The cannabinoids affect both feeding responses and energy balance through mechanisms that are distinctive from those of the melanocortins. The cannabinoid system19 includes two GPCRs, cannabinoid receptors-1 (CB1) and -2 (CB2); transporters and hydrolyzing enzymes responsible for metabolizing lipophilic natural ligands; and the endocannabinoids, anandamide and 2-arachidonoyl glycerol.2021 These endogenous ligands exert potent orexigenic effects and impact reward centers in the brain, thereby eliciting responses that enhance feeding stimuli and palatability. CB1 is expressed centrally in areas responsible for hedonic responses (e.g., nucleus accumbens and hippocampus) and energy homeostasis (hypothalamus and nucleus of the solitary tract) and in epidydimal fat depots where it stimulates lipogenesis.22
The endocannabinoid system is an integral part of the neural circuitry regulated by leptin.23 Whereas administration of leptin reduces the levels of anandamide and 2-arachidonoyl glycerol in the hypothalamus of normal rats, endocannabinoid levels are elevated in leptin-deficient mice and in diet-induced obese mice in which leptin levels are also elevated. CB1-knockout mice are lean, compared to their wild-type littermates, but mechanisms that underlie this leanness appear to differ with age. Young CB1-null mice are hypophagic, while altered metabolism appears to be responsible for the lean phenotype of their adult counterparts.2425
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