Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding.
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.
Judge
M K
MK
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, PO Box 100267, Gainesville, Florida 32610, USA.
Zhang
Y
Y
Scarpace
P J
PJ
D000367:Age Factors; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001823:Body Composition; D004041:Dietary Fats / Q000008:administration & dosage; D002149:Energy Intake / Q000187:drug effects; D006963:Hyperphagia / Q000209:etiology; D007473:Ion Channels / Q000032:analysis; D020738:Leptin / Q000097:blood / Q000494:pharmacology; D008297:Male; D024101:Mitochondrial Proteins / Q000032:analysis; D009765:Obesity / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071256:Uncoupling Protein 1; D015430:Weight Gain / Q000187:drug effects
D001067:Appetite Depressants; D004041:Dietary Fats; D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D000071256:Uncoupling Protein 1; C103505:AM 251