am-356 and Obesity

Ghrelin and anandamide (AEA) can regulate the sensitivity of gastric vagal afferents to stretch, an effect mediated via the transient receptor potential vanilloid 1 (TPRV1) channel. High fat diet (HFD)-induced obesity alters the modulatory effects of ghrelin and AEA on gastric vagal afferent sensitivity. This may be a result of altered gastric levels of these hormones and subsequent changes in the expression of their receptors. Therefore, the current study aimed to determine the effects of ghrelin and AEA on vagal afferent cell body mRNA content of cannabinoid 1 receptor (CB1), ghrelin receptor (GHSR), TRPV1, and the enzyme responsible for the breakdown of AEA, fatty acid amide hydrolase (FAAH).. Mice were fed a standard laboratory diet (SLD) or HFD for 12wks. Nodose ganglia were removed and cultured for 14 h in the absence or presence of ghrelin or methAEA (mAEA; stable analogue of AEA). Relative mRNA content of CB1, GHSR, TRPV1, and FAAH were measured.. In nodose cells from SLD-mice, mAEA increased TRPV1 and FAAH mRNA content, and decreased CB1 and GHSR mRNA content. Ghrelin decreased TRPV1, CB1, and GHSR mRNA content. In nodose cells from HFD-mice, mAEA had no effect on TRPV1 mRNA content, and increased CB1, GHSR, and FAAH mRNA content. Ghrelin decreased TRPV1 mRNA content and increased CB1 and GHSR mRNA content.. AEA and ghrelin modulate receptors and breakdown enzymes involved in the mAEA-vagal afferent satiety signalling pathways. This was disrupted in HFD-mice, which may contribute to the altered vagal afferent signalling in obesity.

Topics: Afferent Pathways; Amidohydrolases; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Diet, High-Fat; Endocannabinoids; Gastric Mucosa; Gene Expression Regulation; Ghrelin; Male; Mice; Mice, Inbred C57BL; Nodose Ganglion; Obesity; Receptor, Cannabinoid, CB1; Receptors, Ghrelin; Signal Transduction; Tissue Culture Techniques; TRPV Cation Channels

Cannabinoid (CB)(1) receptors are present throughout the nervous system, including several areas implicated in the control of food intake. Central and peripheral administration of CB(1) agonists increase food intake while CB(1) receptor antagonists reduce food intake. However, in some previous studies, tolerance to the anorectic effects of CB(1) antagonists develops within days. To further delineate the role of endogenous cannabinoid signaling in energy intake, we studied the effects of the CB(1) antagonist AM 251 (1.25, 2.5 and 5 mg/kg ip), the anandamide membrane transporter inhibitor VDM 11 (10 mg/kg ip), and the CB(1) agonists anandamide (1 mg/kg ip), and methanandamide (1 mg/kg ip), on food intake. A single administration of the CB(1) antagonist AM 251 significantly reduced food intake for a total of 6 days (P<.05). Reductions in food intake brought about by AM 251 were accompanied by reductions in weight gain for 6 days (P<.05). Contrary to expectations, VDM 11 did not increase food intake in this study. Anandamide was also unable to increase food intake; however, the more stable agonist methanandamide significantly increased food intake 3 h after administration (P<.05). These results support the role of CB(1) receptor antagonists in the treatment of obesity and suggest that the anorectic effect of AM 251 may last longer than previously reported.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Dose-Response Relationship, Drug; Eating; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Inbred Lew; Receptor, Cannabinoid, CB1; Time Factors