scholarly journals Paraventricular Thalamic Control of Food Intake and Reward: Role of Glucagon-Like Peptide-1 Receptor Signaling

2017 ◽  
Vol 42 (12) ◽  
pp. 2387-2397 ◽  
Author(s):  
Zhi Yi Ong ◽  
Jing-Jing Liu ◽  
Zhiping P Pang ◽  
Harvey J Grill
Keyword(s):  
Food Intake ◽  
Receptor Signaling ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors

2013 ◽  
Vol 305 (11) ◽  
pp. E1367-E1374 ◽  
Author(s):  
Elizabeth G. Mietlicki-Baase ◽  
Pavel I. Ortinski ◽  
Laura E. Rupprecht ◽  
Diana R. Olivos ◽  
Amber L. Alhadeff ◽  
...  
Keyword(s):  
Food Intake ◽  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Kainate Receptors ◽  
System Control ◽  
Receptor Signaling ◽  
Palatable Food ◽  
Glucagon Like Peptide ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 receptor (GLP-1R) activation in the ventral tegmental area (VTA) is physiologically relevant for the control of palatable food intake. Here, we tested whether the food intake-suppressive effects of VTA GLP-1R activation are mediated by glutamatergic signaling within the VTA. Intra-VTA injections of the GLP-1R agonist exendin-4 (Ex-4) reduced palatable high-fat food intake in rats primarily by reducing meal size; these effects were mediated in part via glutamatergic AMPA/kainate but not NMDA receptor signaling. Additional behavioral data indicated that GLP-1R expressed specifically within the VTA can partially mediate the intake- and body weight-suppressive effects of systemically administered Ex-4, offering the intriguing possibility that this receptor population may be clinically relevant for food intake control. Intra-VTA Ex-4 rapidly increased tyrosine hydroxylase levels within the VTA, suggesting that GLP-1R activation modulates VTA dopaminergic signaling. Further evidence for this hypothesis was provided by electrophysiological data showing that Ex-4 increased the frequency of AMPA-mediated currents and reduced the paired/pulse ratio in VTA dopamine neurons. Together, these data provide novel mechanisms by which GLP-1R agonists in the mesolimbic reward system control for palatable food intake.

scholarly journals Role of the neural pathway from hindbrain to hypothalamus in interaction of GLP1 and leptin in rats

2013 ◽  
Vol 220 (2) ◽  
pp. 109-116 ◽  
Author(s):  
Sayaka Akieda-Asai ◽  
Paul-Emile Poleni ◽  
Kazuya Hasegawa ◽  
Yukari Date
Keyword(s):  
Food Intake ◽  
Neural Pathway ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP1) and leptin are anorectic hormones. Previously, we have shown that i.p. coadministration of subthreshold GLP1 with leptin dramatically reduced food intake in rats. In this study, by using midbrain-transected rats, we investigated the role of the neural pathway from the hindbrain to the hypothalamus in the interaction of GLP1 and leptin in reducing food intake. Food intake reduction induced by coinjection of GLP1 and leptin was blocked in midbrain-transected rats. These findings indicate that the ascending neural pathway from the hindbrain plays an important role in transmitting the anorectic signals provided by coinjection of GLP1 and leptin.

scholarly journals Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS

2013 ◽  
Vol 221 (1) ◽  
pp. T1-T16 ◽  
Author(s):  
L van Bloemendaal ◽  
J S ten Kulve ◽  
S E la Fleur ◽  
R G Ijzerman ◽  
M Diamant
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Physiological Role ◽  
Brain Regions ◽  
Gastric Distension ◽  
Cns Activity ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The delivery of nutrients to the gastrointestinal tract after food ingestion activates the secretion of several gut-derived mediators, including the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 receptor agonists (GLP-1RA), such as exenatide and liraglutide, are currently employed successfully in the treatment of patients with type 2 diabetes mellitus. GLP-1RA improve glycaemic control and stimulate satiety, leading to reductions in food intake and body weight. Besides gastric distension and peripheral vagal nerve activation, GLP-1RA induce satiety by influencing brain regions involved in the regulation of feeding, and several routes of action have been proposed. This review summarises the evidence for a physiological role of GLP-1 in the central regulation of feeding behaviour and the different routes of action involved. Also, we provide an overview of presently available data on pharmacological stimulation of GLP-1 pathways leading to alterations in CNS activity, reductions in food intake and weight loss.

scholarly journals Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control

2016 ◽  
Vol 42 (7) ◽  
pp. 1471-1479 ◽  
Author(s):  
Amber L Alhadeff ◽  
Blake D Mergler ◽  
Derek J Zimmer ◽  
Christopher A Turner ◽  
David J Reiner ◽  
...  
Keyword(s):  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Receptor Signaling ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Intake Control

scholarly journals GLP-1 receptor signaling contributes to anorexigenic effect of centrally administered oxytocin in rats

2002 ◽  
Vol 283 (1) ◽  
pp. R99-R106 ◽  
Author(s):  
Linda Rinaman ◽  
Elizabeth E. Rothe
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Male Rats ◽  
Neural Systems ◽  
Neural Pathways ◽  
Receptor Signaling ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Access To Food ◽  
Anorexigenic Effect

The present study examined possible interactions between central glucagon-like peptide-1 (GLP-1) and oxytocin (OT) neural systems by determining whether blockade of GLP-1 receptors attenuates OT-induced anorexia and vice versa. Male rats were acclimated to daily 4-h food access. In the first experiment, rats were infused centrally with GLP-1 receptor antagonist or vehicle, followed by an anorexigenic dose of synthetic OT. Access to food began 20 min later. Cumulative food intake was measured every 30 min for 4 h. In the second experiment, rats were infused with OT receptor blocker or vehicle, followed by synthetic GLP-1 [(7–36) amide]. Subsequent food intake was monitored as before. The anorexigenic effect of OT was eliminated in rats pretreated with the GLP-1 receptor antagonist. Conversely, GLP-1-induced anorexia was not affected by blockade of OT receptors. In a separate immunocytochemical study, OT-positive terminals were found closely apposed to GLP-1-positive perikarya, and central infusion of OT activated c-Fos expression in GLP-1 neurons. These findings implicate endogenous GLP-1 receptor signaling as an important downstream mediator of anorexia in rats after activation of central OT neural pathways.

Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

2013 ◽  
Vol 304 (7) ◽  
pp. E677-E685 ◽  
Author(s):  
Melissa A. Burmeister ◽  
Jennifer Ayala ◽  
Daniel J. Drucker ◽  
Julio E. Ayala
Keyword(s):  
Food Intake ◽  
Glucose Metabolism ◽  
Dependent Manner ◽  
Anorectic Effect ◽  
Dependent Inhibition ◽  
Glycolytic Inhibitor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Amp Activated Protein Kinase ◽  
Mediated Reduction

Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.

scholarly journals SAT-604 The Role of the Focal Adhesion Kinase Family in Leptin Receptor Signaling

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Colleen Hadley ◽  
Isin Cakir ◽  
Roger D Cone
Keyword(s):  
Food Intake ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Leptin Receptor ◽  
Kinase Activity ◽  
Cytokine Receptor ◽  
Receptor Signaling ◽  
Kinase Family ◽  
Stat3 Phosphorylation

Abstract Overweight and obesity are global concerns affecting nearly one third of the world population. These conditions are characterized by increased adiposity and are accompanied by a proportional increase in circulating leptin, an anorexigenic adipokine. Leptin is responsible for signaling peripheral energy status to the central nervous system to modulate food intake and energy expenditure. As such, neurons within the hypothalamus expressing the long isoform of leptin receptor (LepRb), a type I cytokine receptor, are primarily responsible for mediating the effects of leptin, which signal predominantly through the JAK2-STAT3 transduction mechanism. STAT3 is a latent transcription factor activated upon phosphorylation, which triggers its homodimerization and nuclear translocation. Evidence, however, for JAK2-independent, STAT3-dependent leptin receptor signaling mechanisms exist. FAK (focal adhesion kinase, Ptk2) and Pyk2 (protein tyrosine kinase 2b, Ptk2b) are a subset of nonreceptor protein tyrosine kinases and comprise the focal adhesion kinase family. FAK and Pyk2 are implicated in the regulation of cytokine receptor signaling. Furthermore, Pyk2 knockout mice have an obesity prone phenotype. Here, we studied the role of the focal adhesion kinases in leptin receptor signaling using genetic and pharmacological approaches. We found that overexpression of Pyk2 or FAK increased STAT3 phosphorylation (activation). Overexpression of a FAK or Pyk2 construct with impaired kinase activity, however, attenuated STAT3 phosphorylation, suggesting the increase in STAT3 phosphorylation is largely dependent upon kinase activity of FAK/Pyk2. Treatment of cells with a small molecule dual inhibitor of FAK and Pyk2 (PF431396) attenuated leptin-induced STAT3 phosphorylation in a mouse hypothalamic cell line. Importantly, this effect is independent of JAK2, as PF treatment of two independent JAK2-deficient cell lines exhibited similar attenuation of leptin-induced STAT3 phosphorylation. To assess the physiological relevance of FAK/Pyk2 in leptin receptor signaling in vivo, we administered PF compound to the lateral ventricle of 24-hour fasted lean wild-type mice followed by peripheral leptin administration. Intracerebroventricular (ICV) administration of PF suppressed the anorectic effect of leptin as evidenced by impaired inhibition of food intake upon refeeding. Accordingly, analysis of total hypothalamic lysates from these mice showed ICV PF impaired leptin-induced STAT3 phosphorylation. Taken together, these data suggest that Pyk2 and/or FAK play a role in leptin signal transduction.

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