Ghrelin signaling contributes to fasting-induced attenuation of hindbrain neural activation and hypophagic responses to systemic cholecystokinin in rats

In rats, overnight fasting reduces the ability of systemic cholecystokinin-8 (CCK) to suppress food intake and to activate cFos in the caudal nucleus of the solitary tract (cNTS), specifically within glucagon-like peptide-1 (GLP-1) and noradrenergic (NA) neurons of the A2 cell group. Systemic CCK increases vagal sensory signaling to the cNTS, an effect that is amplified by leptin and reduced by ghrelin. Since fasting reduces plasma leptin and increases plasma ghrelin levels, we hypothesized that peripheral leptin administration and/or antagonism of ghrelin receptors in fasted rats would rescue the ability of CCK to activate GLP-1 neurons and a caudal subset of A2 neurons that coexpress prolactin-releasing peptide (PrRP). To test this, cFos expression was examined in ad libitum-fed and overnight food-deprived (DEP) rats after intraperitoneal CCK, after coadministration of leptin and CCK, or after intraperitoneal injection of a ghrelin receptor antagonist (GRA) before CCK. In fed rats, CCK activated cFos in ~60% of GLP-1 and PrRP neurons. Few or no GLP-1 or PrRP neurons expressed cFos in DEP rats treated with CCK alone, CCK combined with leptin, or GRA alone. However, GRA pretreatment increased the ability of CCK to activate GLP-1 and PrRP neurons and also enhanced the hypophagic effect of CCK in DEP rats. Considered together, these new findings suggest that reduced behavioral sensitivity to CCK in fasted rats is at least partially due to ghrelin-mediated suppression of hindbrain GLP-1 and PrRP neural responsiveness to CCK.

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Brainstem Thyrotropin-Releasing Hormone Regulates Food Intake through Vagal-Dependent Cholinergic Stimulation of Ghrelin Secretion

Endocrinology ◽

10.1210/en.2006-0820 ◽

2006 ◽

Vol 147 (12) ◽

pp. 6004-6010 ◽

Cited By ~ 30

Author(s):

Yan Ao ◽

Vay Liang W. Go ◽

Natalie Toy ◽

Tei Li ◽

Yu Wang ◽

...

Keyword(s):

Food Intake ◽

Receptor Antagonist ◽

Brain Stem ◽

Motor Neurons ◽

Physiological Role ◽

Natural Food ◽

Ghrelin Receptor ◽

Ghrelin Receptor Antagonist ◽

Fasted Rats ◽

Stimulation Of

The brainstem is essential for mediating energetic response to starvation. Brain stem TRH is synthesized in caudal raphe nuclei innervating brainstem and spinal vagal and sympathetic motor neurons. Intracisternal injection (ic) of a stable TRH analog RX77368 (7.5–25 ng) dose-dependently stimulated solid food intake by 2.4- to 3-fold in freely fed rats, an effect that lasted for 3 h. By contrast, RX77368 at 25 ng injected into the lateral ventricle induced a delayed and insignificant orexigenic effect only in the first hour. In pentobarbital-anesthetized rats, RX77368 (50 ng) ic induced a significant bipeak increase in serum total ghrelin levels from the basal of 8.7 ± 1.7 ng/ml to 13.4 ± 2.4 ng/ml at 30 min and 14.5 ± 2.0 ng/ml at 90 min, which was prevented by either bilateral vagotomy (−60 min) or atropine pretreatment (2 mg/kg, −30 min) but magnified by bilateral adrenalectomy (−60 min). TRH analog ic-induced food intake in freely fed rats was abolished by either peripheral atropine or ghrelin receptor antagonist (d-Lys-3)-GHRP-6 (10 μmol/kg) or ic Y1 receptor antagonist 122PU91 (10 nmol/5 μl). Brain stem TRH mRNA and TRH receptor 1 mRNA increased by 57–58 and 33–35% in 24- and 48-h fasted rats and returned to the fed levels after a 3-h refeeding. Natural food intake in overnight fasted rats was significantly reduced by ic TRH antibody, ic Y1 antagonist, and peripheral atropine. These data establish a physiological role of brainstem TRH in vagal-ghrelin-mediated stimulation of food intake, which involves interaction with brainstem Y1 receptors.

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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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GSK1614343, a Novel Ghrelin Receptor Antagonist, Produces an Unexpected Increase of Food Intake and Body Weight in Rodents and Dogs

Neuroendocrinology ◽

10.1159/000328968 ◽

2011 ◽

Vol 94 (2) ◽

pp. 158-168 ◽

Cited By ~ 31

Author(s):

Vivian J.A. Costantini ◽

Elena Vicentini ◽

Fabio M. Sabbatini ◽

Enzo Valerio ◽

Stefano Lepore ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Receptor Antagonist ◽

Ghrelin Receptor ◽

Ghrelin Receptor Antagonist

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Adiposity-independent sympathetic activity in black men

Journal of Applied Physiology ◽

10.1152/japplphysiol.00058.2010 ◽

2010 ◽

Vol 108 (6) ◽

pp. 1613-1618 ◽

Cited By ~ 13

Author(s):

Aamer Abbas ◽

Lidia S. Szczepaniak ◽

Meryem Tuncel ◽

Jonathan M. McGavock ◽

Beverley Huet ◽

...

Keyword(s):

Body Mass Index ◽

Weight Loss ◽

Black Women ◽

Black Men ◽

Body Mass ◽

Sympathetic Activity ◽

Abdominal Fat ◽

New Findings ◽

Visceral Abdominal Fat ◽

Plasma Leptin

Obesity is thought to lead to sympathetic overactivity as a compensatory adjustment to weight gain. However, most of the experimental support for the hypothesis has been derived from white cohorts. Our previous study in blacks indicated that sympathetic nerve activity (SNA) is closely correlated with body mass index only in women, whereas, in black men, SNA is elevated and dissociated from adiposity (Abate et al., Hypertension 38: 379–383, 2001). To further determine whether total and regional adiposity are determinants of SNA in blacks, we performed a prospective weight loss study in 12 normotensive obese black men and 9 obese black women. SNA, body mass index, and abdominal fat mass were measured before and 16 wk after hypocaloric diet. The major new findings are that, in obese black men, the dietary-induced weight loss of 11.3 ± 0.8 kg resulted in reduction in plasma leptin, insulin, and visceral abdominal fat but had no effect on SNA (from baseline of 26 ± 4 to 28 ± 3 bursts/min, P = not significant). In contrast, in black women, weight loss of 8.0 ± 0.9 kg caused similar reductions in plasma leptin, insulin, and visceral abdominal fat and led to a reduction in SNA by 40% (from baseline of 22 ± 2 to 13 ± 3 bursts/min, P < 0.05). In conclusion, these new data from this prospective study provide strong support for a major adiposity-independent sympathetic activity in black men and adiposity-related sympathetic activity in black women.

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Pharmacological characterization of the ghrelin receptor antagonist, GSK1614343 in rat RC-4B/C cells natively expressing GHS type 1a receptors

European Journal of Pharmacology ◽

10.1016/j.ejphar.2010.10.042 ◽

2011 ◽

Vol 650 (1) ◽

pp. 178-183 ◽

Cited By ~ 17

Author(s):

Elisabetta Perdonà ◽

Federico Faggioni ◽

Alberto Buson ◽

Fabio Maria Sabbatini ◽

Corrado Corti ◽

...

Keyword(s):

Receptor Antagonist ◽

C Cells ◽

Pharmacological Characterization ◽

Ghrelin Receptor ◽

Ghrelin Receptor Antagonist

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Ghrelin receptor agonist hexarelin attenuates antinociceptive tolerance to morphine in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0218 ◽

2020 ◽

Author(s):

Tayfun Baser ◽

Ercan Ozdemir ◽

Ahmet Kemal Filiz ◽

Ahmet Sevki Taskiran ◽

Sinan Gursoy

Keyword(s):

Analgesic Activity ◽

Receptor Agonist ◽

Morphine Tolerance ◽

Peptide Hormone ◽

Tail Flick ◽

Analgesic Tolerance ◽

Ghrelin Receptor ◽

Analgesic Effects ◽

Ghrelin Receptor Agonist ◽

Ghrelin Receptor Antagonist

Ghrelin is a peptide hormone released from the gastric endocrine glands and shows analgesic activity apart from its various physiological effects. Nevertheless, the effects of ghrelin receptor (GHS-R) agonists on morphine analgesia and tolerance have not been elucidated yet. The purpose of the study was to evaluate the effects of the ghrelin receptor agonist hexarelin and antagonist [D-Lys3]-GHRP-6 on morphine antinociception and tolerance in rats. A total of 104 Wistar albino male adults rats (weighing approximately 220-240 g) were used in the experiments. To induce morphine tolerance a 3-day cumulative dose regimen was used in rats. Then, randomly selected rats were evaluated for morphine tolerance on day 4. The analgesic effects of hexarelin (0.2 mg/kg), [D-Lys3]-GHRP-6 (10 mg/kg), and morphine (5 mg/kg) were measured at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. The findings suggest that hexarelin in combination with morphine attenuates analgesic tolerance to morphine. On the other hand, ghrelin receptor antagonist [D-Lys3]-GHRP-6 has no significant analgesic activity on the morphine tolerance in analgesia tests. Besides, co-administration of hexarelin and morphine increases the analgesic effect. In conclusion, these data indicate that administration of GHS-R agonist hexarelin with morphine enhances the antinociception and attenuates morphine tolerance.

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A liquid mixed meal or exogenous glucagon-like peptide 1 (GLP-1) do not alter plasma leptin concentrations in healthy volunteers

Acta Diabetologica ◽

10.1007/s005920050079 ◽

1997 ◽

Vol 34 (3) ◽

pp. 230-234 ◽

Cited By ~ 7

Author(s):

C. Drewes ◽

M. A. Nauck ◽

R. Horn ◽

J. Holst ◽

W. Schmiegel ◽

...

Keyword(s):

Healthy Volunteers ◽

Mixed Meal ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Plasma Leptin

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Gastric Mammalian Target of Rapamycin Signaling Regulates Ghrelin Production and Food Intake

Endocrinology ◽

10.1210/en.2009-0372 ◽

2009 ◽

Vol 150 (8) ◽

pp. 3637-3644 ◽

Cited By ~ 54

Author(s):

Geyang Xu ◽

Yin Li ◽

Wenjiao An ◽

Shenduo Li ◽

Youfei Guan ◽

...

Keyword(s):

Food Intake ◽

Energy Homeostasis ◽

Mammalian Target Of Rapamycin ◽

Reciprocal Relationship ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Energy Status ◽

Ghrelin Receptor ◽

Ghrelin Receptor Antagonist ◽

Mtor Activity

Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate food intake. Mammalian target of rapamycin (mTOR) is an intracellular fuel sensor critical for cellular energy homeostasis. Here we showed the reciprocal relationship of gastric mTOR signaling and ghrelin during changes in energy status. mTOR activity was down-regulated, whereas gastric preproghrelin and circulating ghrelin were increased by fasting. In db/db mice, gastric mTOR signaling was enhanced, whereas gastric preproghrelin and circulating ghrelin were decreased. Inhibition of the gastric mTOR signaling by rapamycin stimulated the expression of gastric preproghrelin and ghrelin mRNA and increased plasma ghrelin in both wild-type and db/db mice. Activation of the gastric mTOR signaling by l-leucine decreased the expression of gastric preproghrelin and the level of plasma ghrelin. Overexpression of mTOR attenuated ghrelin promoter activity, whereas inhibition of mTOR activity by overexpression of TSC1 or TSC2 increased its activity. Ghrelin receptor antagonist d-Lys-3-GH-releasing peptide-6 abolished the rapamycin-induced increment in food intake despite that plasma ghrelin remained elevated. mTOR is therefore a gastric fuel sensor whose activity is linked to the regulation of energy intake through ghrelin.

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