1 min−1 (which can be considered physiological) caused an average reduction in ad libitum energy intake of 727 kJ (95% confidence interval, 908–548 kJ), or 11.7%. This effect was dose-dependent in both lean and overweight subjects and linearly related to the administered dose. In addition to interventions with native GLP-1, numerous clinical studies using GLP-1R analogs with prolonged half-lives (liraglutide and exenatide) have demonstrated weight loss in patients with T2DM71 supporting a role of GLP-1 in the control of eating.
Because a significant proportion of a meal empties into the small intestine before eating is terminated,72 it is likely that gastric and post-gastric stimulation influences satiation in parallel, and thus, that GLP-1’s satiating effect is modulated by gastric signals. In humans, interaction effects between gastric and intestinal signals have been investigated mainly by using traditional preload experiments. In one of our laboratories, we used the preload design to investigate the interaction effects between exogenous GLP-1 infusion and gastric distension. In healthy subjects, GLP-1 or saline (control infusion) were infused together with a 400 ml oral preload of either water or a whey protein solution. In line with our hypothesis, we found that the protein preload enhanced the satiating effect of exogenous GLP-1.65 In another experiment, subjects received either an i.g. glucose load or an isocaloric i.d. glucose infusion at rates comparable with the duodenal delivery of glucose under physiological conditions.73 Whereas i.d. infusion of glucose elicited only weak effects on appetite and GLP-1 secretion, identical amounts of glucose delivered i.g. markedly suppressed hunger, increased fullness and greatly elevated plasma GLP-1. These data confirm that gastric and intestinal signals interact to mediate satiation, possibly via a neural link between the stomach and the small intestine that may also potentiate GLP-1 responses. From the perspective of nutrient sensing, however, it is important to note that at present no data support the existence of a nutrient-based gastric phase of GLP-1 secretion.
GLP-1 is secreted with several other gut peptides during meals; it is thus likely that it acts in concert with other hormones to terminate eating. An additive inhibitory effect on eating has been described for i.v. co-infusion of GLP-1 and PYY3-36 in healthy subjects.53, 74 In line with these results are data in humans with oral co-administration of GLP-1 and PYY 3-36 (2 mg and 1 mg, respectively) using a carrier that protected from proteolytic degradation, enhanced absorption and, hence, allowed for oral delivery, although this approach resulted in clearly supraphysiological plasma levels.75 Finally, in a recent study,76 co-infusion of GLP-1 and PYY3-36 reduced energy intake compared with placebo even more than the sum of mono infusions, which is usually interpreted as a synergistic effect (but see Geary77). In contrast, not all GI peptide combinations have shown to interact this way. Whereas infusions of CCK-33 and GLP-1 in healthy men inhibited meal size individually, no greater reduction was found when they were co-administered.78
In summary, exogenous infusions of GLP-1 modulate satiation processes and inhibit ad libitum eating. The peptide meets the physiological dose criterion for a physiological satiation effect in humans because reductions in meal size are seen with exogenous infusions that mimic prandial plasma concentrations. The effect is, however, rather small and does not occur under all test conditions, which indicates that GLP-1, by its own, is a weak satiation signal and possibly requires interaction with multiple signals including signals from the stomach and other GI peptides to exert its full satiating action.
As mentioned above, GLP-1 doses that reliably inhibit eating after i.v. administration in laboratory animals presumably produce supraphysiological plasma levels of active GLP-1.41 Several findings indicate, however, that some of the physiological effects of endogenous GLP-1 in laboratory animals are mediated by a paracrine effect on intestinal vagal afferents. In fact, there is no reason to believe that this should be different in humans, in which it is more difficult to address such a mechanism experimentally. In laboratory animals these effects may be better mimicked by i.p. injections rather than i.v. infusions. Enteroendocrine cells release GLP-1 into the interstitial fluid of the gut wall, the composition of which is fairly well reflected by intestinal lymph.79 I.p. injected peptides reach the intestinal lymph,36 and i.g. nutrient infusions increase the GLP-1 concentration in intestinal lymph more than in the HPV.80 One of our labs recently showed that an i.p. infusion of GLP-1 that reduced meal size under the conditions tested only moderately and transiently increased intestinal lymphatic GLP-1 concentration during the time frame of the meal,81 suggesting that the premature meal termination induced by GLP-1 could be related to this moderate increase of the GLP-1 concentration in the interstitial fluid of the lamina propria (measured in intestinal lymph).82
In the first test of GLP-1R antagonism effects on human eating, one of our labs found that Ex-9 slightly attenuated the decrease in prospective food consumption and desire to eat during ad libitum eating after glucose ingestion in healthy men (P<0.05 and P<0.01, respectively, Figure 2).83 There was, however, no effect of Ex-9 on food and fluid intakes and eating duration, questioning the role of endogenous GLP-1 as satiation signal. Others84 also failed to observe an effect of Ex-9 on ad libitum energy intake. Contrary to what should be expected based on the putative satiating effect of endogenous GLP-1, subjects even reported a greater decrease in hunger after consumption of a breakfast with concomitant Ex-9 infusion. The reason for the failure of Ex-9 to affect eating is unknown, but the unusually high levels of glucagon and PYY that were observed with Ex-9 infusion may be a likely explanation.83, 85 It is conceivable that the increases in glucagon and PYY, which both inhibit eating,86, 87, 88 antagonized an eating-stimulatory effect of Ex-9, but to test this hypothesis will require further research.
Taken together, although in a recent study Ex-9 largely blocked the anorectic effect of the long-acting GLP-1 analog exenatide in lean and obese subjects and patients with T2DM,50 at present GLP-1’s status as a physiological satiation signal in humans based on the antagonist criterion, remains unproven.
Peripheral GLP-1 receptor antagonism studies in rodents so far yielded mixed results.59, 89, 90 Under certain conditions pharmacologic peripheral GLP-1 receptor antagonism blocked the effect of exogenous GLP-1,59, 90 but only in one of these reports and under certain conditions the pharmacological antagonism of GLP-1R by itself also stimulated eating.59 In another study the daily subcutaneous injection of a very potent human-based receptor antagonist increased food intake and body weight in dietary-induced obese mice.91 There are several possible explanations for the unreliable and inconsistent effects of GLP-1R antagonism on eating. If for instance, the effect of endogenous GLP-1 is to a large part due to a paracrine effect on intestinal vagal afferents, it is conceivable that the endogenous GLP-1 reaches the critical receptor sites that are in the immediate vicinity of the enteroendocrine cells much faster and in higher concentrations than what might be achieved even by high concentrations of an antagonist given i.p. The most obvious form of receptor antagonism these days is of course a genetic knock out. This, however, does not necessarily produce meaningful results because developmental compensation may counteract any effect of such manipulations. In fact, mice genetically deficient of GLP-1Rs do not have much of a phenotype.92 Moreover, a recent study showed that mice with a CNS or visceral nerve-specific deletion of GLP-1Rs did not show any alterations in body weight or food intake when fed normal chow or a high-fat diet,55 indicating that GLP-1Rs in the brain or in peripheral nerves are not necessary for normal energy homeostasis. Several lines of reasoning indicate, however, that CNS GLP-1Rs,55, 56 in particular in the Arc,56 are involved in the chronic eating-inhibitory and body weight decreasing effect of the GLP-1R agonist liraglutide. Interestingly, CNS GLP-1Rs do not appear to be involved in the glucose lowering effect of liraglutide.56 As alluded to above, it seems necessary to differentiate between chronic and short-term effects because a knock down of vagal afferent GLP-1R by bilateral nodose ganglion injections of GLP-1R shRNA produced an increase in meal size and meal duration,82 suggesting that vagal afferent GLP-1Rs are in fact involved in the normal control of meal size, but that this effect is compensated for by a concomitant decrease in meal number, leaving daily cumulative food intake unaffected. This finding reminds of West, Frey, and Woods’s classic study with CCK, in which automatic infusions of CCK in relation to each single spontaneous meal consistently reduced meal size over many days, but total 24 h food intake was largely unchanged because of a compensatory increase in meal number.93
Intestinal GLP-1 has numerous physiological effects and, although currently GLP-1 doesn’t appear to fulfill all the criteria listed on Table 1, satiation may be one of these effects. The following pieces of evidence support this hypothesis: (1) GLP-1 is secreted in response to food ingestion. In humans, its plasma levels are increased for several hours after meals, a pattern that is consistent with an endocrine function in meal-ending satiation and postprandial satiety. In rodents fed regular chow, GLP-1 presumably doesn’t act as an endocrine signal of satiation or satiety. Rather, the available evidence suggests that it induces satiation by activating GLP-1R on intestinal vagal afferents. Whether this mechanism of action is also relevant in humans awaits further investigation, but data from patients after truncal vagotomy support such a hypothesis. Also, in humans, there is initial evidence that intestinal GLP-1 may affect eating by acting directly on the brain because relationships between postprandial endogenous GLP-1 responses and changes in neuronal activity have been reported. (2) Exogenous infusion in physiological doses of GLP-1 inhibits food intake both in rodents and in lean subjects as well as obese individuals. (3) Clinical trials in obese patients with synthetic GLP-1 analogs (exenatide, liraglutide) show significant reductions in body weight suggesting that this is, at least in part, due to increased satiation via GLP-1 signaling. (4) Results from studies in patients after bariatric surgery show a substantial enhancement of the meal-induced increase in circulating GLP-1. This correlates with the dramatic weight loss seen post-surgery, although it is currently debatable whether GLP-1 plays a major role in this effect of bariatric surgery. (5) The antagonist Ex-9 significantly augments food intake in rats after i.p. application under certain conditions, in both the light and the late dark period. In another study using chronic subcutaneous administration of a potent GLP-1R antagonist, food intake and body weight were increased in dietary obese mice. In humans, Ex-9 failed to affect food intake, but modestly modulated appetite, although the antagonist demonstrated metabolic effects. The marked increases in plasma PYY and glucagon concentrations (both peptides inhibit eating) observed with Ex-9 may have interfered with and counteracted a desatiating effect of Ex-9 in humans, and a similar phenomenon may be responsible for some of the inconsistent results in rodents, although to our knowledge this has never been specifically examined. (6) Finally, GLP-1 slows gastric emptying both in rodents and humans, an effect that is likely to contribute to the satiating potency of GLP-1.
In sum, the satiating effect of endogenous GLP-1 is presumably small and does not appear under all test conditions, indicating that GLP-1 requires interaction with other signals, including signals from the stomach and other GI peptides to exert its full satiating capacity. Nevertheless, the available evidence suggests that pharmacological interventions in GLP-1R signaling via long-acting GLP-1R antagonists or dipeptidyl peptidase-4 inhibitors are a promising new treatment for obesity.
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ETH Zurich Research Grant 47 12-2 (WL).
The authors declare no conflict of interest.
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Steinert, R., Beglinger, C. & Langhans, W. Intestinal GLP-1 and satiation: from man to rodents and back. Int J Obes 40, 198–205 (2016). https://doi.org/10.1038/ijo.2015.172
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