Effects of the CB1 cannabinoid receptor inverse agonist AM251 on food intake and body weight in mice lacking μ-opioid receptors

Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

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In Vivo Characterization of High Basal Signaling from the Ghrelin Receptor

Endocrinology ◽

10.1210/en.2008-1638 ◽

2009 ◽

Vol 150 (11) ◽

pp. 4920-4930 ◽

Cited By ~ 74

Author(s):

Pia Steen Petersen ◽

David P. D. Woldbye ◽

Andreas Nygaard Madsen ◽

Kristoffer L. Egerod ◽

Chunyu Jin ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Uncoupling Protein ◽

Inverse Agonist ◽

Single Amino Acid ◽

Separate Experiment ◽

Ghrelin Receptor ◽

Control Peptide ◽

Constitutively Active

The receptor for the orexigenic peptide, ghrelin, is one of the most constitutively active 7TM receptors known, as demonstrated under in vitro conditions. Change in expression of a constitutively active receptor is associated with change in signaling independent of the endogenous ligand. In the following study, we found that the expression of the ghrelin receptor in the hypothalamus was up-regulated approximately 2-fold in rats both during 48-h fasting and by streptozotocin-induced hyperphagia. In a separate experiment, to probe for the effect of the high basal signaling of the ghrelin receptor in vivo, we used intracerebroventricular administration by osmotic pumps of a peptide [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P. This peptide selectively displays inverse agonism at the ghrelin receptor as compared with an inactive control peptide with just a single amino acid substitution. Food intake and body weight were significantly decreased in the group of rats treated with the inverse agonist, as compared with the groups treated with the control peptide or the vehicle. In the hypothalamus, the expression of neuropeptide Y and uncoupling protein 2 was decreased by the inverse agonist. In a hypothalamic cell line that endogenously expresses the ghrelin receptor, we observed high basal activity of the cAMP response element binding protein, an important signaling transduction pathway for appetite regulation. The activation was further increased by ghrelin administration and decreased by administration of the inverse agonist. It is suggested that the high constitutive signaling activity is important for the in vivo function of the ghrelin receptor in the control of food intake and body weight.

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Effects of a [Met]-enkephalin analogue ([d-Ala2,N-Me-Phe4,Met-(O)5-ol]-enkephalin) on canine pituitary function

Journal of Endocrinology ◽

10.1677/joe.0.1270265 ◽

1990 ◽

Vol 127 (2) ◽

pp. 265-271 ◽

Cited By ~ 7

Author(s):

B. P. Meij ◽

A. Rijnberk ◽

J. A. Mol

Keyword(s):

Body Weight ◽

Opioid Receptors ◽

Arginine Vasopressin ◽

Plasma Concentrations ◽

Pituitary Function ◽

Opiate Antagonist ◽

Beagle Dogs ◽

Dose Rates ◽

Dose Dependent ◽

Μ Opioid Receptors

ABSTRACT In adult healthy beagle dogs, plasma concentrations of ACTH, cortisol, α-MSH, GH, prolactin and arginine vasopressin (AVP) were measured after i.v. administration of [d-Ala2,N-Me-Phe4,Met-(O)5-ol]-enkephalin (DAMME) at doses of 0·1, 0·5, 1, 5 and 10 μg/kg body weight. Significant dose-dependent increases occurred for ACTH, cortisol and GH at dose rates of 0·5, 1, 5 and 10 μg/kg body weight. Increments in plasma concentrations of prolactin were significant only at 5 and 10 μg DAMME/kg, and there was no significant effect on plasma concentrations of α-MSH and AVP. Prior i.v. administration of the opiate antagonist naloxone (0·1 mg/kg) attenuated the DAMME (10 μg/kg)-stimulated release of ACTH and cortisol. The results demonstrate that the [Met]-enkephalin analogue DAMME stimulates the release of ACTH, cortisol, GH and prolactin in dogs, and that this stimulation is, at least in part, mediated by μ-opioid receptors. The observations for ACTH and cortisol are different from those in man, where DAMME lowers their basal concentrations. Journal of Endocrinology (1990) 127, 265–271

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