Insulinotropic Actions of GLP-1: How Much in the Brain and How Much in the Periphery?

Eva Tudurí

Insulinotropic Actions of GLP-1: How Much in the Brain and How Much in the Periphery?

Endocrinology, 2017

NEWS AND VIEWS Insulinotropic Actions of GLP-1: How Much in the Brain and How Much in the Periphery? Eva Tudur´ ı 1,2 and Ruben Nogueiras 1,2,3 1 Instituto de Investigaciones Sanitarias, Centro de Investigaciones M ´ edicas de la Universidad de Santiago (CIMUS), University of Santiago de Compostela, Santiago de Compostela 15782, Spain; 2 Centro de Investigaci ´ on Biom ´ edica en Red (CIBER) Fisiopatolog´ ıa de la Obesidad y Nutrici ´ on, Santiago de Compostela 15706, Spain; and 3 Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain G lucagonlike peptide-1 (GLP-1) is a 30–amino acid peptide hormone that upon food consumption is produced and secreted by intestinal enteroendocrine L-cells and certain neurons in the nucleus of the solitary tract in the brainstem. GLP-1 is recognized mainly as an incretin but is involved in a large variety of biological actions because of the wide distribution of its receptor. The GLP-1 receptor is highly expressed in the central nervous system (CNS), including the lateral septum, the subfornical organ, the thalamus, the hypothalamus, the interpeduncular nucleus, the posterodorsal tegmental nucleus, the area postrema, the inferior olive, and the nucleus of the solitary tract (1). The activation of CNS GLP-1 receptors is related to some metabolic actions, such as food intake suppression, activation of brown adipose tissue, nutrient partitioning, and regulation of glucose homeostasis. The central in- jection of the GLP-1 agonist Ex-4 increased insulin se- cretion during hyperglycemia induced by intravenous infusion of glucose (2). Along the same lines, acute central administration of GLP-1 transiently lowered blood glu- cose levels (3) and increased insulin secretion in response to a glucose load (3, 4), whereas a GLP-1 receptor an- tagonist impaired glucose tolerance (3, 4). In the present issue, Jessen et al. (5) report that ad- ministration of the GLP-1 receptor antagonist Ex-9 in the third ventricle impairs insulin response to hyperglycemia and causes elevated postprandial glucose (5). Thus, these results indicate that endogenous brain GLP-1 may have an insulinotropic effect. However, the authors also found that the central administration of GLP-1 reduced insulin release and elevated glucagon secretion (Fig. 1), which ultimately increased fasting glucose (5). These last results were unexpected but are explainable by the effects of CNS GLP-1 on the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), both of which are known to produce hyperglycemia. In the study by Jessen et al. (5), central GLP-1 increased neuronal activity in brain regions (paraventricular nu- cleus and the nucleus of the solitary tract) mediating autonomic nervous system and HPA activation and stimulated circulating levels of corticosterone and epi- nephrine (5). These actions probably override and co- found the insulinotropic effect of endogenous CNS GLP-1. Importantly, the effects of CNS Ex-9 on im- paired insulin secretion did not affect the autonomic ner- vous system and the HPA, implying that the main physiological role of brain GLP-1 involves the control of glucose metabolism. If this is the case, testing lower doses of GLP-1 might help clarify whether the insulinotropic action occurs when the activation of SNS and HPA is absent. Another important aspect of the current study is that central Ex-9 infusions disrupted the tight regulation of postprandial blood glucose found in rats freely ingesting a test meal, which occurred independently of changes in insulin secretion or gastric emptying (5). This means that during meals, CNS GLP-1 uses alternative mechanisms to control blood glucose, and according to previous studies, this alternative seems to be the control of hepatic metabolism. In line with this, under a ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in USA Copyright © 2017 Endocrine Society Received 28 April 2017. Accepted 5 May 2017. For article see page 2124 Abbreviations: CNS, central nervous system; GLP-1, glucagonlike peptide-1; HPA, hypothalamic–pituitary–adrenal; SNS, sympathetic nervous system. doi: 10.1210/en.2017-00410 Endocrinology, July 2017, 158(7):2071–2073 https://academic.oup.com/endo 2071 Downloaded from https://academic.oup.com/endo/article/158/7/2071/3920680 by guest on 15 February 2024

hyperinsulinemic–euglycemic clamp, activation of CNS GLP-1 receptor stimulates hepatic glycogen stores and decreases muscle insulin-stimulated glucose utilization (2). Moreover, the administration of GLP-1 directly into the hypothalamic arcuate nucleus reduced hepatic glu- cose production (4). Despite compelling evidence indicating that brain GLP-1 is a physiological modulator of glucose homeo- stasis, there is an ongoing debate on why GLP-1 would need to reach the brain to control glucose metabolism if the entire machinery for exerting its antidiabetic actions is available in the periphery. An elegant article showed that pancreatic GLP-1 receptor activation is sufficient for the effects of GLP-1 on glucose metabolism and that this effect does not require neural pathways (6), and a sep- arate study reported that the lack of neuronal GLP-1 receptor does not affect glucose metabolism (7). One possibility is that disruption of CNS GLP-1 receptor in adulthood (achieved with pharmacological tools) and not in embryonic stages (as it occurs in genetic models) is necessary to detect the importance of CNS GLP-1 in glucose homeostasis. Thus, the use of more sophisticated tools such as pharmacogenetics, optogenetics, and in- ducible knockouts would probably help clarify this issue. Assuming that the CNS plays a relevant role in glucose homeostasis, important aspects remain to be elucidated. One important caveat is the scarce knowledge on what regulates GLP-1 in the CNS. It has been reported that leptin and cholecystokinin modulate the activity of GLP- 1–expressing neurons, suggesting that central GLP-1 ex- pression might be regulated by peripheral signals involved in energy homeostasis or glucose metabolism. Obviously, central mechanisms responding to changes in glucose and nutrient avail- ability might also regulate the expres- sion of GLP-1. Clearly, more studies are needed to assess these issues. On the other hand, given the complexity of the numerous neuronal pathways controlling glucose metabolism, it will be also important to identify the neuronal populations by which CNS GLP-1 regulates insulin secretion from islets and insulin sensitivity in other peripheral tissues such as liver, muscle, and adipose tissue. The hypo- thalamus and the brainstem, where GLP-1 receptor is located, have been studied largely as key centers for the regulation of glucose metabolism. Therefore, it might be possible that different brain areas control different peripheral tissues affecting insulin se- cretion and sensitivity and glucose production and uptake. Supporting this idea, the activation of GLP-1 receptors in the arcuate nucleus, but not in the paraventricular nucleus, reduces hepatic glucose production (4). This specificity might also be important to dissect the different actions of CNS GLP-1, because the manipulation of GLP-1 receptor in some areas probably affects one function (i.e., insulin secretion) but not others (e.g., stress, food intake). Another intriguing topic of the study by Jessen et al. (5) is the possibility that during meals, unlike in fasting conditions, central GLP-1 action on blood glucose is not insulin dependent. Why and how CNS GLP-1 exerts its effects depending on the nutrient status raises relevant questions about the physiology of GLP-1. Importantly, most of the studies assessing the role of brain GLP-1 have been done in animals fed a chow diet. If nutrient availability causes a switch in CNS GLP-1–dependent mechanisms, it seems plausible to hypothesize that these pathways might be different in lean and obese conditions. So far, in mice fed a high-fat diet, central activation of GLP-1 receptor increased basal insulin levels and did not modify glucose- stimulated insulin secretion, whereas its blockade de- creased hyperinsulinemia and reversed insulin resistance. Finally, the most relevant question is perhaps how im- portant the CNS GLP-1 system is in controlling glucose metabolism in the clinical situation. GLP-1 receptor is indeed expressed in the human brain. Functional studies in the human brain have obvious limitations, and to our knowledge there is no clear evidence of an association between brain GLP-1 and insulin sensitivity in humans. However, one study indicated that intranasal GLP-1 administration had benefi- cial metabolic effects in patients with type 2 diabetes (8), and Figure 1. Effects of activation (GLP-1) and blockade (GLP-1 antagonist) of central GLP-1 receptors on pancreatic hormone release. The central administration of the GLP-1 receptor antagonist Ex-9 in the third ventricle impairs insulin response to hyperglycemia and causes elevated postprandial glucose. However, the central administration of GLP-1 also reduced insulin release and elevated glucagon secretion. The effects of GLP-1 seem to be mediated by the activation of the HPA axis and the SNS. 2072 Tudur´ ı and Nogueiras Insulinotropic Actions of GLP-1 Endocrinology, July 2017, 158(7):2071–2073 Downloaded from https://academic.oup.com/endo/article/158/7/2071/3920680 by guest on 15 February 2024

N E W S A N D V I EW S Insulinotropic Actions of GLP-1: How Much in the Brain and How Much in the Periphery? Eva Tudurı́1,2 and Ruben Nogueiras1,2,3 1 G lucagonlike peptide-1 (GLP-1) is a 30–amino acid peptide hormone that upon food consumption is produced and secreted by intestinal enteroendocrine L-cells and certain neurons in the nucleus of the solitary tract in the brainstem. GLP-1 is recognized mainly as an incretin but is involved in a large variety of biological actions because of the wide distribution of its receptor. The GLP-1 receptor is highly expressed in the central nervous system (CNS), including the lateral septum, the subfornical organ, the thalamus, the hypothalamus, the interpeduncular nucleus, the posterodorsal tegmental nucleus, the area postrema, the inferior olive, and the nucleus of the solitary tract (1). The activation of CNS GLP-1 receptors is related to some metabolic actions, such as food intake suppression, activation of brown adipose tissue, nutrient partitioning, and regulation of glucose homeostasis. The central injection of the GLP-1 agonist Ex-4 increased insulin secretion during hyperglycemia induced by intravenous infusion of glucose (2). Along the same lines, acute central administration of GLP-1 transiently lowered blood glucose levels (3) and increased insulin secretion in response to a glucose load (3, 4), whereas a GLP-1 receptor antagonist impaired glucose tolerance (3, 4). In the present issue, Jessen et al. (5) report that administration of the GLP-1 receptor antagonist Ex-9 in the third ventricle impairs insulin response to hyperglycemia and causes elevated postprandial glucose (5). Thus, these results indicate that endogenous brain GLP-1 may have an insulinotropic effect. However, the authors also found that the central administration of GLP-1 reduced insulin release and elevated glucagon secretion (Fig. 1), which ultimately increased fasting glucose (5). These last results were unexpected but are explainable by the effects of CNS GLP-1 on the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), both of which are known to produce hyperglycemia. In the study by Jessen et al. (5), central GLP-1 increased neuronal activity in brain regions (paraventricular nucleus and the nucleus of the solitary tract) mediating autonomic nervous system and HPA activation and stimulated circulating levels of corticosterone and epinephrine (5). These actions probably override and cofound the insulinotropic effect of endogenous CNS GLP-1. Importantly, the effects of CNS Ex-9 on impaired insulin secretion did not affect the autonomic nervous system and the HPA, implying that the main physiological role of brain GLP-1 involves the control of glucose metabolism. If this is the case, testing lower doses of GLP-1 might help clarify whether the insulinotropic action occurs when the activation of SNS and HPA is absent. Another important aspect of the current study is that central Ex-9 infusions disrupted the tight regulation of postprandial blood glucose found in rats freely ingesting a test meal, which occurred independently of changes in insulin secretion or gastric emptying (5). This means that during meals, CNS GLP-1 uses alternative mechanisms to control blood glucose, and according to previous studies, this alternative seems to be the control of hepatic metabolism. In line with this, under a ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in USA Copyright © 2017 Endocrine Society Received 28 April 2017. Accepted 5 May 2017. Abbreviations: CNS, central nervous system; GLP-1, glucagonlike peptide-1; HPA, hypothalamic–pituitary–adrenal; SNS, sympathetic nervous system. For article see page 2124 doi: 10.1210/en.2017-00410 Endocrinology, July 2017, 158(7):2071–2073 https://academic.oup.com/endo 2071 Downloaded from https://academic.oup.com/endo/article/158/7/2071/3920680 by guest on 15 February 2024 Instituto de Investigaciones Sanitarias, Centro de Investigaciones Médicas de la Universidad de Santiago (CIMUS), University of Santiago de Compostela, Santiago de Compostela 15782, Spain; 2Centro de Investigación Biomédica en Red (CIBER) Fisiopatologı́a de la Obesidad y Nutrición, Santiago de Compostela 15706, Spain; and 3Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain 2072 Tudurı́ and Nogueiras Insulinotropic Actions of GLP-1 Endocrinology, July 2017, 158(7):2071–2073 Downloaded from https://academic.oup.com/endo/article/158/7/2071/3920680 by guest on 15 February 2024 central mechanisms responding to changes in glucose and nutrient availability might also regulate the expression of GLP-1. Clearly, more studies are needed to assess these issues. On the other hand, given the complexity of the numerous neuronal pathways controlling glucose metabolism, it will be also important to identify the neuronal populations by which CNS GLP-1 regulates insulin secretion from islets and insulin sensitivity in other peripheral tissues such as liver, muscle, and adipose tissue. The hypothalamus and the brainstem, where Figure 1. Effects of activation (GLP-1) and blockade (GLP-1 antagonist) of central GLP-1 GLP-1 receptor is located, have been receptors on pancreatic hormone release. The central administration of the GLP-1 receptor studied largely as key centers for the antagonist Ex-9 in the third ventricle impairs insulin response to hyperglycemia and causes elevated postprandial glucose. However, the central administration of GLP-1 also reduced regulation of glucose metabolism. insulin release and elevated glucagon secretion. The effects of GLP-1 seem to be mediated by Therefore, it might be possible that the activation of the HPA axis and the SNS. different brain areas control different peripheral tissues affecting insulin secretion and sensitivity and glucose production and uptake. hyperinsulinemic–euglycemic clamp, activation of CNS Supporting this idea, the activation of GLP-1 receptors in GLP-1 receptor stimulates hepatic glycogen stores and the arcuate nucleus, but not in the paraventricular nucleus, decreases muscle insulin-stimulated glucose utilization reduces hepatic glucose production (4). This specificity (2). Moreover, the administration of GLP-1 directly into might also be important to dissect the different actions of the hypothalamic arcuate nucleus reduced hepatic gluCNS GLP-1, because the manipulation of GLP-1 receptor cose production (4). in some areas probably affects one function (i.e., insulin Despite compelling evidence indicating that brain secretion) but not others (e.g., stress, food intake). GLP-1 is a physiological modulator of glucose homeoAnother intriguing topic of the study by Jessen et al. (5) stasis, there is an ongoing debate on why GLP-1 would is the possibility that during meals, unlike in fasting need to reach the brain to control glucose metabolism if conditions, central GLP-1 action on blood glucose is not the entire machinery for exerting its antidiabetic actions is insulin dependent. Why and how CNS GLP-1 exerts its available in the periphery. An elegant article showed that effects depending on the nutrient status raises relevant pancreatic GLP-1 receptor activation is sufficient for the questions about the physiology of GLP-1. Importantly, effects of GLP-1 on glucose metabolism and that this most of the studies assessing the role of brain GLP-1 have effect does not require neural pathways (6), and a sepbeen done in animals fed a chow diet. If nutrient availability arate study reported that the lack of neuronal GLP-1 causes a switch in CNS GLP-1–dependent mechanisms, it receptor does not affect glucose metabolism (7). One seems plausible to hypothesize that these pathways might possibility is that disruption of CNS GLP-1 receptor in be different in lean and obese conditions. So far, in mice adulthood (achieved with pharmacological tools) and not fed a high-fat diet, central activation of GLP-1 receptor in embryonic stages (as it occurs in genetic models) is increased basal insulin levels and did not modify glucosenecessary to detect the importance of CNS GLP-1 in stimulated insulin secretion, whereas its blockade deglucose homeostasis. Thus, the use of more sophisticated creased hyperinsulinemia and reversed insulin resistance. tools such as pharmacogenetics, optogenetics, and inFinally, the most relevant question is perhaps how imducible knockouts would probably help clarify this issue. portant the CNS GLP-1 system is in controlling glucose Assuming that the CNS plays a relevant role in glucose metabolism in the clinical situation. GLP-1 receptor is indeed homeostasis, important aspects remain to be elucidated. expressed in the human brain. Functional studies in the One important caveat is the scarce knowledge on what human brain have obvious limitations, and to our knowledge regulates GLP-1 in the CNS. It has been reported that there is no clear evidence of an association between brain leptin and cholecystokinin modulate the activity of GLPGLP-1 and insulin sensitivity in humans. However, one study 1–expressing neurons, suggesting that central GLP-1 exindicated that intranasal GLP-1 administration had benefipression might be regulated by peripheral signals involved cial metabolic effects in patients with type 2 diabetes (8), and in energy homeostasis or glucose metabolism. Obviously, doi: 10.1210/en.2017-00410 these actions might be, at least partially, due to absorption of GLP-1 directly into the brain as it occurs with insulin. While endocrinologists wait for more answers, studies like the one from Jessen et al. (5) are helping to build on our understanding of the complex puzzle constituted by multiple organs and mechanisms of the GLP-1 biology. Acknowledgments References 1. Göke R, Larsen PJ, Mikkelsen JD, Sheikh SP. Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci. 1995;7(11):2294–2300. 2073 2. Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Grémeaux T, Drucker DJ, Kahn CR, Girard J, Tanti JF, Delzenne NM, Postic C, Burcelin R. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest. 2005;115(12):3554–3563. 3. Tudurı́ E, Beiroa D, Porteiro B, López M, Diéguez C, Nogueiras R. Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice. Diabetes Obes Metab. 2015;17(8):789–799. 4. Sandoval DA, Bagnol D, Woods SC, D’Alessio DA, Seeley RJ. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes. 2008;57(8):2046–2054. 5. Jessen L, Smith EP, Ulrich-Lai Y, Herman JP, Seeley RJ, Sandoval D, D’Alessio D. Central nervous system GLP-1 receptors regulate islet hormone secretion and glucose homeostasis in male rats. Endocrinology. 2017;158(7):2124–2133. 6. Lamont BJ, Li Y, Kwan E, Brown TJ, Gaisano H, Drucker DJ. Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice. J Clin Invest. 2012;122(1): 388–402. 7. Sisley S, Gutierrez-Aguilar R, Scott M, D’Alessio DA, Sandoval DA, Seeley RJ. Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect. J Clin Invest. 2014;124(6):2456–2463. 8. Ueno H, Mizuta M, Shiiya T, Tsuchimochi W, Noma K, Nakashima N, Fujihara M, Nakazato M. Exploratory trial of intranasal administration of glucagon-like peptide-1 in Japanese patients with type 2 diabetes. Diabetes Care. 2014;37(7):2024–2027. Downloaded from https://academic.oup.com/endo/article/158/7/2071/3920680 by guest on 15 February 2024 Address all correspondence and requests for reprints to: Ruben Nogueiras, PhD, Department of Physiology, Centro de Investigaciones Médicas de la Universidad de Santiago, University of Santiago de Compostela, and Centro de Investigación Biomédica en Red (CIBER) Fisiopatologı́a de la Obesidad y Nutrición, Avda de Barcelona s/n, 15782 Santiago de Compostela (A Coru~ na), Spain. E-mail: ruben.nogueiras@usc.es. Disclosure Summary: The authors have nothing to disclose. https://academic.oup.com/endo

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Insulinotropic Actions of GLP-1: How Much in the Brain and How Much in the Periphery?