Mice Expressing a "Hyper-Sensitive" Form of the Cannabinoid Receptor 1

Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB.sub.1 in rodents leads to reduced body weight, resistance to diet-induced obesity, decreased intake of highly palatable food, and increased...

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Bibliographic Details
Published in:PloS one 2016-08, Vol.11 (8), p.e0160462
Main Authors: Marcus, David J, Zee, Michael L, Davis, Brian J, Haskins, Chris P, Andrews, Mary-Jeanette, Amin, Randa, Henderson-Redmond, Angela N, Mackie, Ken, Czyzyk, Traci A, Morgan, Daniel J
Format: Article
Language:English
Subjects:
Blood glucose
Body weight
Obesity
Physiological aspects
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Summary:Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB.sub.1 in rodents leads to reduced body weight, resistance to diet-induced obesity, decreased intake of highly palatable food, and increased energy expenditure. Cannabinoid agonists stimulate feeding in rodents and increased levels of endocannabinoids can disrupt lipid metabolism. Therefore, the hypothesis that sustained endocannabinoid signaling can lead to obesity and diabetes was examined in this study using S426A/S430A mutant mice expressing a desensitization-resistant CB.sub.1 receptor. These mice display exaggerated and prolonged responses to acute administration of phytocannabinoids, synthetic cannabinoids, and endocannabinoids. As a consequence these mice represent a novel model for determining the effect of enhanced endocannabinoid signaling on metabolic disease. S426A/S430A mutants consumed equivalent amounts of both high fat (45%) and low fat (10%) chow control diet compared to wild-type littermate controls. S426A/S430A mutants and wild-type mice fed either high or low fat control diet displayed similar fasting blood glucose levels and normal glucose clearance following a 2 g/kg glucose challenge. Furthermore, S426A/S430A mutants and wild-type mice consumed similar amounts of chow following an overnight fast. While both THC and JZL195 significantly increased food intake two hours after injection, this increase was similar between the S426A/S430A mutant and wildtype control mice Our results indicate that S426A/S430A mutant mice expressing the desensitization-resistant form of CB.sub.1 do not exhibit differences in body weight, food intake, glucose homeostasis, or re-feeding following a fast.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0160462