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. 2009 Apr 23;150(7):2997–3001. doi: 10.1210/en.2009-0220

Minireview: Finding the Sweet Spot: Peripheral Versus Central Glucagon-Like Peptide 1 Action in Feeding and Glucose Homeostasis

Diana L Williams 1
PMCID: PMC2703557  PMID: 19389830

Abstract

Glucagon-like peptide 1 (GLP-1) is both a gut-derived hormone and a neurotransmitter synthesized in the brain. Early reports suggested that GLP-1 acts in the periphery to promote insulin secretion and affect glucose homeostasis, whereas central GLP-1 reduces food intake and body weight. However, current research indicates that in fact, GLP-1 in each location plays a role in these functions. This review summarizes the evidence for involvement of peripheral and brain GLP-1 in food intake regulation and glucose homeostasis and proposes a model for the coordinated actions of GLP-1 at multiple sites.

This review summarizes the evidence for involvement of peripheral and brain glucagon-like peptide 1 (GLP-1) in food intake regulation and glucose homeostasis, and proposes a model for the coordinated actions of GLP-1 at multiple sites.

Glucagon-like peptide 1 (GLP-1) is perhaps best known as a gut-derived incretin hormone. One of several cleavage products of the pre-proglucagon gene, GLP-1 is secreted by the enteroendocrine L cells of the distal intestine in response to incoming nutrients (1). This description, although true, is incomplete because GLP-1 is also a neurotransmitter synthesized by a small population of neurons in the nucleus of the solitary tract (NTS) in the caudal brainstem (2). Over the past two decades, numerous studies have suggested a role for GLP-1 not only in insulin secretion but also in the control of food intake and body weight, gastric emptying, cardiovascular function, stress and illness responses, and proliferation and survival of several different cell types (3). Attention to this system has further increased with the recent emergence of GLP-1-based pharmacological therapies for type II diabetes (4), along with the speculation that GLP-1 plays a role in the efficacy of Roux-en-Y gastric bypass surgery for the treatment of obesity and diabetes (5). The growing clinical relevance of GLP-1 and its receptors makes it all the more important that we improve our understanding of the underlying physiology. Given that the peptide itself is produced both peripherally and centrally, and GLP-1 receptors (GLP-1-R) are expressed in a variety of peripheral tissues as well as the brain, it is not surprising that the question of neural vs. peripheral mediation has been debated for many effects of GLP-1. For food intake and glucose homeostasis, current evidence favors the idea that both sites of action play a role.

Food Intake Control

Many studies have demonstrated that peripherally administered GLP-1 and GLP-1-R agonists reduce food intake (6,7), but because brain GLP-1 treatment reduces feeding as well, the question of which GLP-1-R populations mediate the effects of systemic GLP-1 has arisen. Several lines of evidence support the argument that endogenous gut-derived GLP-1 affects food intake by acting on nearby enteric GLP-1-R. Biologically active GLP-17–36NH2 is rapidly degraded by dipeptidyl peptidase IV (DPP-IV) and therefore has an extremely short half-life in the circulation (1–2 min). Only about 25% of the GLP-1 released from intestinal L cells is estimated to remain in active form upon arrival in the hepatic portal vein. Further degradation takes place in the liver, leaving only about 10–15% to enter the systemic circulation where DPP-IV is present and continues to inactivate the peptide (8). GLP-1 can readily diffuse across the blood-brain barrier (BBB) (9), but considering the postsecretion fate of GLP-1, the chance that any significant amount of active GLP-1 travels from the gut to the brain seems slim.

Substantial behavioral evidence supports the view that peripheral GLP-1 reduces food intake through an effect on peripheral GLP-1-R. The GLP-1-albumin fusion protein Albugon does not cross the BBB and reduces feeding when administered systemically (10). Although the commonly used degradation-resistant GLP-1-R agonist exendin-4 (Ex4) can cross the BBB (11), several pieces of data suggest that it, as well as native GLP-1, acts to reduce food intake primarily via vagal afferent activation. GLP-1-R mRNA is expressed in the nodose ganglion (12), and GLP-1-R has been observed on vagal terminals innervating the hepatic portal vein (HPV) (13). The expression of GLP-1-R on vagal afferent fibers innervating the intestine has not been reported, but it is not unreasonable to speculate that they may be present in that location as well. Of course, the mere presence of GLP-1-R on vagal fibers does not guarantee that they play a role in mediating GLP-1’s effects on feeding, but it has been demonstrated that either total subdiaphragmatic vagotomy (6) or selective vagal deafferentation (14) prevents ip injected GLP-1-induced anorexia, and vagal sensory ablation by capsaicin treatment prevents ip Ex4-induced anorexia (15). Recent pharmacological studies using the competitive GLP-1-R antagonist exendin (9–39) (Ex9) provide further support for this perspective. Peripherally administered Ex9 increases food intake when delivered to satiated rats and also blocks the satiety induced by nutrient preloads (16). These effects appear to be based on ip administered Ex9’s ability to block peripheral GLP-1-R, because the same dose of ip Ex9 that blocked the anorexic effect of systemic GLP-1 failed to blunt the anorexic effect of central nervous system (CNS) GLP-1 administration. Conversely, intracerebroventricular (icv) Ex9 blocked the feeding-inhibitory effect of icv GLP-1 but failed to attenuate peripheral GLP-1-induced anorexia (16). Taken together, these data support the idea that GLP-1 released by the intestine promotes satiety by activating peripheral GLP-1-R, whereas neuronal GLP-1 affects feeding through GLP-1-R in the brain.

Evidence that peripheral GLP-1-R play a role in satiety does not rule out a role for GLP-1 and its receptors in the CNS. To the contrary, it is clear that brain GLP-1 is involved in feeding and body weight control. The first indication that GLP-1 action in any location may affect feeding behavior came from Turton and colleagues (17), who showed that central (third-icv) injection of GLP-1 decreased feeding and body weight, and importantly, third-icv injection of Ex9 increased food intake. Shortly thereafter, it became clear that CNS GLP-1 treatment supports conditioned taste aversion (CTA) (18), suggesting that GLP-1 may reduce food intake because it causes nausea, as opposed to normal satiety. Indeed, endogenous neuronal GLP-1 and GLP-1-R stimulation appears to play an important role in the anorexic response to viscerosensory stress and illness. Both LiCl and lipopolysaccharide activate GLP-1 neurons in the NTS (19), and the anorexia induced by each of those treatments is strongly attenuated by CNS GLP-1-R blockade (20,21). However, it is clear that the anorexic response to GLP-1 in the brain is not entirely dependent on malaise. Site-specific injection studies revealed that GLP-1 administration directly to the central nucleus of the amygdala induced CTA without causing anorexia, whereas hindbrain-directed fourth-icv injections or reduced food intake but did not support CTA (22). In a separate study, infusion of GLP-1 into the paraventricular nucleus of the hypothalamus (PVN) also reduced food intake without causing a CTA or other signs of illness (23). These data nicely illustrate the idea that neuropeptide GLP-1 has multiple functions, at least some of which are mediated by distinct receptor populations.

There is some evidence that neuronal GLP-1 plays a role in the compensatory response to changes in body adiposity, largely driven by changes in leptin levels. Soon after CNS GLP-1 was shown to have an anorexic effect on food intake, Goldstone and colleagues (24) demonstrated that leptin receptors are expressed by GLP-1 neurons, and leptin treatment up-regulates GLP-1 mRNA in the hindbrain (25). Recent data suggest that there may be mouse/rat species differences in the ability of GLP-1 neurons to respond to changes in metabolic state and leptin (26), but despite some unresolved questions, the behavioral effects of GLP-1 and GLP-1-R antagonist treatment are suggestive. Central injection of the GLP-1-R antagonist Ex9, at a dose subthreshold for an independent effect, attenuated leptin’s ability to reduce feeding and body weight (24). Repeated daily third-icv injection of GLP-1 reduced body weight, an effect that may be pharmacological in nature, but chronic third-icv administration of Ex9 increased body weight (27).

More recently, the role of central GLP-1-R in meal-related satiety has been examined. Early investigations of GLP-1 neuron response to gastrointestinal stimulation yielded somewhat conflicting results. Vrang and colleagues (28) found that physiological-volume gastric balloon distention activated GLP-1 neurons (as measured by c-Fos-like immunoreactivity), however, Rinaman (19) showed that ingestion of even a relatively large meal had no affect on c-Fos expression in GLP-1 neurons. Despite the apparent disagreement, recent behavioral data from Hayes and Grill (29) support a role for hindbrain GLP-1-R in the response to gastric loads, showing that blockade of hindbrain GLP-1-R attenuates the satiety induced by an orally consumed nutrient preload or gastric balloon distension.

Glucose Homeostasis

The first, and perhaps best known, physiological role suggested for GLP-1 is that of an incretin, and the abundant evidence for this has been reviewed previously (30). Peripheral GLP-1 administration potently increases insulin secretion and improves glucose tolerance in rodents and humans, and these effects provide the basis for GLP-1-related therapies for type II diabetes. The early literature focused on the idea that systemic GLP-1 exerts these effects via GLP-1-R in the viscera, particularly those expressed by pancreatic B cells. In vitro studies show that GLP-1 can act directly on B cells, and pharmacological doses of GLP-1 or Ex4 in vivo may indeed have such effects (31,32). However, given the rapid degradation of GLP-1 by DPP-IV, it is not clear that endogenous gut-derived GLP-1’s insulinotropic effect is mediated by direct action on pancreatic receptors. Considerable evidence suggests that peripheral GLP-1 affects glucose metabolism through an autonomic pathway. Hepatic portal vein GLP-1 infusion activates vagal afferents along with a descending efferent vagal signal to the pancreas (33), and ganglionic blockade has been shown to impair the ability of HPV GLP-1 to enhance insulin secretion in the presence of glucose (34). Strong support for an effect of endogenous GLP-1 at an HPV site comes from the demonstration that HPV infusion of the GLP-1-R antagonist [des-His1,Glu9] Ex4 impaired glucose tolerance, whereas the same dose of the antagonist delivered via intrajugular infusion had no effect (13).

Recent studies support a role for CNS GLP-1-R in peripheral glucose metabolism as well. That the brain is involved in glucose homeostasis is no longer in question; numerous studies have shown that in particular, hypothalamic neurons can effect changes in glucose metabolism by modulating autonomic outputs (35,36). Evidence that CNS GLP-1 may affect peripheral glucose metabolism first came from the report that icv administration of Ex4 vs. Ex9 had opposing effects on insulin secretion and on liver and muscle glucose uptake (37). Furthermore, brain GLP-1-R blockade prevented the effects of intragastric glucose infusions on whole-body glucose turnover, glycolysis, and glycogen synthesis (38). Most recently, Sandoval and colleagues (39) demonstrated that icv GLP-1-R blockade impaired glucose tolerance, whereas icv GLP-1 injection increased glucose-stimulated insulin release. Because GLP-1-R are expressed in the arcuate nucleus of the hypothalamus (ARC), an area known to contribute to peripheral glucose metabolism, this site was targeted for further investigation. Indeed, they showed that during hyperinsulinemic-euglycemic clamps, intra-ARC GLP-1 injection significantly reduced glucose production, whereas administration of GLP-1 to the nearby PVN had no such effect (39). It will be important to determine whether these effects of intra-ARC GLP-1 are pharmacological or representative of normal physiology.

Many questions about the role of GLP-1 in glucose metabolism remain unresolved. It would be useful to determine whether any of these effects of peripheral GLP-1 (either endogenously produced or pharmacologically administered) are mediated by brain GLP-1-R. Does CNS GLP-1-R blockade impair the ability of peripheral GLP-1 or Ex4 to affect insulin secretion and glucose tolerance? If such an effect were observed, at least two distinct interpretations would be plausible. First, the peripheral GLP-1 agonist may cross the BBB and act directly on CNS receptors. Although the effects of HPV GLP-1-R stimulation appear to be vagally mediated, the ability of GLP-1-R agonists administered systemically at pharmacological doses (as used in the clinical setting) may involve direct CNS action. Alternatively, the vagal afferent activation caused by peripheral GLP-1 may in turn stimulate NTS GLP-1 neurons, which then release the peptide in GLP-1-R-expressing brain regions that modulate peripheral glucose metabolism. Pharmacological studies have limited potential to distinguish between these two scenarios, and both may in fact be correct.

Another open question about brain GLP-1 effects on glucose homeostasis is whether nuclei other than the ARC play a role. For example, GLP-1-R are expressed in the caudal brainstem in areas associated with autonomic function, such as the NTS and area postrema (40). Recently, Wan and colleagues (41) demonstrated that GLP-1 activates vagal motor neurons that project to the pancreas, observing both direct effects of GLP-1 on some cells and synaptically mediated effects in others. Like its effects on food intake, CNS GLP-1’s ability to affect peripheral glucose metabolism may be mediated by receptors in multiple brain regions.

An Integrated Model of GLP-1’s Effects on Feeding and Glucose Homeostasis

Based on the available data, we can begin to generate a model for how GLP-1 in both the brain and the periphery plays a role in the control of food intake and glucose metabolism (see Fig. 1), similar in some respects to the model for GLP-1’s control of glucose metabolism recently proposed by Sandoval (42). It appears that through coordinated actions in both the gut and the brain, GLP-1 facilitates the body’s handling of incoming nutrients. Effects of GLP-1 not discussed here, such as slowing the rate of gastric emptying and gastric acid secretion (3), fit well within that framework. In response to the presence of nutrients in the gastrointestinal tract, intestinal L cells release GLP-1, which binds to receptors on vagal afferents innervating the gut and portal area. The resulting vagal activation sends a signal to the brain that promotes satiety and activates a descending vagal efferent output to the pancreas, increasing insulin secretion. Food intake also promotes the release of other gastrointestinal hormones such as cholecystokinin, which has been shown to activate GLP-1 neurons in the NTS (19), most likely through a vagal afferent pathway. These gut peptide signals (possibly including GLP-1), along with the gastric distension that accompanies food intake, stimulate GLP-1 neurons in the NTS, which project to brain areas responsible for modulating food intake and glucose metabolism. We cannot conclusively state which central GLP-1 projections and receptor populations are responsible for specific effects, but we can list a few distinct possibilities. An activated projection to the ARC GLP-1-R population may function to modulate insulin release and peripheral insulin sensitivity (likely through a vagal motor pathway) but does not appear to affect food intake (39). GLP-1 release in the PVN, on the other hand, would reduce feeding without effect on glucose metabolism (23,39). The GLP-1 projection to the central nucleus of the amygdala may be stimulated only in cases of illness or stress (22), remaining inactive under normal circumstances. Release of GLP-1 within the NTS and other hindbrain nuclei may contribute to satiety (29,43), in addition to activating a vagal motor output to the pancreas for the purpose of increasing insulin secretion (41).

Figure 1.

Figure 1

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A, The ingestion of food promotes the release of GLP-1 and other satiety signals, such as cholecystokinin, from the intestine. Along with gastric distension, these signals activate vagal afferents. Cells within the NTS, including GLP-1-producing neurons, respond to this vagal afferent activity. CNS pathways involved in the control of food intake include the release of GLP-1 within the NTS and the projection of GLP-1 neurons to the PVN, where GLP-1-R activation promotes anorexia and/or satiety. B, Gut-derived GLP-1 likely affects glucose homeostasis through a similar vagal afferent pathway. Activated GLP-1 neurons of the NTS also project to the ARC, which is hypothesized to modulate vagal motor outflow to the pancreas and other tissues not depicted, increasing insulin secretion and insulin sensitivity.

In conclusion, ample evidence suggests that brain GLP-1 and GLP-1-R play a role in the control of both feeding and glucose homeostasis, as do peripheral GLP-1 and GLP-1-R. Further investigation is required to determine their relative contributions and specific sites of action for each function. Such information could be clinically valuable for the treatment of diabetes and obesity, in addition to providing clarification of the basic physiology. Given the available information, it seems reasonable to think of the GLP-1 systems in the CNS and in the periphery as partners in the service of the following goal: to ingest no more than the required amount of food and to handle the metabolism and disposal of those incoming nutrients as efficiently as possible.

Footnotes

The author’s work is supported by National Institutes of Health Grant 7K99DK078779.

Disclosure Summary: D.L.W. has nothing to declare.

First Published Online April 23, 2009

Abbreviations: ARC, Arcuate nucleus of the hypothalamus; BBB, blood-brain barrier; CNS, central nervous system; CTA, conditioned taste aversion; DPP-IV, dipeptidyl peptidase IV; Ex4, exendin-4; Ex9, exendin (9–39); GLP-1, glucagon-like peptide 1; GLP-1-R, GLP-1 receptor; HPV, hepatic portal vein; icv, intracerebroventricular; 3rd-icv, third ventricle icv; NTS, nucleus of the solitary tract; PVN, paraventricular nucleus of the hypothalamus.

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