Attenuation of lipopolysaccharide anorexia by antagonism of caudal brain stem but not forebrain GLP-1-R

The central glucagon-like peptide-1 (GLP-1) system has been implicated in the control of feeding behavior. Here we explore GLP-1 mediation of the anorexic response to administration of systemic LPS and address the relative importance of caudal brain stem and forebrain GLP-1 receptor (GLP-1-R) for the mediation of the response. Fourth-intracerebroventricular delivery of the GLP-1-R antagonist exendin-(9–39) (10 μg) did not itself affect food intake in the 24 h after injection but significantly attenuated the otherwise robust (∼60%) reduction in food intake obtained after LPS (100 μg/kg) treatment. This result highlights a role for caudal brain stem GLP-1-R in the mediation of LPS anorexia but does not rule out the possibility that forebrain receptors also contribute to the response. Forebrain contribution was addressed by delivery of the GLP-1-R antagonist to the third ventricle with the caudal flow of cerebrospinal fluid blocked by occlusion of the cerebral aqueduct. Exendin-(9–39) delivery thus limited to forebrain did not attenuate the anorexic response to LPS. These data suggest that LPS anorexia is mediated, in part, by release of the native peptide acting on GLP-1-R within the caudal brain stem.

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Evidence that Intestinal Glucagon-Like Peptide-1 Plays a Physiological Role in Satiety

Endocrinology ◽

10.1210/en.2008-1045 ◽

2008 ◽

Vol 150 (4) ◽

pp. 1680-1687 ◽

Cited By ~ 198

Author(s):

Diana L. Williams ◽

Denis G. Baskin ◽

Michael W. Schwartz

Keyword(s):

Third Ventricle ◽

Physiological Role ◽

Meal Size ◽

Glucose Load ◽

Distal Intestine ◽

The Third ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Peripheral Site

A physiological role in satiety is proposed for glucagon-like peptide-1 (GLP-1), secreted by the distal intestine in response to ingested nutrients. Here we report that in rats, ip injection of the GLP-1 receptor (GLP-1-R) antagonist exendin 9-39 (Ex9) elicited hyperphagia, but only at times of day when intake is otherwise low. Furthermore, ip administration of Ex9 attenuated satiety induced by either a voluntarily consumed sucrose meal (by 100%) or an intragastric glucose load (by 40%). To determine whether these effects involve blockade of GLP-1-R in brain or at a peripheral site, we injected Ex9 either centrally (into the third ventricle) or peripherally (ip) prior to GLP-1 injected either centrally or peripherally. Anorexia induced by peripheral GLP-1 was fully blocked by peripheral, but not central, pretreatment with Ex9, whereas the opposite was true for anorexic effect of central GLP-1. Thus, ip Ex9 appears to attenuate satiety via peripheral GLP-1-R blockade. Finally, anorexia induced by ip injection of exendin-4 (a GLP-1-R agonist) was due to both reduced meal size and increased duration between meals. We conclude that GLP-1 released from the intestine in response to ingested nutrients is a physiologically active satiety signal.

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Blockade of the cerebral aqueduct in rats provides evidence of antagonistic leptin responses in the forebrain and hindbrain

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00661.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. E414-E423 ◽

Cited By ~ 2

Author(s):

Michael I. Vaill ◽

Bhavna N. Desai ◽

Ruth B. S. Harris

Keyword(s):

Weight Loss ◽

Food Intake ◽

Body Fat ◽

Fourth Ventricle ◽

Third Ventricle ◽

Cerebral Aqueduct ◽

Sprague Dawley ◽

Leptin Receptors ◽

The Third ◽

Inhibit Food Intake

Previously, we reported that low-dose leptin infusions into the fourth ventricle produced a small but significant increase in body fat. These data contrast with reports that injections of higher doses of leptin into the fourth ventricle inhibit food intake and weight gain. In this study, we tested whether exogenous leptin in the fourth ventricle opposed or contributed to weight loss caused by third ventricle leptin infusion by blocking diffusion of CSF from the third to the fourth ventricle. Male Sprague-Dawley rats received third ventricle infusions of PBS or 0.3 μg leptin/24 h from miniosmotic pumps. After 4 days, rats received a 3-μl cerebral aqueduct injection of saline or of thermogelling nanoparticles (hydrogel) that solidified at body temperature. Third ventricle leptin infusion inhibited food intake and caused weight loss. Blocking the aqueduct exaggerated the effect of leptin on food intake and weight loss but had no effect on the weight of PBS-infused rats. Leptin reduced both body fat and lean body mass but did not change energy expenditure. Blocking the aqueduct decreased expenditure of rats infused with PBS or leptin. Infusion of leptin into the third ventricle increased phosphorylated STAT3 in the VMHDM of the hypothalamus and the medial NTS in the hindbrain. Blocking the aqueduct did not change hypothalamic p-STAT3 but decreased p-STAT3 in the medial NTS. These results support previous observations that low-level activation of hindbrain leptin receptors has the potential to blunt the catabolic effects of leptin in the third ventricle.

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Abstract 438: Peripheral but Not Central Glucagon-Like Peptide-1 Receptor Agonism Regulates Fasting Dyslipidemia by Reducing VLDL Production

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.438 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Jennifer Taher ◽

Chris Baker ◽

Carmelle Cuizon ◽

Mark Naples ◽

Sarah Farr ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Food Intake ◽

De Novo ◽

Lipid Analysis ◽

Third Ventricle ◽

Lipid Lowering ◽

Fasting Plasma ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces plasma glucose levels and thus acts as an important drug target in the treatment of type 2 diabetes (T2D). Our laboratory has further shown that GLP-1 regulates intestinal lipoprotein metabolism and may also play a similar role in the liver. Hepatic lipids are packaged with apolipoprotein B-100 (apoB100) into very low density lipoproteins (VLDL) and secreted into the plasma. Dysregulation of VLDL production results in the fasting dyslipidemia that is observed in T2D. We postulate that GLP-1 receptor (GLP-1R) agonism regulates fasting dyslipidemia by decreasing VLDL production in insulin resistance through a peripheral or central pathway. To test this, experiments were conducted in fructose-fed insulin resistant Syrian golden hamsters. Hamsters were given twice daily intraperitoneal(i.p) injections of the GLP-1R agonist exendin-4 (ex4; 5nM/kg) for 7 days and placed into metabolic cages. Plasma was collected for lipid analysis following i.p poloxamer to prevent lipoprotein uptake and livers were excised. Peripheral ex4 prevented fructose-induced fasting dyslipidemia and decreased fasting plasma- and VLDL-triglyceride (TG), -cholesterol and -apoB100 accumulation. Ex4 also reduced food intake and body weight and thus pair-fed controls were added. Pair-feeding did not account for the full ex4 lipid-lowering effect. In comparison to both controls, ex4 treated hamsters had reduced respiratory exchange ratio and CO 2 production indicating a switch from glucose to fat metabolism as the main source of energy, and also decreased hepatic mRNA markers for de novo lipogenesis. To determine involvement of a central pathway, hamsters received a 4 day intracerebroventricular administration of ex4 (250ng) into the third ventricle. Central ex4 reduced body weight and food intake but did not modulate fasting plasma and VLDL-lipid or apoB100 accumulation, further suggesting that decreases in food intake cannot solely explain the changes in VLDL production. Our studies suggest that GLP-1R agonism reduces fasting dyslipidemia in insulin resistance by decreasing VLDL production through a peripheral pathway. GLP-1R agonism may be a potential therapy in the treatment of fasting dyslipidemia.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00446.2012 ◽

2013 ◽

Vol 304 (7) ◽

pp. E677-E685 ◽

Cited By ~ 34

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.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00243.2015 ◽

2016 ◽

Vol 310 (10) ◽

pp. R906-R916 ◽

Cited By ~ 9

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.

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Neuroendoscopic Aspiration of Blood Clots in the Cerebral Aqueduct and Third Ventricle During Posterior Fossa Surgery in the Prone Position

Operative Neurosurgery ◽

10.1093/ons/opy324 ◽

2018 ◽

Vol 17 (2) ◽

pp. 143-148 ◽

Cited By ~ 1

Author(s):

Alberto Feletti ◽

Riccardo Stanzani ◽

Matteo Alicandri-Ciufelli ◽

Giuliano Giliberto ◽

Matteo Martinoni ◽

...

Keyword(s):

Prone Position ◽

Posterior Fossa ◽

Fourth Ventricle ◽

Blood Clot ◽

Third Ventricle ◽

Cerebral Aqueduct ◽

Posterior Fossa Surgery ◽

The Third ◽

Blood Clots ◽

Surgical Field

AbstractBACKGROUNDDuring surgery in the posterior fossa in the prone position, blood can sometimes fill the surgical field, due both to the less efficient venous drainage compared to the sitting position and the horizontally positioned surgical field itself. In some cases, blood clots can wedge into the cerebral aqueduct and the third ventricle, and potentially cause acute hydrocephalus during the postoperative course.OBJECTIVETo illustrate a technique that can be used in these cases: the use of a flexible scope introduced through the opened roof of the fourth ventricle with a freehand technique allows the navigation of the fourth ventricle, the cerebral aqueduct, and the third ventricle in order to explore the cerebrospinal fluid pathways and eventually aspirate blood clots and surgical debris.METHODSWe report on one patient affected by an ependymoma of the fourth ventricle, for whom we used a flexible neuroendoscope to explore and clear blood clots from the cerebral aqueduct and the third ventricle after the resection of the tumor in the prone position. Blood is aspirated with a syringe using the working channel of the scope as a sucker.RESULTSA large blood clot that was lying on the roof of the third ventricle was aspirated, setting the ventricle completely free. Other clots were aspirated from the right foramen of Monro and from the optic recess.CONCLUSIONWe describe this novel technique, which represents a safe and efficient way to clear the surgical field at the end of posterior fossa surgery in the prone position. The unusual endoscopic visual perspective and instrument maneuvers are easily handled with proper neuroendoscopic training.

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Glucagon-like peptid-1 in obese and diabetic patients after bariatric interventions

Vestnik of Russian military medical Academy ◽

10.17816/brmma57488 ◽

2021 ◽

Vol 23 (1) ◽

pp. 89-94

Author(s):

Anna R. Volkova ◽

Galina V. Semikova ◽

Valentina S. Mozgunova ◽

Margarita N. Maltseva ◽

Vladimir L. Bondarenko ◽

...

Keyword(s):

Diabetes Mellitus ◽

Body Weight ◽

Weight Gain ◽

Diabetic Patients ◽

Obese Patients ◽

Weight Retention ◽

Plateau Phase ◽

The Third ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The relationship between the level of glucagon-like peptide-1 and repeated weight gain was evaluated in 31 patients suffering from grade IIIII obesity and type 2 diabetes mellitus after bariatric interventions for 3 years. It was found that the level of stimulated glucagon-like peptide-1 significantly increased by the third day after sleeve gastroplasty and gastroschunt compared to the initial parameters (p = 0.001 for obese patients; p = 0.000 for obese patients and diabetes mellitus). In the plateau phase (body weight retention) after bariatric intervention, the level of stimulated glucagon-like peptide-1 in obese patients and patients suffering from obesity in combination with diabetes mellitus did not significantly differ from the indicators of healthy individuals. There was no association between the level of glucagon-like peptide-1 and repeated weight gain. This may be due to the limited contribution of glucagon-like peptide-1 to body weight dynamics after bariatric interventions and the predominance of patient compliance. Thus, the level of stimulated glucagon-like peptide-1 at baseline, on the third day and in the plateau phase after bariatric intervention was not associated with the value of repeated weight gain.

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The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00356.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. R1479-R1485 ◽

Cited By ~ 55

Author(s):

Matthew R. Hayes ◽

Scott E. Kanoski ◽

Bart C. De Jonghe ◽

Theresa M. Leichner ◽

Amber L. Alhadeff ◽

...

Keyword(s):

Food Intake ◽

Vagal Afferents ◽

Oral Glucose ◽

Afferent Fibers ◽

The Common ◽

Vagal Afferent ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

And Control ◽

Hepatic Branch

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9–39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7–36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.

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