Glucagon-like peptide 1-(7–36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats

2003 ◽  
Vol 284 (6) ◽  
pp. R1427-R1435 ◽  
Author(s):  
Rafael R. Schick ◽  
Jens P. Zimmermann ◽  
Thomas vorm Walde ◽  
Volker Schusdziarra
Keyword(s):  
Food Intake ◽  
Feeding Behavior ◽  
Effective Dose ◽  
Ventromedial Hypothalamus ◽  
Brain Regions ◽  
Central Administration ◽  
Minimal Effective Dose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Fasted Rats

Glucagon-like peptide 1-(7–36) amide (GLP-1) potently inhibits rat feeding behavior after central administration. Because third ventricular injection of GLP-1 appeared to be less effective than lateral ventricular injection, we have reexamined this issue. In addition, we attempted to identify brain regions other than the paraventricular nucleus of the hypothalamus that are sensitive toward GLP-1-induced feeding suppression. Finally, we examined the local role of endogenous GLP-1 by specific GLP-1 receptor blockade. After lateral ventricular injection, GLP-1 significantly inhibited food intake of 24-h-fasted rats in a dose-dependent fashion with a minimal effective dose of 1 μg. After third ventricular injection, GLP-1 (1 μg) was similarly effective in suppressing food intake, which extends previous findings. Intracerebral microinjections of GLP-1 significantly suppressed food intake in the lateral (LH), dorsomedial (DMH), and ventromedial hypothalamus (VMH), but not in the medial nucleus of the amygdala. The minimal effective dose of GLP-1 was 0.3 μg at LH sites and 1 μg at DMH or VMH sites. LH microinjections of exendin-(9–39) amide, a GLP-1 receptor antagonist, at 1 or 2.5 μg did not alter feeding behavior in 24-h-fasted rats. In satiated animals, however, a single LH injection of 1 μg exendin-(9–39) amide significantly augmented food intake, but only during the first 20 min (0.6 vs. 0.1 g). With three repeated injections of 2.5 μg exendin-(9–39) amide every 20 min, 1-h food intake was significantly increased by 300%. These data strongly support and extend the concept of GLP-1 as a physiological regulator of food intake in the hypothalamus.

scholarly journals Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats

1997 ◽  
Vol 272 (2) ◽  
pp. R726-R730 ◽  
Author(s):  
T. E. Thiele ◽  
G. Van Dijk ◽  
L. A. Campfield ◽  
F. J. Smith ◽  
P. Burn ◽  
...  
Keyword(s):  
Side Effects ◽  
Food Intake ◽  
Consummatory Behavior ◽  
Central Administration ◽  
Short Term ◽  
Nonspecific Effects ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Ob Protein

Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogenous regulatory agents, central administration of these peptides may have aversive side effects, which could explain the anorexia. In the present experiment, exposure to a saccharine taste was immediately followed by central administration of leptin or GLP-1 to determine if these drugs could produce a conditioned taste aversion (CTA) in rats. At doses equated for producing comparable reductions in short-term food intake, GLP-1, but not leptin, generated a robust CTA. Although leptin caused no aversion, this peptide was the only drug to cause relatively long-term reductions in food consumption (16 h) and body weight (24 h). Hence, the results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLP-1.

scholarly journals Glucagon-Like Peptide-1 (GLP-1) in the Integration of Neural and Endocrine Responses to Stress

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3304
Author(s):  
Yolanda Diz-Chaves ◽  
Salvador Herrera-Pérez ◽  
Lucas C. González-Matías ◽  
José Antonio Lamas ◽  
Federico Mallo
Keyword(s):  
Food Intake ◽  
Feeding Behavior ◽  
Stress Responses ◽  
Food Motivation ◽  
Hedonic Value ◽  
Central Actions ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Second Messenger Pathways ◽  
The Brain

Glucagon like-peptide 1 (GLP-1) within the brain is produced by a population of preproglucagon neurons located in the caudal nucleus of the solitary tract. These neurons project to the hypothalamus and another forebrain, hindbrain, and mesolimbic brain areas control the autonomic function, feeding, and the motivation to feed or regulate the stress response and the hypothalamic-pituitary-adrenal axis. GLP-1 receptor (GLP-1R) controls both food intake and feeding behavior (hunger-driven feeding, the hedonic value of food, and food motivation). The activation of GLP-1 receptors involves second messenger pathways and ionic events in the autonomic nervous system, which are very relevant to explain the essential central actions of GLP-1 as neuromodulator coordinating food intake in response to a physiological and stress-related stimulus to maintain homeostasis. Alterations in GLP-1 signaling associated with obesity or chronic stress induce the dysregulation of eating behavior. This review summarized the experimental shreds of evidence from studies using GLP-1R agonists to describe the neural and endocrine integration of stress responses and feeding behavior.

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 The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity

2017 ◽  
Vol 313 (6) ◽  
pp. E651-E662 ◽  
Author(s):  
Melissa A. Burmeister ◽  
Jacob D. Brown ◽  
Jennifer E. Ayala ◽  
Doris A. Stoffers ◽  
Darleen A. Sandoval ◽  
...  
Keyword(s):  
Food Intake ◽  
Mammalian Target Of Rapamycin ◽  
Chinese Hamster ◽  
Ventromedial Hypothalamus ◽  
Anorectic Effect ◽  
Inhibition Of Glycolysis ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Amp Activated Protein Kinase ◽  
Nutrient Homeostasis

Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH Glp1r conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis.

scholarly journals Potential modulation of plasma ghrelin and glucagon-like peptide-1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide

2004 ◽  
Vol 92 (5) ◽  
pp. 757-761 ◽  
Author(s):  
Patrice D. Cani ◽  
Maite Lasa Montoya ◽  
Audrey M. Neyrinck ◽  
Nathalie M. Delzenne ◽  
Didier M. Lambert
Keyword(s):  
Gastrointestinal Tract ◽  
Food Intake ◽  
Receptor Antagonist ◽  
Food Consumption ◽  
Cannabinoid Receptor ◽  
Short Term ◽  
Cannabinoid Compounds ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Fasted Rats

The CB1 cannabinoid receptor antagonist, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant; SR141716A), and oleoylethanolamide (OEA) are known to reduce food consumption, by, at least partially, a peripheral regulation of feeding. The effects of systemic SR141716A or OEA (5 mg/kg) administrations on food consumption in 24 h food-deprived and fed rats were investigated. In fasted rats, SR141716A and OEA produced an inhibition in food intake measurable the first 20 min following injection. The increase in ghrelin levels observed in the vehicle-injected rats was abolished in animals receiving OEA and significantly reduced with SR141716A. Neither OEA nor SR141716A modified glucagon-like peptide-1 (7–36) amide portal levels 20 min after the administration. In fed rats, plasma ghrelin levels of SR141716A- and OEA-treated rats were 35% lower as compared with those of the vehicle-injected rats. These results show an influence of cannabinoid agents on circulating ghrelin levels and suggest that their short-term action on appetite seems to be in accordance with the control of secretion of gastrointestinal orexigenic peptides, mainly expressed in the upper part of the gastrointestinal tract.

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 Hindbrain glucagon-like peptide-1 neurons track intake volume and contribute to injection stress-induced hypophagia in meal-entrained rats

2016 ◽  
Vol 310 (10) ◽  
pp. R906-R916 ◽  
Author(s):  
Alison D. Kreisler ◽  
Linda Rinaman
Keyword(s):  
Food Intake ◽  
Potential Role ◽  
Liquid Diet ◽  
Neural Activation ◽  
Intracerebroventricular Injection ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Diet Intake ◽  
Published Research ◽  
Diet Type

Published research supports a role for central glucagon-like peptide 1 (GLP-1) signaling in suppressing food intake in rodent species. However, it is unclear whether GLP-1 neurons track food intake and contribute to satiety, and/or whether GLP-1 signaling contributes to stress-induced hypophagia. To examine whether GLP-1 neurons track intake volume, rats were trained to consume liquid diet (LD) for 1 h daily until baseline intake stabilized. On test day, schedule-fed rats consumed unrestricted or limited volumes of LD or unrestricted volumes of diluted (calorically matched to LD) or undiluted Ensure. Rats were perfused after the test meal, and brains processed for immunolocalization of cFos and GLP-1. The large majority of GLP-1 neurons expressed cFos in rats that consumed satiating volumes, regardless of diet type, with GLP-1 activation proportional to intake volume. Since GLP-1 signaling may limit intake only when such large proportions of GLP-1 neurons are activated, a second experiment examined the effect of central GLP-1 receptor (R) antagonism on 2 h intake in schedule-fed rats. Compared with baseline, intracerebroventricular vehicle (saline) suppressed Ensure intake by ∼11%. Conversely, intracerebroventricular injection of vehicle containing GLP-1R antagonist increased intake by ∼14% compared with baseline, partly due to larger second meals. We conclude that GLP-1 neural activation effectively tracks liquid diet intake, that intracerebroventricular injection suppresses intake, and that central GLP-1 signaling contributes to this hypophagic effect. GLP-1 signaling also may contribute to satiety after large volumes have been consumed, but this potential role is difficult to separate from a role in the hypophagic response to intracerebroventricular injection.

scholarly journals Effect of Chronic Central Administration of Glucagon-Like Peptide-1 (7-36) Amide on Food Consumption and Body Weight in Normal and Obese Rats

1998 ◽  
Vol 6 (2) ◽  
pp. 147-156 ◽  
Author(s):  
Harry R. Davis ◽  
Deborra E. Mullins ◽  
Jesse M. Pines ◽  
Lizbeth M. Hoos ◽  
Constance F. France ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Consumption ◽  
Central Administration ◽  
Obese Rats ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Genetic variation affects binge feeding behavior in female inbred mouse strains

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Brandon A. Newmyer ◽  
Ciarra M. Whindleton ◽  
Nandan Srinivasa ◽  
Marieke K. Jones ◽  
Michael M. Scott
Keyword(s):  
Genetic Variation ◽  
Food Intake ◽  
Feeding Behavior ◽  
Inbred Mouse ◽  
Treatment Strategies ◽  
Brain Regions ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Behavioral Differences ◽  
Calorie Diet

Abstract Identifying genetic variants that regulate binge eating (BE) is critical for understanding the factors that control this behavior and for the development of pharmacological treatment strategies. Although several studies have revealed specific genes capable of affecting BE behavior, less is known about how genetic variation modulates BE. Thus, through a paradigm that promoted binge-like food intake through intermittent access to high calorie diet (HCD), we quantified food-intake in four inbred mouse strains: C57Bl/6J (B6), NOD/LtJ (NOD), 129S1/SvlmJ (S1), and A/J (AJ). We report that genetic variation likely influences the chronic regulation of food intake and the binge-like consumption of a palatable HCD. AJ mice consumed more of both standard chow and HCD than the other three strains tested when both diets were available ad libitum, while S1 mice consumed significantly less HCD than other strains during intermittent HCD access. Behavioral differences were also associated with differential changes in c-Fos immunohistochemistry in brain regions traditionally associated with appetite regulation. Our results identify 129S1/SvlmJ as a strain that exhibits low levels of binge feeding behavior and suggests that this strain could be useful in the investigation of the influence of genetic variation in the control of binge food intake.

Modulation of feeding by endogenous sugar acids acting as hunger or satiety factors

1984 ◽  
Vol 246 (4) ◽  
pp. R542-R550 ◽  
Author(s):  
N. Shimizu ◽  
Y. Oomura ◽  
T. Sakata
Keyword(s):  
Food Intake ◽  
Feeding Behavior ◽  
Food Consumption ◽  
Single Neuron ◽  
Cerebral Ventricle ◽  
Neuron Activity ◽  
Hypothalamic Area ◽  
The Third ◽  
Single Neuron Activity ◽  
Fasted Rats

Endogenous sugar acids, 3,4-dihydroxybutanoic acid (2-deoxytetronic acid, 2-DTA) and 2,4,5-trihydroxypentanoic acid (3-deoxypentonic acid, 3-DPA), have been identified in the serum of fasted rats. Effects of these sugar acids on rat feeding behavior and neuron activity were investigated. Injections of 2-DTA (2.5 mumol) into the third cerebral ventricle of chronic rats suppressed food intake and single-neuron activity in the lateral hypothalamic area (LHA). Food consumption was reduced for 24 h, even in 72-h food-deprived rats. The same amounts of 3-DPA elicited feeding and increased LHA single-neuron activity with latencies of 6-8 min. Electrophoretically applied 2-DTA significantly and specifically suppressed activity of glucose-sensitive neurons in the LHA, whereas 3-DPA facilitated the activity. Nonglucose-sensitive LHA neurons were not affected by these sugar acids. The high correlation between modulation of feeding behavior and changes in LHA neuron activity after injection of these sugar acids suggested that 2-DTA may act as an endogenous satiety substance and 3-DPA as a hunger substance. The effects may be mediated through glucose-sensitive neurons in the LHA.

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