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

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00163.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. R1190-R1193 ◽

Cited By ~ 38

Author(s):

Harvey J. Grill ◽

Jill S. Carmody ◽

L. Amanda Sadacca ◽

Diana L. Williams ◽

Joel M. Kaplan

Keyword(s):

Food Intake ◽

Brain Stem ◽

Third Ventricle ◽

Cerebral Aqueduct ◽

Relative Importance ◽

The Third ◽

Native Peptide ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Rule Out

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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The deletion of glucagon-like peptide-1 receptors expressing neurons in the dorsomedial hypothalamic nucleus disrupts the diurnal feeding pattern and induces hyperphagia and obesity

Nutrition & Metabolism ◽

10.1186/s12986-021-00582-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Yuko Maejima ◽

Shoko Yokota ◽

Masaru Shimizu ◽

Shoichiro Horita ◽

Daisuke Kobayashi ◽

...

Keyword(s):

Nucleus Tractus Solitarius ◽

Physiological Role ◽

Feeding Pattern ◽

Hypothalamic Nucleus ◽

Acid Decarboxylase ◽

Mrna Levels ◽

Dorsomedial Hypothalamic Nucleus ◽

Fos Expression ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Background Feeding rhythm disruption contributes to the development of obesity. The receptors of glucagon-like peptide-1 (GLP-1) are distributed in the wide regions of the brain. Among these regions, GLP-1 receptors (GLP-1R) are expressed in the dorsomedial hypothalamic nucleus (DMH) which are known to be associated with thermogenesis and circadian rhythm development. However, the physiological roles of GLP-1R expressing neurons in the DMH remain elusive. Methods To examine the physiological role of GLP-1R expressing neurons in the DMH, saporin-conjugated exenatide4 was injected into rat brain DMH to delete GLP-1R-positive neurons. Subsequently, locomotor activity, diurnal feeding pattern, amount of food intake and body weight were measured. Results This deletion of GLP-1R-positive neurons in the DMH induced hyperphagia, the disruption of diurnal feeding pattern, and obesity. The deletion of GLP-1R expressing neurons also reduced glutamic acid decarboxylase 67 and cholecystokinin A receptor mRNA levels in the DMH. Also, it reduced the c-fos expression after refeeding in the suprachiasmatic nucleus (SCN). Thirty percent of DMH neurons projecting to the SCN expressed GLP-1R. Functionally, refeeding after fasting induced c-fos expression in the SCN projecting neurons in the DMH. As for the projection to the DMH, neurons in the nucleus tractus solitarius (NTS) were found to be projecting to the DMH, with 33% of those neurons being GLP-1-positive. Refeeding induced c-fos expression in the DMH projecting neurons in the NTS. Conclusion These findings suggest that GLP-1R expressing neurons in the DMH may mediate feeding termination. In addition, this meal signal may be transmitted to SCN neurons and change the neural activities.

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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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Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00099.2013 ◽

2013 ◽

Vol 305 (5) ◽

pp. R499-R505 ◽

Cited By ~ 12

Author(s):

Hyun-Ju Kim ◽

Eun-Young Park ◽

Mi-Jeong Oh ◽

Sung-Soo Park ◽

Kyung-Ho Shin ◽

...

Keyword(s):

Body Weight ◽

Energy Balance ◽

Food Intake ◽

Third Ventricle ◽

Meal Size ◽

Dependent Manner ◽

Central Administration ◽

Mediobasal Hypothalamus ◽

S6 Kinase ◽

The Third

Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 μg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 μg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr389 and AMPK at Ser485/491 in the mediobasal hypothalamus, while AMPK phosphorylation at Thr172 was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway.

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Congenital Glucagon-like Peptide-1 Deficiency in the Pathogenesis of Protracted Diarrhea in Mitchell–Riley Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa916 ◽

2020 ◽

Author(s):

Sara Nóbrega ◽

Mariana P Monteiro ◽

Luís Pereira-da-Silva ◽

Sofia S Pereira ◽

Bolette Hartmann ◽

...

Keyword(s):

Rescue Therapy ◽

Gene Mutations ◽

Neonatal Diabetes ◽

Rapid Improvement ◽

Distal Intestine ◽

Off Label ◽

Type 2 Diabetes Treatment ◽

Beta Cell Maturation ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Context Mitchell–Riley syndrome due to RFX6 gene mutations is characterized by neonatal diabetes and protracted diarrhea. The RFX6 gene encodes a transcription factor involved in enteroendocrine cell differentiation required for beta-cell maturation. In contrast to the pathway by which RFX6 mutations leads to diabetes, the mechanisms underlying protracted diarrhea are unknown. Objective To assess whether glucagon-like peptide-1 (GLP-1) was involved in the pathogenesis of Mitchell–Riley syndrome protracted diarrhea. Methods Two case report descriptions. in a tertiary pediatric hospital. “Off-label” treatment with liraglutide. We describe 2 children diagnosed with Mitchell–Riley syndrome, presenting neonatal diabetes and protracted diarrhea. Both patients had nearly undetectable GLP-1 plasma levels and absence of GLP-1 immunostaining in distal intestine and rectum. The main outcome was to evaluate whether GLP-1 analogue therapy could improve Mitchell–Riley syndrome protracted diarrhea. Results “Off-label” liraglutide treatment, licensed for type 2 diabetes treatment in children, was started as rescue therapy for protracted intractable diarrhea resulting in rapid improvement during the course of 12 months. Conclusion Congenital GLP-1 deficiency was identified in patients with Mitchell–Riley syndrome. The favorable response to liraglutide further supports GLP-1 involvement in the pathogenesis of protracted diarrhea and its potential therapeutic use.

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Intrameal Hepatic Portal and Intraperitoneal Infusions of Glucagon-Like Peptide-1 Reduce Spontaneous Meal Size in the Rat via Different Mechanisms

Endocrinology ◽

10.1210/en.2008-1221 ◽

2008 ◽

Vol 150 (3) ◽

pp. 1174-1181 ◽

Cited By ~ 186

Author(s):

Elisabeth B. Rüttimann ◽

Myrtha Arnold ◽

Jacquelien J. Hillebrand ◽

Nori Geary ◽

Wolfgang Langhans

Keyword(s):

Food Intake ◽

Vena Cava ◽

Meal Size ◽

Dark Phase ◽

Hepatic Portal Vein ◽

Vagal Afferent ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Hepatic Portal ◽

Afferent Signaling

Peripheral administration of glucagon-like peptide (GLP)-1 reduces food intake in animals and humans, but the sites and mechanism of this effect and its physiological significance are not yet clear. To investigate these issues, we prepared rats with chronic catheters and infused GLP-1 (0.2 ml/min; 2.5 or 5.0 min) during the first spontaneous dark-phase meals. Infusions were remotely triggered 2–3 min after meal onset. Hepatic portal vein (HPV) infusion of 1.0 or 3.0 (but not 0.33) nmol/kg GLP-1 reduced the size of the ongoing meal compared with vehicle without affecting the subsequent intermeal interval, the size of subsequent meals, or cumulative food intake. In double-cannulated rats, HPV and vena cava infusions of 1.0 nmol/kg GLP-1 reduced meal size similarly. HPV GLP-1 infusions of 1.0 nmol/kg GLP-1 also reduced meal size similarly in rats with subdiaphragmatic vagal deafferentations and in sham-operated rats. Finally, HPV and ip infusions of 10 nmol/kg GLP-1 reduced meal size similarly in sham-operated rats, but only HPV GLP-1 reduced meal size in subdiaphragmatic vagal deafferentation rats. These data indicate that peripherally infused GLP-1 acutely and specifically reduces the size of ongoing meals in rats and that the satiating effect of ip, but not iv, GLP-1 requires vagal afferent signaling. The findings suggest that iv GLP-1 infusions do not inhibit eating via hepatic portal or hepatic GLP-1 receptors but may act directly on the brain. Intrameal hepatic portal and intraperitoneal (IP) infusions of GLP-1 reduce meal size in rats, but only IP GLP-1 requires vagal afferent signaling for this effect.

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Effects of truncated glucagon-like peptide-1 on the responses of starved sheep to glucose

Journal of Endocrinology ◽

10.1677/joe.0.1290055 ◽

1991 ◽

Vol 129 (1) ◽

pp. 55-58 ◽

Cited By ~ 9

Author(s):

A. Faulkner ◽

H. T. Pollock

Keyword(s):

Plasma Insulin ◽

Plasma Concentrations ◽

Amino Nitrogen ◽

Insulin Response ◽

Not Given ◽

Glucose Load ◽

Glucose Administration ◽

Gut Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

ABSTRACT The effects of i.v. glucagon-like peptide-1-(7–36)amide (GLP-1; 10 μg) on starved sheep given an i.v. glucose load (5 g) were studied. Plasma insulin concentrations rose significantly more after glucose administration in fed than in starved sheep. Giving GLP-1 to starved sheep increased the insulin response to the glucose load. The rise in plasma insulin concentrations in starved sheep given GLP-1 was similar to that observed in fed sheep. Plasma glucose concentrations returned to normal values more quickly in the starved sheep given GLP-1 than in starved sheep not given gut hormone. Plasma concentrations of free fatty acid, urea and α-amino nitrogen decreased more quickly following glucose administration in starved sheep given GLP-1 than in those not given GLP-1. The data suggest a role for GLP-1 in regulating plasma insulin concentrations and hence metabolism in ruminant animals. The possible role of gut hormones in ruminants is discussed. Journal of Endocrinology (1991) 129, 55–58

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