PMID:19679649

Citation	Judge, MK, Zhang, Y and Scarpace, PJ (2009) Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding. J. Endocrinol. 203:281-90
Abstract	Endocannabinoids (EC) are involved in regulating energy homeostasis, particularly in promoting hyperphagia and the consumption of a palatable diet. We have previously shown that rats given a high-fat (HF) diet display a transient hyperphagia that is normalized by a process partially dependent on leptin. We now propose that the induction of this hyperphagia is mediated, at least partially, by the EC signaling system. Obesity, including diet-induced and age-related, is associated with dysregulation of the EC system, and obese rodent models are hypersensitive to a cannabinoid-1 (CB1) receptor antagonist. This suggests that aged rats will be more responsive to the anorectic effects of a CB1 receptor antagonist. To test this, we examined the responsiveness to CB1 receptor antagonist, AM251, in young and aged rats during two experimental paradigms. First, we administered AM251 simultaneously with the introduction of an HF diet. Second, AM251 treatment began after the establishment of diet-induced obesity. Responses were measured by changes in body weight and composition, calorie intake, serum leptin, and biochemical indicators. The results demonstrated three key findings. 1) CB1 receptor activity contributes to the hyperphagia seen with the introduction of an HF diet. 2) Increased AM251 sensitivity and efficacy is increased with age and HF feeding, with the greatest responsiveness observed in HF-fed, aged rats. 3) AM251 sensitivity is elevated to a greater extent with HF diet than with established obesity. Thus, both age and an HF diet are associated with enhanced anorectic responses to AM251, but the underlying mechanism of these responses remains speculative.
Links	PubMed Online version:10.1677/JOE-09-0210
Keywords	Age Factors; Animals; Appetite Depressants/pharmacology; Body Composition; Dietary Fats/administration & dosage; Energy Intake/drug effects; Hyperphagia/etiology; Ion Channels/analysis; Leptin/blood; Leptin/pharmacology; Male; Mitochondrial Proteins/analysis; Obesity/drug therapy; Piperidines/pharmacology; Pyrazoles/pharmacology; Rats; Rats, Inbred F344; Receptor, Cannabinoid, CB1/antagonists & inhibitors; Receptor, Cannabinoid, CB1/physiology; STAT3 Transcription Factor/metabolism; Weight Gain/drug effects
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:CNR1	involved_in	GO:0007568: aging	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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