Dose combinations of exendin-4 and salmon calcitonin produce additive and synergistic reductions in food intake in nonhuman primates

Glucagon-like peptide-1 (GLP-1) and amylin mediate the feedback control of eating by seemingly separate, but overlapping mechanisms. This study examined the effects of combined doses of the GLP-1 agonist, exendin-4 (Ex-4), and the amylin analog, salmon calcitonin (sCT), on food intake and meal patterns in adult male rhesus monkeys. Monkeys received intramuscular injections of Ex-4 (0, 0.1, 0.32, or 0.56 μg/kg), sCT (0, 0.1, or 0.32 μg/kg), or combinations thereof before a 6-h daily access to food. Dose combinations produced reductions in food intake that were significantly greater than those produced by the individual doses. Surface plots of the hourly intake indicated a synergistic interaction at lower doses of Ex-4 and sCT during the first 4 h of feeding and additive effects at hours 5 and 6. Meal pattern analysis revealed the combinational doses reduced average meal size and meal frequency by additive interactions, whereas infra-additive effects were apparent at lower doses for first meal size. Combinational doses were further characterized by administration of repeated daily injections of 0.56 μg/kg Ex-4 + 0.32 μg/kg sCT for 5 days. This resulted in sustained reductions in daily food intake (>70% from saline baseline) for 5 days with residual reductions (∼48% from saline baseline) persisting on day 1 following the injections. In contrast, when pair-fed an identical amount of daily food, there was a compensatory food intake increase on day 1 following the pair-feeding (∼132% of saline baseline). Such data suggest Ex-4 and sCT interact in an overall additive fashion to reduce food intake and further the understanding of how GLP-1 and amylin agonist combinations influence feeding behavior.

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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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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 ◽

10.1210/endo.140.1.6421 ◽

1999 ◽

Vol 140 (1) ◽

pp. 244-250 ◽

Cited By ~ 134

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.

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Salmon calcitonin reduces food intake through changes in meal sizes in male rhesus monkeys

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90327.2008 ◽

2008 ◽

Vol 295 (1) ◽

pp. R76-R81 ◽

Cited By ~ 11

Author(s):

Nicholas T. Bello ◽

Matthew H. Kemm ◽

Timothy H. Moran

Keyword(s):

Food Intake ◽

Salmon Calcitonin ◽

Rhesus Monkeys ◽

Nonhuman Primates ◽

Dose Range ◽

Meal Size ◽

Meal Patterns ◽

Daily Food Intake ◽

Daily Food ◽

Male Rhesus

Amylinergic mechanisms are believed to be involved in the control of appetite. This study examined the effects of the amylin agonist, salmon calcitonin, on food intake and meal patterns in adult male rhesus monkeys. Fifteen minutes before the onset of their 6-h daily feeding period, monkeys received intramuscular injections of various doses of salmon calcitonin (0.032, 0.056, 0.1, 0.32, and 1 μg/kg) or saline. Salmon calcitonin dose dependently reduced total daily and hourly food intake, with significant decreases at the 0.1, 0.32, and 1 μg/kg doses. Daily food intake was reduced by ∼35%, 62%, and 96%, at these doses, respectively. An analysis of meal patterns revealed that size of the first meal was significantly reduced across the dose range of 0.056 to 1 μg/kg, while average meal size was reduced with the 0.32 and 1 μg/kg doses. Meal number was only affected at the 1 μg/kg dose. Repeated 5-day administration of the 0.1 μg/kg dose resulted in a reduction in daily food intake only on injection day 2, while significant reductions in food intake were observed on all five injection days with a 0.32 μg/kg dose. Daily food intake was also reduced for 1 day after the termination of the 5-day injections of the 0.32 μg/kg salmon calcitonin dose. These sustained reductions in intake were expressed through decreases in meal size. These data demonstrate that salmon calcitonin acutely and consistently decreases food intake mainly through reductions in meal sizes in nonhuman primates.

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The GLP-1 agonist exendin-4 reduces food intake in nonhuman primates through changes in meal size

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00323.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. R983-R987 ◽

Cited By ~ 68

Author(s):

Karen A. Scott ◽

Timothy H. Moran

Keyword(s):

Food Intake ◽

Rhesus Macaques ◽

Specific Effect ◽

Meal Size ◽

Reduce Food Intake ◽

Dependent Manner ◽

Primate Model ◽

Glucagon Like Peptide 1 ◽

Long Acting ◽

Dose Dependent

Exendin-4 (Ex4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to reduce food intake and suppress gastric emptying in rodents and humans. In this study we investigated the effects of peripheral administration of Ex4 on food intake and meal patterns in adult male rhesus macaques. Rhesus macaques ( n = 4) that had been trained to lever press for food pellets were injected intramuscularly 15 min before the start of their 6-h daily feeding period. Ex4 was given at doses of 0.10, 0.32, 0.56, 1.0, and 3.0 μg/kg. Ex4 suppressed food intake in a dose-dependent manner, with the 3.0 μg/kg dose completely preventing feeding during the 6-h period and the 0.10 μg/kg dose suppressing intake by 17%. Doses of 0.32, 0.56, 1.0, and 3.0 μg/kg caused significant reductions in cumulative intake at all six hourly time points. Ex4 inhibited food intake through a specific effect on meal size. Meal size was significantly reduced in a dose-dependent manner with significant reductions at the 0.32 and 1.0 μg/kg doses ( P < 0.05). Day 2 and 3intakes returned to baseline levels with no compensation for Ex4-induced feeding suppression. Administration of doses of 0.32 and 0.56 μg/kg Ex4 over 5 consecutive days led to sustained reductions in intake with no evidence of compensation. Again, these reductions were due to specific effects on meal size. These results demonstrate that activation of GLP-1 pathways has potent effects on the controls of meal size and overall food intake in a nonhuman primate model.

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Adrenomedullin and glucagon-like peptide-1 have additive effects on food intake in mice

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.10.040 ◽

2019 ◽

Vol 109 ◽

pp. 167-173 ◽

Cited By ~ 5

Author(s):

Esben M. Bech ◽

Kristoffer Voldum-Clausen ◽

Søren L. Pedersen ◽

Katrine Fabricius ◽

Lise C.B. Rudkjær ◽

...

Keyword(s):

Food Intake ◽

Additive Effects ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Suppression of Food Intake by Glucagon-Like Peptide-1 Receptor Agonists: Relative Potencies and Role of Dipeptidyl Peptidase-4

Endocrinology ◽

10.1210/en.2012-1358 ◽

2012 ◽

Vol 153 (12) ◽

pp. 5735-5745 ◽

Cited By ~ 17

Author(s):

Lene Jessen ◽

Benedikt A. Aulinger ◽

Jonathan L. Hassel ◽

Kyle J. Roy ◽

Eric P. Smith ◽

...

Keyword(s):

Gastric Bypass ◽

Food Intake ◽

Dipeptidyl Peptidase ◽

Reduce Food Intake ◽

Wild Type ◽

Dipeptidyl Peptidase 4 ◽

Receptor Agonists ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

High Doses

Abstract Administration of the glucagon-like peptide-1 (GLP-1) receptor agonists GLP-1 and exendin-4 (Ex-4) directly into the central nervous system decreases food intake. But although Ex-4 potently suppresses food intake after peripheral administration, the effects of parenteral GLP-1 are variable and not as strong. A plausible explanation for these effects is the rapid inactivation of circulating GLP-1 by dipeptidyl peptidase-4 (DPP-4), an enzyme that does not alter Ex-4 activity. To test this hypothesis, we assessed the relative potency of Ex-4 and GLP-1 under conditions in which DPP-4 activity was reduced. Outbred rats, wild-type mice, and mice with a targeted deletion of DPP-4 (Dpp4−/−) were treated with GLP-1 alone or in combination with the DPP-4 inhibitor vildagliptin, Ex-4, or saline, and food intake was measured. GLP-1 alone, even at high doses, did not affect feeding in wild-type mice or rats but did reduce food intake when combined with vildagliptin or given to Dpp4−/− mice. Despite plasma clearance similar to DPP-4-protected GLP-1, equimolar Ex-4 caused greater anorexia than vildagliptin plus GLP-1. To determine whether supraphysiological levels of endogenous GLP-1 would suppress food intake if protected from DPP-4, rats with Roux-en-Y gastric bypass and significantly elevated postprandial plasma GLP-1 received vildagliptin or saline. Despite 5-fold greater postprandial GLP-1 in these animals, vildagliptin did not affect food intake in Roux-en-Y gastric bypass rats. Thus, in both mice and rats, peripheral GLP-1 reduces food intake significantly less than Ex-4, even when protected from DPP-4. These findings suggest distinct potencies of GLP-1 receptor agonists on food intake that cannot be explained by plasma pharmacokinetics.

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Food intake in lean and obese mice after peripheral administration of glucagon-like peptide 2

Journal of Endocrinology ◽

10.1530/joe-12-0092 ◽

2012 ◽

Vol 213 (3) ◽

pp. 277-284 ◽

Cited By ~ 25

Author(s):

Sara Baldassano ◽

Anna Lisa Bellanca ◽

Rosa Serio ◽

Flavia Mulè

Keyword(s):

Gastric Emptying ◽

Food Intake ◽

Reduce Food Intake ◽

Additive Effects ◽

Obese Mice ◽

Short Term ◽

Gastric Emptying Rate ◽

Anorectic Effect ◽

Glucagon Like Peptide

We investigated the potential anorectic action of peripherally administered glucagon-like peptide 2 (GLP2) in lean and diet-induced obese (DIO) mice. Mice, fasted for 16 h, were injected i.p. with native GLP2 or [Gly2]GLP2, stable analog of GLP2, before or after GLP2 (3–33), a GLP2 receptor (GLP2R) antagonist, or exendin (9–39), a GLP1R antagonist. Food intake was measured at intervals 1, 2, 4, 8, and 24 h postinjection. In addition, we tested in lean mice the influence of [Gly2]GLP2 on gastric emptying and the effects of GLP1 alone or in combination with [Gly2]GLP2 on food intake. [Gly2]GLP2 dose dependently and significantly inhibited food intake in lean and DIO mice. The reduction of food intake occurred in the first hour postinjection and it was sustained until 4 h postinjection in lean mice while it was sustained until 2 h postinjection in DIO mice. GLP2 significantly inhibited food intake in both lean and DIO mice but only in the first hour postinjection. The efficiency of [Gly2]GLP2 or GLP2 in suppressing food intake was significantly weaker in DIO mice compared with lean animals. The [Gly2]GLP2 anorectic actions were blocked by the GLP2R antagonist GLP2 (3–33) or by the GLP1R antagonist exendin (9–39). The coadministration of [Gly2]GLP2 and GLP1 did not cause additive effects. [Gly2]GLP2 decreased the gastric emptying rate. Results suggest that GLP2 can reduce food intake in mice in the short term, likely acting at a peripheral level. DIO mice are less sensitive to the anorectic effect of the peptide.

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GLP-1 receptor signaling contributes to anorexigenic effect of centrally administered oxytocin in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00008.2002 ◽

2002 ◽

Vol 283 (1) ◽

pp. R99-R106 ◽

Cited By ~ 59

Author(s):

Linda Rinaman ◽

Elizabeth E. Rothe

Keyword(s):

Food Intake ◽

Receptor Antagonist ◽

Male Rats ◽

Neural Systems ◽

Neural Pathways ◽

Receptor Signaling ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Access To Food ◽

Anorexigenic Effect

The present study examined possible interactions between central glucagon-like peptide-1 (GLP-1) and oxytocin (OT) neural systems by determining whether blockade of GLP-1 receptors attenuates OT-induced anorexia and vice versa. Male rats were acclimated to daily 4-h food access. In the first experiment, rats were infused centrally with GLP-1 receptor antagonist or vehicle, followed by an anorexigenic dose of synthetic OT. Access to food began 20 min later. Cumulative food intake was measured every 30 min for 4 h. In the second experiment, rats were infused with OT receptor blocker or vehicle, followed by synthetic GLP-1 [(7–36) amide]. Subsequent food intake was monitored as before. The anorexigenic effect of OT was eliminated in rats pretreated with the GLP-1 receptor antagonist. Conversely, GLP-1-induced anorexia was not affected by blockade of OT receptors. In a separate immunocytochemical study, OT-positive terminals were found closely apposed to GLP-1-positive perikarya, and central infusion of OT activated c-Fos expression in GLP-1 neurons. These findings implicate endogenous GLP-1 receptor signaling as an important downstream mediator of anorexia in rats after activation of central OT neural pathways.

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Modulation of Food Intake by Differential TAS2R Stimulation in Rat

Nutrients ◽

10.3390/nu12123784 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3784

Author(s):

Carme Grau-Bové ◽

Alba Miguéns-Gómez ◽

Carlos González-Quilen ◽

José-Antonio Fernández-López ◽

Xavier Remesar ◽

...

Keyword(s):

Food Intake ◽

Peptide Yy ◽

Reduce Food Intake ◽

Intestinal Segments ◽

Regulate Food Intake ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Specific Stimulation ◽

Ghrelin Secretion ◽

Stimulation Of

Metabolic surgery modulates the enterohormone profile, which leads, among other effects, to changes in food intake. Bitter taste receptors (TAS2Rs) have been identified in the gastrointestinal tract and specific stimulation of these has been linked to the control of ghrelin secretion. We hypothesize that optimal stimulation of TAS2Rs could help to modulate enteroendocrine secretions and thus regulate food intake. To determine this, we have assayed the response to specific agonists for hTAS2R5, hTAS2R14 and hTAS2R39 on enteroendocrine secretions from intestinal segments and food intake in rats. We found that hTAS2R5 agonists stimulate glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), and reduce food intake. hTAS2R14 agonists induce GLP1, while hTASR39 agonists tend to increase peptide YY (PYY) but fail to reduce food intake. The effect of simultaneously activating several receptors is heterogeneous depending on the relative affinity of the agonists for each receptor. Although detailed mechanisms are not clear, bitter compounds can stimulate differentially enteroendocrine secretions that modulate food intake in rats.

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Effects of glucagon-like peptide 1 and oxyntomodulin on neuronal activity of ghrelin-sensitive neurons in the hypothalamic arcuate nucleus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00438.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. R1061-R1067 ◽

Cited By ~ 14

Author(s):

Thomas Riediger ◽

Nicole Eisele ◽

Caroline Scheel ◽

Thomas A. Lutz

Keyword(s):

Food Intake ◽

Neuronal Activity ◽

Mode Of Action ◽

Gastrointestinal Hormones ◽

Reduce Food Intake ◽

Hypothalamic Arcuate Nucleus ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

A Minor

Glucagon-like peptide 1 (GLP-1) and oxyntomodulin (OXM) are structurally related gastrointestinal hormones that are secreted in response to food intake. They reduce food intake and body weight and exert partly overlapping actions on glucose homeostasis and gastrointestinal function. The hypothalamic arcuate (ARC) nucleus is among the central structures expressing a high density of GLP-1 receptors (GLP-1R), which are known to be activated by both peptides. It was the aim of our electrophysiological studies to characterize the effects of GLP-1 and OXM on functionally defined ghrelin-sensitive ARC neurons. GLP-1 and OXM (10−7 M) exerted excitatory effects in about two-thirds of ghrelin-inhibited neurons and in approximately one-third of ghrelin-excited cells. In addition, a minor fraction of the ghrelin-excited cells was inhibited by both peptides. There was a high degree of cosensitivity to GLP-1 and OXM, and the effects of both hormones were blocked by the GLP-1R antagonist exendin(9–39). The GLP-1R-mediated excitations and inhibitions persisted under synaptic blockade, indicating a direct postsynaptic mode of action. Our results demonstrate that GLP-1 and OXM directly and similarly alter neuronal activity in the ARC, probably via a common GLP-1R-mediated mechanism. Ghrelin-antagonistic effects on neuronal activity, which might be implicated in ghrelin-antagonistic in vivo actions, resulting from GLP-1R stimulation (e.g., GLP-1R dependent supression of food intake), predominated in ghrelin-inhibited ARC neurons. However, a subset of ghrelin-excited ARC neurons showed responses to OXM or GLP-1, suggesting the existence of a common mode of action for these hormones; the functional relevance of this effect remains to be elucidated.

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