title: Mice Expressing a "Hyper-Sensitive" Form of the Cannabinoid Receptor 1 (CB1) Are Neither Obese Nor Diabetic.
abstract: Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB1 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 CB1 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 CB1 do not exhibit differences in body weight, food intake, glucose homeostasis, or re-feeding following a fast.
authors: Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, 47405,United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, 47405, United States of America.|Department of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania, 17033, United States of America.
authors: David J
authors: DJ
authors: Marcus
authors: Department of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania, 17033, United States of America.
authors: Michael L
authors: ML
authors: Zee
authors: Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, 47405,United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, 47405, United States of America.
authors: Brian J
authors: BJ
authors: Davis
authors: Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, 47405,United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, 47405, United States of America.|Department of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania, 17033, United States of America.
authors: Chris P
authors: CP
authors: Haskins
authors: Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, 47405,United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, 47405, United States of America.|Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, 47405, United States of America.
authors: Mary-Jeanette
authors: MJ
authors: Andrews
authors: Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, 47405,United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, 47405, United States of America.|Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, 47405, United States of America.
authors: Randa
authors: R
authors: Amin
authors: Department of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania, 17033, United States of America.
authors: Angela N
authors: AN
authors: Henderson-Redmond
authors: Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, 47405,United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, 47405, United States of America.|Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, 47405, United States of America.
authors: Ken
authors: K
authors: Mackie
authors: Department of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania, 17033, United States of America.
authors: Traci A
authors: TA
authors: Czyzyk
authors: Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, 47405,United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, 47405, United States of America.|Department of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania, 17033, United States of America.|Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, 47405, United States of America.
authors: Daniel J
authors: DJ
authors: Morgan
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D002219:Carbamates / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects / Q000235:genetics*; D005951:Glucose Tolerance Test; D008297:Male; D008817:Mice, Mutant Strains; D009765:Obesity / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D002219:Carbamates; C000592052:JZL195; D010879:Piperazines; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol