scholarly journals Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding

2014 ◽  
Vol 307 (4) ◽  
pp. R465-R470 ◽  
Author(s):  
Amber L. Alhadeff ◽  
Harvey J. Grill
Keyword(s):  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Progressive Ratio ◽  
Ratio Schedule ◽  
Inhibitory Effects ◽  
Medial Nucleus ◽  
Neural Processes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Central glucagon-like peptide-1 receptor (GLP-1R) signaling reduces food intake by affecting a variety of neural processes, including those mediating satiation, motivation, and reward. While the literature suggests that separable neurons and circuits control these processes, this notion has not been adequately investigated. The intake inhibitory effects of GLP-1R signaling in the hindbrain medial nucleus tractus solitarius (mNTS) have been attributed to interactions with vagally transmitted gastrointestinal satiation signals that are also processed by these neurons. Here, behavioral and pharmacological techniques are used to test the novel hypothesis that the reduction of food intake following mNTS GLP-1R stimulation also results from effects on food-motivated appetitive behaviors. Results show that mNTS GLP-1R activation by microinjection of exendin-4, a long-acting GLP-1R agonist, reduced 1) intake of a palatable high-fat diet, 2) operant responding for sucrose under a progressive ratio schedule of reinforcement and 3) the expression of a conditioned place preference for a palatable food. Together, these data demonstrate that the intake inhibitory effects of mNTS GLP-1R signaling extend beyond satiation and include effects on food reward and motivation that are typically ascribed to midbrain and forebrain neurons.

scholarly journals GLP-1 and weight loss: unraveling the diverse neural circuitry

2016 ◽  
Vol 310 (10) ◽  
pp. R885-R895 ◽  
Author(s):  
Scott E. Kanoski ◽  
Matthew R. Hayes ◽  
Karolina P. Skibicka
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Direct Action ◽  
Neural Systems ◽  
Reduce Food Intake ◽  
Hypothalamic Area ◽  
Medial Nucleus ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Glucagon-like peptide-1 (GLP-1) is currently one of the most promising biological systems for the development of effective obesity pharmacotherapies. Long-acting GLP-1 analogs potently reduce food intake and body weight, and recent discoveries reveal that peripheral administration of these drugs reduces food intake largely through humoral pathways involving direct action on brain GLP-1 receptors (GLP-1R). Thus, it is of critical importance to understand the neural systems through which GLP-1 and long-acting GLP-1 analogs reduce food intake and body weight. In this review, we discuss several neural, physiological, cellular and molecular, as well as behavioral mechanisms through which peripheral and central GLP-1R signaling reduces feeding. Particular attention is devoted to discussion regarding the numerous neural substrates through which GLP-1 and GLP-1 analogs act to reduce food intake and body weight, including various hypothalamic nuclei (arcuate nucleus of the hypothalamus, periventricular hypothalamus, lateral hypothalamic area), hindbrain nuclei (parabrachial nucleus, medial nucleus tractus solitarius), hippocampus (ventral subregion; vHP), and nuclei embedded within the mesolimbic reward circuitry [ventral tegmental area (VTA) and nucleus accumbens (NAc)]. In some of these nuclei [VTA, NAc, and vHP], GLP-1R activation reduces food intake and body weight without concomitant nausea responses, suggesting that targeting these specific pathways may be of particular interest for future obesity pharmacotherapy. The widely distributed neural systems through which GLP-1 and GLP-1 analogs act to reduce body weight highlight the complexity of the neural systems regulating energy balance, as well as the challenges for developing effective obesity pharmacotherapies that reduce feeding without producing parallel negative side effects.

The inhibitory effects of peripheral administration of peptide YY3–36 and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal–brainstem–hypothalamic pathway

2005 ◽  
Vol 1044 (1) ◽  
pp. 127-131 ◽  
Author(s):  
Caroline R. Abbott ◽  
Mariana Monteiro ◽  
Caroline J. Small ◽  
Arshia Sajedi ◽  
Kirsty L. Smith ◽  
...  
Keyword(s):  
Food Intake ◽  
Inhibitory Effects ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Peripheral and Central GLP-1 Receptor Populations Mediate the Anorectic Effects of Peripherally Administered GLP-1 Receptor Agonists, Liraglutide and Exendin-4

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3103-3112 ◽  
Author(s):  
Scott E. Kanoski ◽  
Samantha M. Fortin ◽  
Myrtha Arnold ◽  
Harvey J. Grill ◽  
Matthew R. Hayes
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Body Weight ◽  
Food Intake ◽  
Vagal Afferents ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting ◽  
Higher Doses ◽  
Cns Delivery

The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after ip delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [third intracerebroventricular (3rd ICV)] of the GLP-1R antagonist exendin-(9–39) (100 μg), attenuated the intake suppression by ip liraglutide (10 μg) and exendin-4 (3 μg), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9–39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after ip delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4. Conclusion: Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.

scholarly journals The Effects of Mutual Interaction of Orexin-A and Glucagon-Like Peptide-1 on Reflex Swallowing Induced by SLN Afferents in Rats

2020 ◽  
Vol 21 (12) ◽  
pp. 4422
Author(s):  
Motoi Kobashi ◽  
Yuichi Shimatani ◽  
Masako Fujita ◽  
Yoshihiro Mitoh ◽  
Ryusuke Yoshida ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Nucleus Tractus Solitarius ◽  
Superior Laryngeal Nerve ◽  
Mutual Interaction ◽  
Sprague Dawley ◽  
Orexin A ◽  
Medial Nucleus ◽  
Sprague Dawley Rats ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

(1) Background: Our previous studies revealed that orexin-A, an appetite-increasing peptide, suppressed reflex swallowing via the commissural part of the nucleus tractus solitarius (cNTS), and that glucagon-like peptide-1 (GLP-1), an appetite-reducing peptide, also suppressed reflex swallowing via the medial nucleus of the NTS (mNTS). In this study, we examined the mutual interaction between orexin-A and GLP-1 in reflex swallowing. (2) Methods: Sprague–Dawley rats under urethane–chloralose anesthesia were used. Swallowing was induced by electrical stimulation of the superior laryngeal nerve (SLN) and was identified by the electromyographic (EMG) signals obtained from the mylohyoid muscle. (3) Results: The injection of GLP-1 (20 pmol) into the mNTS reduced the swallowing frequency and extended the latency of the first swallow. These suppressive effects of GLP-1 were not observed after the fourth ventricular administration of orexin-A. After the injection of an orexin-1 receptor antagonist (SB334867) into the cNTS, an ineffective dose of GLP-1 (6 pmol) into the mNTS suppressed reflex swallowing. Similarly, the suppressive effects of orexin-A (1 nmol) were not observed after the injection of GLP-1 (6 pmol) into the mNTS. After the administration of a GLP-1 receptor antagonist (exendin-4(5-39)), an ineffective dose of orexin-A (0.3 nmol) suppressed reflex swallowing. (4) Conclusions: The presence of reciprocal inhibitory connections between GLP-1 receptive neurons and orexin-A receptive neurons in the NTS was strongly suggested.

scholarly journals Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake

2011 ◽  
Vol 301 (6) ◽  
pp. R1755-R1764 ◽  
Author(s):  
Naomi J. McKay ◽  
Scott E. Kanoski ◽  
Matthew R. Hayes ◽  
Derek Daniels
Keyword(s):  
Food Intake ◽  
Water Intake ◽  
Intraperitoneal Administration ◽  
Time Frame ◽  
Receptor Agonists ◽  
Mediated Effects ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
Long Acting

Glucagon-like peptide-1 (GLP-1) is produced by and released from the small intestine following ingestion of nutrients. GLP-1 receptor (GLP-1R) agonists applied peripherally or centrally decrease food intake and increase glucose-stimulated insulin secretion. These effects make the GLP-1 system an attractive target for the treatment of type 2 diabetes mellitus and obesity. In addition to these more frequently studied effects of GLP-1R stimulation, previous reports indicate that GLP-1R agonists suppress water intake. The present experiments were designed to provide greater temporal resolution and site specificity for the effect of GLP-1 and the long-acting GLP-1R agonists, exendin-4 and liraglutide, on unstimulated water intake when food was and was not available. All three GLP-1R ligands suppressed water intake after peripheral intraperitoneal administration, both in the presence of and the absence of food; however, the magnitude and time frame of water intake suppression varied by drug. GLP-1 had an immediate, but transient, hypodipsic effect when administered peripherally, whereas the water intake suppression by IP exendin-4 and liraglutide was much more persistent. Additionally, intracerebroventricular administration of GLP-1R agonists suppressed water intake when food was absent, but the suppression of intake showed modest differences depending on whether the drug was administered to the lateral or fourth ventricle. To the best of our knowledge, this is the first demonstration of GLP-1 receptor agonists affecting unstimulated, overnight intake in the absence of food, the first test for antidipsogenic effects of hindbrain application of GLP-1 receptor agonists, and the first test of a central effect (forebrain or hindbrain) of liraglutide on water intake. Overall, these results show that GLP-1R agonists have a hypodipsic effect that is independent of GLP-1R-mediated effects on food intake, and this occurs, in part, through central nervous system GLP-1R activation.

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 NTS and VTA oxytocin reduces food motivation and food seeking

2020 ◽  
Vol 319 (6) ◽  
pp. R673-R683 ◽  
Author(s):  
Hallie S. Wald ◽  
Ananya Chandra ◽  
Anita Kalluri ◽  
Zhi Yi Ong ◽  
Matthew R. Hayes ◽  
...  
Keyword(s):  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Progressive Ratio ◽  
Food Motivation ◽  
Inhibitory Effects ◽  
Self Administration ◽  
Seeking Behavior ◽  
Operant Reinforcement ◽  
Food Seeking

Oxytocin (OT) is a neuropeptide whose central receptor-mediated actions include reducing food intake. One mechanism of its behavioral action is the amplification of the feeding inhibitory effects of gastrointestinal (GI) satiation signals processed by hindbrain neurons. OT treatment also reduces carbohydrate intake in humans and rodents, and correspondingly, deficits in central OT receptor (OT-R) signaling increase sucrose self-administration. This suggests that additional processes contribute to central OT effects on feeding. This study investigated the hypothesis that central OT reduces food intake by decreasing food seeking and food motivation. As central OT-Rs are expressed widely, a related focus was to assess the role of one or more OT-R-expressing nuclei in food motivation and food-seeking behavior. OT was delivered to the lateral ventricle (LV), nucleus tractus solitarius (NTS), or ventral tegmental area (VTA), and a progressive ratio (PR) schedule of operant reinforcement and an operant reinstatement paradigm were used to measure motivated feeding behavior and food-seeking behavior, respectively. OT delivered to the LV, NTS, or VTA reduced 1) motivation to work for food and 2) reinstatement of food-seeking behavior. Results provide a novel and additional interpretation for central OT-driven food intake inhibition to include the reduction of food motivation and food seeking.

scholarly journals Medial nucleus tractus solitarius oxytocin receptor signaling and food intake control: the role of gastrointestinal satiation signal processing

2015 ◽  
Vol 308 (9) ◽  
pp. R800-R806 ◽  
Author(s):  
Zhi Yi Ong ◽  
Amber L. Alhadeff ◽  
Harvey J. Grill
Keyword(s):  
Signal Processing ◽  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Oxytocin Receptor ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Medial Nucleus ◽  
A Site ◽  
Intake Control

Central oxytocin (OT) administration reduces food intake and its effects are mediated, in part, by hindbrain oxytocin receptor (OT-R) signaling. The neural substrate and mechanisms mediating the intake inhibitory effects of hindbrain OT-R signaling are undefined. We examined the hypothesis that hindbrain OT-R-mediated feeding inhibition results from an interaction between medial nucleus tractus solitarius (mNTS) OT-R signaling and the processing of gastrointestinal (GI) satiation signals by neurons of the mNTS. Here, we demonstrated that mNTS or fourth ventricle (4V) microinjections of OT in rats reduced chow intake in a dose-dependent manner. To examine whether the intake suppressive effects of mNTS OT-R signaling is mediated by GI signal processing, rats were injected with OT to the 4V (1 μg) or mNTS (0.3 μg), followed by self-ingestion of a nutrient preload, where either treatment was designed to be without effect on chow intake. Results showed that the combination of mNTS OT-R signaling and GI signaling processing by preload ingestion reduced chow intake significantly and to a greater extent than either stimulus alone. Using enzyme immunoassay, endogenous OT content in mNTS-enriched dorsal vagal complex (DVC) in response to ingestion of nutrient preload was measured. Results revealed that preload ingestion significantly elevated endogenous DVC OT content. Taken together, these findings provide evidence that mNTS neurons are a site of action for hindbrain OT-R signaling in food intake control and that the intake inhibitory effects of hindbrain mNTS OT-R signaling are mediated by interactions with GI satiation signal processing by mNTS neurons.

scholarly journals TrkB receptor signaling in the nucleus tractus solitarius mediates the food intake-suppressive effects of hindbrain BDNF and leptin

2012 ◽  
Vol 302 (10) ◽  
pp. E1252-E1260 ◽  
Author(s):  
Andrea M. Spaeth ◽  
Scott E. Kanoski ◽  
Matthew R. Hayes ◽  
Harvey J. Grill
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Receptor Antagonist ◽  
Nucleus Tractus Solitarius ◽  
Receptor Activation ◽  
Reduce Food Intake ◽  
Receptor Signaling ◽  
Inhibitory Effects ◽  
Trkb Receptor ◽  
Medial Nucleus

Brain-derived neurotrophic factor (BDNF) and TrkB receptor signaling contribute to the central nervous system (CNS) control of energy balance. The role of hindbrain BDNF/TrkB receptor signaling in energy balance regulation is examined here. Hindbrain ventricular BDNF suppressed body weight through reductions in overall food intake and meal size and by increasing core temperature. To localize the neurons mediating the energy balance effects of hindbrain ventricle-delivered BDNF, ventricle subthreshold doses were delivered directly to medial nucleus tractus solitarius (mNTS). mNTS BDNF administration reduced food intake significantly, and this effect was blocked by preadministration of a highly selective TrkB receptor antagonist {[N2–2-2-Oxoazepan-3-yl amino]carbonyl phenyl benzo (b)thiophene-2-carboxamide (ANA-12)}, suggesting that TrkB receptor activation mediates hindbrain BDNF's effect on food intake. Because both BDNF and leptin interact with melanocortin signaling to reduce food intake, we also examined whether the intake inhibitory effects of hindbrain leptin involve hindbrain-specific BDNF/TrkB activation. BDNF protein content within the dorsal vagal complex of the hindbrain was increased significantly by hindbrain leptin delivery. To assess if BDNF/TrkB receptor signaling acts downstream of leptin signaling in the control of energy balance, leptin and ANA-12 were coadministered into the mNTS. Administration of the TrkB receptor antagonist attenuated the intake-suppressive effects of leptin, suggesting that mNTS TrkB receptor activation contributes to the mediation of the anorexigenic effects of hindbrain leptin. Collectively, these results indicate that TrkB-mediated signaling in the mNTS negatively regulates food intake and, in part, the intake inhibitory effects of leptin administered into the NTS.

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