CNS GLP-1 is synthesized largely in the brainstem and transported along axonal networks to diverse CNS regions, including the hypothalamus. The GLP-1 receptor has been localized to numerous CNS nuclei using a combination of receptor autoradiography or in situ hybridization studies. The intriguing studies by Turton, Bloom and colleagues demonstrated that ICV GLP-1 clearly inhibits food intake A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996 4;379(6560):69-72.  GLP-1 and its receptor have also been localized to the human CNS, and administration of peripheral GLP-1 to normal human subjects significantly reduces glucose metabolism in the hypothalamus and brainstem as outlined in The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J Neurochem. 2005 Feb;92(4):798-806

Neuroprotection, learning and memory in the CNS

Does GLP-1 receptor activation mediate neuronal damage in the CNS? A study in rats infused with an exendin (5-39) GLP-1R antagonist demonstrated decreased neurotoxicity following infusion with beta amyloid protein. See Brain Res 2000 Sep 29;878(1-2):194-198

Conversely, the GLP-1 receptor is expressed in the subventricular zone of the rat brain and administration of GLP-1 or exendin-4 in vitro increased the number of neural stem/progenitor cells and the expression of neuronal markers. Moreover peripheral administration of exendin-4 increased cell proliferation in the CNS, and exendin-4 treatment for 3 weeks improved functional and histological parameters of disease activity in in the 6-hydroxydopamine model of Parkinson's disease. See Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of parkinson's disease. J Neurosci Res. 2007 Sep 5; [Epub ahead of print]

Studies using the rat PC12 pheochromocytoma cell line, which expresses the GLP-1 receptor, suggest that GLP-1 agonists promote neurite outgrowth and NGF-induced differentiation, and may enhance cell survival following withdrawal of NGF, depending on the timing of exendin-4 administration. The differentiation actions of GLP-1 were abrogated by the kinase inhibitors LY294002 or PD98059, but the PKA inhibitor H-89 had only modest effects on these actions. Hence, these findings suggest that GLP-1R signaling, perhaps independent of PKA activation, may be neurotrophic in the correct cellular context. See A novel neurotrophic property of glucagon-like Peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther. 2002 Mar;300(3):958-66. A follow-up study from the Greig lab demonstrated that GLP-1, and exendin-4, can completely protect cultured rat hippocampal neurons against glutamate-induced apoptosis, and both GLP-1 and exendin-4  reduced ibotenic acid-induced depletion of choline acetyltransferase immunoreactivity in rat basal forebrain cholinergic neurons. Similarly, GLP-1 can reduce the levels of amyloid-beta peptide (Abeta) in the brain in vivo and reduced levels of amyloid precursor protein (APP) in cultured neuronal cells. Furthermore, GLP-1 and exendin-4 protect cultured hippocampal neurons against death induced by Abeta and iron See Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res. 2003 Jun 1;72(5):603-12. 

Hence, these results suggests that GLP-1 action in the brain may be neuroprotective, perhaps via activation of anti-apoptotic signaling pathways in specific neurons. See Protection and reversal of excitotoxic neuronal damage by glucagon-like Peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002 Sep;302(3):881-8

During and colleagues have shown, using a variety of gene therapy, and peptide-based technologies, that activation of CNS GLP-1R signaling enhances associative and spatial learning through GLP-1R. These investigators used a novel N-terminal exendin-4 derivative, [Ser(2)]exendin(1-9), which when administered peripherally, gains access to the CNS, and activates the CNS GLP-1R system. GLP-1R-deficient mice exhibit a learning deficit phenotype which  is restored after hippocampal GLP-1R gene transfer. Furthermore, gain of function studies in rats over-expressing the GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with correction after GLP-1R gene transfer in hippocampal somatic cells. Systemic administration of the GLP-1R agonist peptide [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons.See Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9

GLP-1R signaling in the CNS regulates peripheral glucose homeostasis

GLP-1 receptors in the CNS are important for transduction of signals coupled to satiety and aversive stimulation. Brain GLP-1R signaling also appears to control glucose flux in muscle and liver. Under conditions of a hyperglycemic hyperinsulinemic clamp, intracerebroventricular administration of the specific GLP-1 receptor antagonist Exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content in mice. This effect did not require muscle insulin action as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist Exendin-4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by intravenous infusion of glucose, icv Ex-4, but not Ex9, caused a four-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen, with no effects of icv Ex-4. Furthermore, central blockade of GLP-1R signaling or peripheral administration of the antagonist Ex9 improved insulin sensitivity in mice. These findings provide further evidence linking GLP-1 action in the brain with the peripheral control of glucose flux, insulin sensitivity and insulin secretion as described in Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest. 2005 Dec 1;115(12):3554-3563

Complementary studies examined the regions of the CNS important for GLP-1R-dependent control of glucose homeostasis. Blockade of arcuate GLP-1 receptors by central injection of the antagonist des-His1-Glu8-exendin-4 increased glycemic excursion during an IPGTT in rats whereas injection of GLP-1 into the arcuate nucleus reduced plasma glucose excursion. These actions of the GLP-1 antagonist were not associated with changes in insulin secretion however administration of GLP-1 into the third ventricle did increase insulin secretion during peripheral glucose loading. The GLP-1R+ cells colocalized with POMC+ cells in the acuate nucleus. Intriguingly, the central effects of GLP-1GLP-1 on glucose production and glucose uptake were blocked by concomitant central administration of glibenclamide. See Arcuate GLP-1 receptors regulate glucose homeostasis but not food intake Diabetes published online on May 16, 2008 as 10.2337/db07-1824

Does GLP-1 acting on the brain arise centrally, or does peripheral GLP-1 also signal the CNS?

Peripheral administration of GLP-1 is taken up into the CNS, as illustrated in Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. J Mol Neurosci. 2002 Feb-Apr;18(1-2):7-14. Administration of the radiolabelled protease-resistant analogue [Ser8]GLP-1, revealed uptake of this peptide into the CNS that was not saturable, nor competed by wildtype GLP-1 or the GLP-1 receptor antagonist exendin(9-39), suggesting that the GLP-1 receptor is not involved in the rapid entry into brain. [Ser8]GLP-1 was detected within the brain parenchyma, but a large proportion was loosely associated with the vasculature at the BBB. These studies demonstrate that a radiolabelled GLP-1 analogue can enter the brain, but whether GLP-1 needs to enter the brain to affect food intake of gut motility, remains unclear. Similar studies using CD1 mice have demonstrated that exendin-4 readily crosses the blood brain barrier, even more efficiently than native GLP-1, as illustrated in Entry of exendin-4 into brain is rapid but may be limited at high doses. Int J Obes Relat Metab Disord. 2003 Mar;27(3):313-318

Does GLP-1 need to penetrate the brain to activate central GLP-1R-dependent networks?

The available data suggests that peripheral administration of native GLP-1 or GLP-1R agonists activates GLP-1R receptors in the brain coupled to c-fos activation, inhibition of food intake, activation of the HPA axis, and potentially, induction of an aversive stress response. Endogenous GLP-1 is also synthesized in the brain, and peripheral GLP-1 communicates with central GLP-1 networks in the CNS. One approach to assess the extent to which peripheral GLP-1 signals regulate CNS GLP-1 activity involves the use of larger hybrid GLP-1-albumin proteins which retain the ability to activate GLP-1 receptor signaling, yet do not readily cross the blood brain barrier. Albugon, a recombinant-GLP-1 protein, lowers blood glucose and enhances insulin secretion in mice, and  stimulates GLP-1R-dependent cAMP accumulation in cells expressing the GLP-1 receptor. Remarkably, Albugon also activates c-fos expression in multiple regions of the central nervous system, and inhibits food intake in mice following both icv and peripheral administration. For an overview of the data, see A Recombinant Human Glucagon-Like Peptide (GLP)-1-Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 Receptor-Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and Glucose Homeostasis. Diabetes. 2004 Sep;53(9):2492-500. 

Similar conclusions can be inferred from studies of the mechanisms of action of CJC1134, an exendin-4:albumin conjugate, on the pancreas, gut and CNS in WT and Glp1r-/- mice. Although high molecular weight CJC1134 does not appear to rapidly traverse the blood brain barrier and directly engage central GLP-1 receptors, peripheral administration of CJC1134 rapidly activates c-FOS in multiple regions of the CNS. Moreover, CJC1134 promotes satiety and inhibits gastric emptying in a GLP-1R-dependent manner, and chronic administration is associated with weight loss in mice. Hence, these findings provide further evidence supporting the importance of ascending GLP-1R-dependent neural signals for transmission of responses controlling satiety and gut motility in vivo. See An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis Gastroenterology 2008, do1:10.1053/j.gastro.2008.01.017

GLP-1, aversive stimulation, stress and the CNS

Although the data linking GLP-1 to inhibition of food intake are quite solid, it is also important to consider a role for GLP-1 in the CNS response to aversive stimuli. A link between GLP-1 and the stress response was first suggested, albeit indirectly, by studies from Larsen and colleagues who demonstrated that ICV GLP-1 activated hypothalamic CRH+ neuroendocrine neurons leading to increased corticosterone secretion in rats Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology. 1997 138(10):4445-55 

More recent experiments have confirmed the intricate anatomical association between GLP-1R+ nerve terminals in neuronal projections that abut CRH+ neurons in the hypothalamic PVN, as described in Glucagon like peptide-1 (7-36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Brain Res. 2003 Sep 26;985(2):163-8

A series of experiments from Randy Seeley, David D'Alessio and their colleagues next demonstrated that many of the aversive effects of Lithium chloride administration in rats are blocked by ICV preadministration of exendin (9-39), the GLP-1 receptor antagonist, as illustrated in J Neurosci 2000 Feb 15; 20(4):1616-21 The role of CNS glucagon-like peptide-1 (7-36) amide receptors in mediating the visceral illness effects of lithium chloride. 

Intriguingly however, although lithium chloride also activated proglucagon/GLP-1+ cells in the mouse NTS, the GLP-1R does not appear to be essential for transduction of LiCl-induced anorexia or a CTA in mice, as demonstrated in studies using either the antagonist exendin(9-39), or GLP-1R-/- mice.  These findings demonstrate considerable species-specificity with respect to the role of central GLP-1R signaling pathways in components of the aversive response, as described in The role of central glucagon-like Peptide-1 in mediating the effects of visceral illness: differential effects in rats and mice. Endocrinology. 2005 Jan;146(1): 458-62.

To localize the CNS regions responsive to GLP-1 that mediate the anorexic versus visceral illness (CTA) effects of GLP-1, Kinzig and colleagues injected various doses of GLP-1 into the lateral or 4th ventricle of rats. Both sites could transduce a GLP-1 signal linked to food intake, whereas only GLP-1 instilled into the lateral ventricle evoked a CTA response. The central nucleus of the amygdala was identified as a key GLP-1R+ site important for the response to visceral illness. These findings illustrate the compartmentalization of the CNS GLP-1R response to differential CNS inputs as outlined in The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J Neurosci. 2002 Dec 1;22(23):10470-6. Similar experiments demonstrated that the endocrine component of the stress response is activated following GLP-1 injection into the hypothalamic PVN, whereas the anxiety response is induced by GLP-1 administration in the central nucleus of the amygdala. See CNS glucagon-like peptide-1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors. J Neurosci. 2003 Jul 16;23(15):6163-70

Studies from the Rinaman lab corroborate the GLP-1-mediated activation of stress-related signaling pathways in the CNS. The data in Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus. Am J Physiol. 1999 Aug;277(2 Pt 2): R582-590 demonstrates that LiCl, LPS and CCK activate GLP-1 neurons, whereas the same neurons are not activated following ingestion of a large meal. A similar story emerges in A functional role for central glucagon-like peptide-1 receptors in lithium chloride-induced anorexia. Am J Physiol. 1999 Nov;277(5 Pt 2):R1537-40. Central infusion of the GLP-1 antagonist exendin (9-39) increases the febrile response to LPS, suggesting that GLP-1R signaling may normally function to attenuate the response in vivo. See Antagonism of central glucagon-like peptide-1 receptors enhances lipopolysaccharide-induced fever. Auton Neurosci. 2000 Dec 20;85(1-3):98-101. Analysis of the specific regions of the brain important for mediating the aversive effects of LPS demonstrated that the caudal brainstem GLP-1R is important for transducing the reduction in food intake observed following LPS administration. See Attenuation of Lipopolysaccharide Anorexia By Antagonism of Caudal Brainstem But Not Forebrain GLP-1-R. Am J Physiol Regul Integr Comp Physiol. 2004 Jul 1

Complementary studies in mice demonstrate that several behavioral tests that reflect anxiety, as well as the corticosterone response to stress, are abnormal in the absence of intact GLP-1R signaling. Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling. Endocrinology. 2000 Feb;141(2):752-62.

Central and peripheral cardiovascular effects of GLP-1

Studies from the Blazquez laboratory have demonstrated that both icv and peripheral GLP-1 administration increase heart rate and blood pressure in rats. See Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats. Am J Physiol. 1994 Mar;266(3 Pt 1):E459-66 and Interactions of exendin-(9-39) with the effects of glucagon-like peptide-1-(7-36) amide and of exendin-4 on arterial blood pressure and heart rate in rats. Regul Pept. 1996 Nov 14;67(1):63-8 and Neural contribution to the effect of glucagon-like peptide-1-(7-36) amide on arterial blood pressure in rats. Am J Physiol. 1999 Nov;277(5 Pt 1):E784-91.

  Similar observations have been made in calves Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7-36) amide in the conscious calf. Exp Physiol. 1997 Jul;82(4):709-16. The hypertensive and chronotropic actions of GLP-1 in the rat are evident even in the setting of hypovolemia, and associated with further augmentation of circulating vasopressin and oxytocin, as shown in Effects of glucagon-like peptide-1(7?36) amide on neurohypophysial and cardiovascular functions under hypo- or normotensive hypovolaemia in the rat. J Endocrinol. 2002 Feb;172(2):303-310

More recent studies have demonstrated that even moderate doses of GLP-1 agonists at levels not sufficient to lower blood glucose result in activation of central sympathetic neurons and adrenal medullary chromaffin cells  that produce catecholamines. Centrally and peripherally administered GLP-1R agonists including native GLP-1 and the lizard peptide exendin-4 dose-dependently increased blood pressure and heart rate in rats. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in AP neurons which express the GLP-1R, as shown in Glucagon-Like Peptide-1-Responsive Catecholamine Neurons in the Area Postrema Link Peripheral Glucagon-Like Peptide-1 with Central Autonomic Control Sites. J Neurosci. 2003 Apr 1;23(7):2939-2946. These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in the rodent, and are consistent with previous reports demonstrating that GLP-1R systems function as a component of neural networks transducing the CNS response to aversive stimuli. See Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons J. Clin. Invest. 2002;110 43-52

ICV GLP-1 has also been shown to increase fecal output in rats, and these actions were blocked by treatment with either exendin (9-39) or the CRF receptor antagonist, astressin. Hence, these findings provide yet another link between GLP-1 actions in the CNS, stress, and the CRH pathway. Peripheral GLP-1 administration did not effect fecal output. Glucagon-like peptide (GLP-1) is involved in the central modulation of fecal output in rats AJP - GI 2000 278: G924-G929

What is the connection between leptin and GLP-1 in the CNS? Data from the Bloom laboratory suggests that GLP-1 may be downstream of leptin action in the brain. Indeed, studies from Elias and Elmquist show that leptin activates a subset of GLP-1 neurons in the brainstem Chemical characterization of leptin-activated neurons in the rat brain. Elias CF, Kelly JF, Lee CE, Ahima RS, Drucker DJ, Saper CB, Elmquist JK. Nevertheless, GLP-1 receptor signaling is not required for leptin action in the CNS, as illustrated in studies of the ob/ob:GLP-1R-/- mouse. Elimination of GLP-1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action Diabetes 2000 49:1552-1560

To review data on the control of food intake, see GLP-1 and food intake