scholarly journals Circulating GLP-1 and CCK-8 reduce food intake by capsaicin-insensitive, nonvagal mechanisms

2012 ◽  
Vol 302 (2) ◽  
pp. R264-R273 ◽  
Author(s):  
Jingchuan Zhang ◽  
Robert C. Ritter
Keyword(s):  
Food Intake ◽  
Plasma Concentrations ◽  
Vagal Afferents ◽  
Reduce Food Intake ◽  
Sucrose Intake ◽  
Paracrine Effects ◽  
Distal Small Intestine ◽  
Nodose Ganglia ◽  
Glucagon Like Peptide ◽  
The Brain

Previous reports suggest that glucagon-like peptide (GLP-1), a peptide secreted from the distal small intestine, is an endocrine satiation signal. Nevertheless, there are conflicting reports regarding the site where circulating GLP-1 acts to reduce food intake. To test the hypothesis that vagal afferents are necessary for reduction of food intake by circulating GLP-1, we measured intake of 15% sucrose during intravenous GLP-1 infusion in intact, vagotomized, and capsaicin-treated rats. We also measured sucrose intake during intravenous infusion of cholecystokinin, a peptide known to reduce food intake via abdominal vagal afferents. We found that reduction of intake by GLP-1 was not diminished by capsaicin treatment or vagotomy. In fact, reduction of sucrose intake by our highest GLP-1 dose was enhanced in vagotomized and capsaicin-treated rats. Intravenous GLP-1 induced comparable increases of hindbrain c-Fos immunoreactivity in intact, capsaicin-treated, and vagotomized rats. Plasma concentrations of active GLP-1 in capsaicin-treated rats did not differ from those of controls during the intravenous infusions. Finally, capsaicin treatment was not associated with altered GLP-1R mRNA in the brain, but nodose ganglia GLP-1R mRNA was significantly reduced in capsaicin-treated rats. Although reduction of food intake by intraperitoneal cholecystokinin was abolished in vagotomized and capsaicin-treated rats, reduction of intake by intravenous cholecystokinin was only partially attenuated. These results indicate that vagal or capsaicin-sensitive neurons are not necessary for reduction of food intake by circulating (endocrine) GLP-1, or cholecystokinin. Vagal participation in satiation by these peptides may be limited to paracrine effects exerted near the sites of their secretion.

scholarly journals Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

2011 ◽  
Vol 301 (2) ◽  
pp. R448-R455 ◽  
Author(s):  
Jason Wright ◽  
Carlos Campos ◽  
Thiebaut Herzog ◽  
Mihai Covasa ◽  
Krzysztof Czaja ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Fourth Ventricle ◽  
Nmda Receptor Antagonist ◽  
Behavioral Pattern ◽  
Vagal Afferents ◽  
Nmda Receptor Antagonists ◽  
The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

Cholecystokinin is a Satiety Hormone in Humans at Physiological Post-Prandial Plasma Concentrations

1995 ◽  
Vol 89 (4) ◽  
pp. 375-381 ◽  
Author(s):  
Anne Ballinger ◽  
Lorraine McLoughlin ◽  
Sami Medbak ◽  
Michael Clark
Keyword(s):  
Food Intake ◽  
Test Meal ◽  
Plasma Concentrations ◽  
Standard Test ◽  
Saline Infusion ◽  
Reduce Food Intake ◽  
Subsequent Test ◽  
Gut Hormone ◽  
Plasma Cholecystokinin ◽  
Satiety Hormone

1. Intravenous infusions of the brain/gut hormone, cholecystokinin, have been shown to reduce food intake in a subsequent test meal. However, in previous studies the doses administered were large and likely to have produced plasma concentrations far in excess of the normal post-prandial range. 2. In this study cholecystokinin-8 was infused intravenously to six healthy subjects in doses that reproduced physiological post-prandial concentrations. Plasma concentrations of cholecystokinin were measured using a novel sensitive and specific radioimmunoassay. The effect of cholecystokinin-8 infusion on subsequent food intake in a standard test meal was compared with the effect of saline infusion in the same subjects. 3. Food intake (mean ± SEM) was significantly less during cholecystokinin (5092 ± 665 kJ) than during saline infusion (6418 ± 723 kJ, P = 0.03). During cholecystokinin infusion, plasma concentrations increased from 0.45 ± 0.06 pmol/l to 7.28 ± 2.43 pmol/l immediately before the meal. With saline infusion there was no premeal increase in plasma cholecystokinin concentration. 4. This paper describes a novel radioimmunoassay for measurement of plasma concentrations of cholecystokinin. Using this assay we have demonstrated that cholecystokinin is important in control of satiety in humans.

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

2011 ◽  
Vol 301 (5) ◽  
pp. R1479-R1485 ◽  
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.

Appetite hormones and addiction

2018 ◽  
Author(s):  
David J. Nutt ◽  
Liam J. Nestor
Keyword(s):  
Eating Disorder ◽  
Food Intake ◽  
Food Consumption ◽  
Neural Substrates ◽  
Reward Sensitivity ◽  
Substance Addiction ◽  
Alcohol And Drugs ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Brain

Many of the same behavioural and brain disturbances observed in addiction are also seen in obesity and binge-eating disorder. This suggests that there are shared neural substrates between substance addiction and compulsive food consumption. Food intake and appetite are regulated by numerous appetite hormones that exert their effects through brain systems involved in reward sensitivity, stress, impulsivity, and compulsivity. There is now emerging evidence that appetite hormones (e.g. ghrelin, glucagon-like peptide-1, orexin) can modulate addictive behaviours (e.g. craving) and the intake of alcohol and drugs. Therefore, there is an emerging shift into a new field of testing drugs that affect appetite hormones and their receptors in the brain, and their use in regulating the brain mechanisms that lead to relapse in addiction disorders.

Leptin and CCK modulate complementary background conductances to depolarize cultured nodose neurons

2006 ◽  
Vol 290 (2) ◽  
pp. C427-C432 ◽  
Author(s):  
J. H. Peters ◽  
R. C. Ritter ◽  
S. M. Simasko
Keyword(s):  
Food Intake ◽  
Outward Current ◽  
Vagal Afferents ◽  
Afferent Neurons ◽  
Inward Current ◽  
Adult Rat ◽  
Nodose Ganglia ◽  
Sodium Dependent ◽  
Ionic Mechanisms ◽  
Vagal Afferent

We have previously reported that intraceliac infusion of leptin induces a reduction of meal size that depends on intact vagal afferents. This effect of leptin is enhanced in the presence of cholecystokinin (CCK). The mechanisms by which leptin and CCK activate vagal afferent neurons are not known. In the present study, we have begun to address this question by using patch-clamp electrophysiological techniques to examine the mechanisms by which leptin and CCK activate cultured vagal afferents from adult rat nodose ganglia. We found that leptin depolarized 41 (60%) of 68 neurons. The magnitude of membrane depolarization was dependent on leptin concentration and occurred in both capsaicin-sensitive and capsaicin-insensitive neurons. We also found that a majority (16 of 22; 73%) of nodose neurons activated by leptin were also sensitive to CCK. CCK-induced depolarization was primarily associated with the increase of an inward current (11 of 12), whereas leptin induced multiple changes in background conductances through a decrease in an outward current (7 of 13), an increase in an inward current (3 of 13), or both (3 of 13). However, further isolation of background currents by recording in solutions that contained only sodium or only potassium revealed that both leptin and CCK were capable of increasing a sodium-dependent conductance or inhibiting a potassium-dependent conductance. Our results support the hypothesis that vagal afferents are a point of convergence and integration of leptin and CCK signaling for control of food intake and suggest multiple ionic mechanisms by which leptin and CCK activate vagal afferent neurons.

scholarly journals Blockade of hindbrain NMDA receptors containing NR2 subunits increases sucrose intake

2009 ◽  
Vol 296 (4) ◽  
pp. R921-R928 ◽  
Author(s):  
Douglas B. Guard ◽  
Timothy D. Swartz ◽  
Robert C. Ritter ◽  
Gilbert A. Burns ◽  
Mihai Covasa
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Sucrose Solution ◽  
Vagal Afferents ◽  
Sucrose Intake ◽  
Nr2b Subunit ◽  
Glutamate Binding ◽  
Nmda Channels ◽  
Nr2 Subunits

We have previously shown that blockade of N-methyl-d-aspartate (NMDA) receptors in the caudal brain stem delays satiation and increases food intake. NMDA receptors are heterodimers made up of distinct, but different, ion channel subunits. The NR2 subunits of the NMDA receptor contain the binding site for glutamate. About half of vagal afferents express immunoreactivity for NMDA NR2B subunit and about half of the NR2B expressing afferents also express NMDA NR2C or NR2D subunits. This suggests that increased food intake may be evoked by interference with glutamate binding to NMDA channels containing the NR2B subunit. To test this, we measured deprivation-induced intake of 15% sucrose solution following fourth ventricle and intra-nucleus of the solitary tract (intra-NTS) injections of Conantokin G (Con G; NR2B blocker), d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene; NR2B/2A blocker), and (±)-cis-1-(phenanthren-2yl-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA; NR2D/C blocker). Fourth ventricular administration of Con G (5, 20, 40, 80 ng), d-CPPene (3.0, 6.25, 12.5, 25, 50, 100 ng), and PPDA (300, 400 ng) increased sucrose intake significantly compared with control. Likewise, injections of Con G (10 ng), d-CPPene (5 ng, 10 ng), and PPDA (0.5, 1.0, 2.5, 5.0 ng) directly into the NTS significantly increased sucrose intake. These results show that hindbrain injection of competitive NMDA antagonists with selectivity or preference for the NMDA receptor NR2B or NR2C subunits increases food intake.

scholarly journals Repeated Intracerebroventricular Administration of Glucagon-Like Peptide-1-(7–36) Amide or Exendin-(9–39) Alters Body Weight in the Rat**This work was supported by the United Kingdom Medical Research Council.

Endocrinology ◽  
1999 ◽  
Vol 140 (1) ◽  
pp. 244-250 ◽  
Author(s):  
Karim Meeran ◽  
Donal O’Shea ◽  
C. Mark B. Edwards ◽  
Mandy D. Turton ◽  
Melanie M. Heath ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Research Council ◽  
Medical Research Council ◽  
Reduce Food Intake ◽  
The United Kingdom ◽  
Ad Libitum ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Central nervous system glucagon-like peptide-1-(7–36) amide (GLP-1) administration has been reported to acutely reduce food intake in the rat. We here report that repeated intracerebroventricular (icv) injection of GLP-1 or the GLP-1 receptor antagonist, exendin-(9–39), affects food intake and body weight. Daily icv injection of 3 nmol GLP-1 to schedule-fed rats for 6 days caused a reduction in food intake and a decrease in body weight of 16 ± 5 g (P < 0.02 compared with saline-injected controls). Daily icv administration of 30 nmol exendin-(9–39) to schedule-fed rats for 3 days caused an increase in food intake and increased body weight by 7 ± 2 g (P < 0.02 compared with saline-injected controls). Twice daily icv injections of 30 nmol exendin-(9–39) with 2.4 nmol neuropeptide Y to ad libitum-fed rats for 8 days increased food intake and increased body weight by 28 ± 4 g compared with 14 ± 3 g in neuropeptide Y-injected controls (P < 0.02). There was no evidence of tachyphylaxis in response to icv GLP-1 or exendin-(9–39). GLP-1 may thus be involved in the regulation of body weight in the rat.

scholarly journals Preproglucagon neurons in the hindbrain have IL-6 receptor-α and show Ca2+ influx in response to IL-6

2016 ◽  
Vol 311 (1) ◽  
pp. R115-R123 ◽  
Author(s):  
Fredrik Anesten ◽  
Marie K. Holt ◽  
Erik Schéle ◽  
Vilborg Pálsdóttir ◽  
Frank Reimann ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Food Intake ◽  
Extracellular Space ◽  
Solitary Tract ◽  
Neuronal Marker ◽  
Reporter Mice ◽  
The Central Nervous System ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Brain

Neuronal circuits in the hypothalamus and hindbrain are of importance for control of food intake, energy expenditure, and fat mass. We have recently shown that treatment with exendin-4 (Ex-4), an analog of the proglucagon-derived molecule glucagon-like peptide 1 (GLP-1), markedly increases mRNA expression of the cytokine interleukin-6 (IL-6) in the hypothalamus and hindbrain and that this increase partly mediates the suppression of food intake and body weight by Ex-4. Endogenous GLP-1 in the central nervous system (CNS) is produced by preproglucagon (PPG) neurons of the nucleus of the solitary tract (NTS) in the hindbrain. These neurons project to various parts of the brain, including the hypothalamus. Outside the brain, IL-6 stimulates GLP-1 secretion from the gut and pancreas. In this study, we aim to investigate whether IL-6 can affect GLP-1-producing PPG neurons in the nucleus of the solitary tract (NTS) in mouse hindbrain via the ligand binding part of the IL-6 receptor, IL-6 receptor-α (IL-6Rα). Using immunohistochemistry, we found that IL-6Rα was localized on PPG neurons of the NTS. Recordings of these neurons in GCaMP3/GLP-1 reporter mice showed that IL-6 enhances cytosolic Ca2+ concentration in neurons capable of expressing PPG. We also show that the Ca2+ increase originates from the extracellular space. Furthermore, we found that IL-6Rα was localized on cells in the caudal hindbrain expressing immunoreactive NeuN (a neuronal marker) or CNP:ase (an oligodendrocyte marker). In summary, IL-6Rα is present on PPG neurons in the NTS, and IL-6 can stimulate these cells by increasing influx of Ca2+ to the cytosol from the extracellular space.

scholarly journals Inhibition of Sham Feeding-Stimulated Human Gastric Acid Secretion by Glucagon-Like Peptide-2

1999 ◽  
Vol 84 (7) ◽  
pp. 2513-2517 ◽  
Author(s):  
Morten Wøjdemann ◽  
Andre Wettergren ◽  
Bolette Hartmann ◽  
Linda Hilsted ◽  
Jens J. Holst
Keyword(s):  
Gastric Secretion ◽  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Plasma Concentrations ◽  
Saline Infusion ◽  
Sham Feeding ◽  
Distal Small Intestine ◽  
Glucagon Like Peptide

Glucagon-like peptide (GLP)-2 is formed from proglucagon in the intestinal L cells and is secreted postprandially in parallel with the insulinotropic hormone GLP-1, the latter of which, in addition, acts to inhibit gastric secretion and motility by inhibiting central parasympathetic outflow. We now studied the effect of GLP-2 on gastric secretion stimulated by sham feeding to test the hypothesis that also GLP-2 acts as an enterogastrone. Eight healthy volunteers were studied twice on separate days. They were sham fed with and without GLP-2 infused iv at a rate of 0.8 pmol/kg·min. Gastric contents were aspirated continuously by a nasogastric tube for determination of acid secretion, volume, and osmolarity. Sham feeding increased gastric acid secretion nearly 5-fold. Infusion of GLP-2 reduced incremental acid secretion by 65 ± 6%, compared with saline infusion (Δ8.75 ± 0.37 vs. Δ3.04± 0.47 mmol × 60 min; P < 0.01). Plasma concentrations of GLP-2 rose from a basal mean of 3.3 ± 0.9 to a mean of 115 ± 8 pmol/L (range, 57–149 pmol/L) during infusion of GLP-2 and remained at basal level during saline infusion. Plasma concentrations of GLP-1, gastrin, cholecystokinin, and secretin remained low and unchanged on both study days. We conclude that GLP-2 is a powerful inhibitor of gastric acid secretion in man. Further investigations will show to what extent GLP-2 contributes to the inhibitory effects on gastric secretion exerted by hormones from the distal small intestine, under physiological circumstances.

A high-fat diet attenuates the central response to within-meal satiation signals and modifies the receptor expression of vagal afferents in mice

2009 ◽  
Vol 296 (6) ◽  
pp. R1681-R1686 ◽  
Author(s):  
Wahiba Nefti ◽  
Catherine Chaumontet ◽  
Gilles Fromentin ◽  
Daniel Tomé ◽  
Nicolas Darcel
Keyword(s):  
Food Intake ◽  
Dietary Intervention ◽  
Body Weight Gain ◽  
Receptor Expression ◽  
Vagal Afferents ◽  
Afferent Neuron ◽  
Short Term ◽  
Vagal Afferent ◽  
The Brain ◽  
Term Response

During digestion, macronutrients are sensed within the small intestine. This sensory process is dependent upon the action of gut mediators, such as cholecystokinin (CCK) or serotonin (5-HT), on vagal afferents that, in turn, convey peripheral information to the brain to influence the control of food intake. Recent studies have suggested that dietary conditions alter vagal sensitivity to CCK and 5-HT. This phenomenon may be of importance to the onset of eating disorders. The aim of the present study was thus to investigate the effects of subjecting mice to 15 days of either an HF diet (30% fat, 54% carbohydrate) or an NF diet (10% fat, 74% carbohydrate) on 1) daily and short-term food intake, 2) vagal sensitivity to peripheral anorectic factors and macronutrient loads, and 3) vagal afferent neuron receptor expression. The results indicated that compared with an NF diet, and while increasing food intake and body weight gain, an HF diet altered the short-term response to CCK-8 and intragastric macronutrient loads, while decreasing vagal activation by CCK-8 and modifying the receptor expression of vagal neurons. These findings, therefore, suggest that dietary intervention effect on food intake could be linked to changes in vagal afferent receptor profiles.

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