ABSTRACT
Although, as outlined in theprevious chapters of this book, the functions of the endocannabinoid system in the peripheral control of metabolism under physiologic conditions are still not fully understood, there is increasing evidence for an important role played by endocannabinoids under conditions of unbalanced energyhomeostasis, such as obesity andhyperglycemia. Several observations suggest that a dysregulation of endocannabinoid tone at CB1 receptors occurs during such conditions: (i) a given dose of an antagonist at a certain receptor is expected to have higher efficacy in the presence of a higher tone of endogenous agonists of that receptor-this is also true to some extent for CB1 antagonists like rimonabant (1), even though these compounds have been described to act in vitro as inverse agonists at high doses (and hence also produce effects opposite to those of agonists in the absence of endogenous agonists); (ii) blockade of CB1 receptors inhibits food intake and decreases body weight more efficaciously in obese rodents than in lean animals (2,3); (iii) even in lean rodents, CB1 receptor antagonists appear to be more efficacious in the presence of a demonstrated higher tone of the endocannabinoid system in the brain areas that control food intake, such as following brief periods of food deprivation or when animals are exposed to palatable foods (4). Thus, the higher efficacy against food intake observed in obese versus lean animals with CB1 antagonists such as rimonabant or AM251 (2,5), and the sensitivity to these agents of obese rodents also in the absence of food deprivation (3), strongly suggest that a higher endocannabinoid tone stimulates food consumption in obesity. Accordingly, hypothalamic endocannabinoid levels are significantly higher in ob/ob and db/db mice or in Zucker rats (3), as it could have been expected from the fact that these rodents possess defective leptin signaling or levels, and also from the fact that leptin negatively controls EC levels (3). Importantly, daily systemic administration of CB1 antagonists in obese rodents for several weeks causes a reduction of body weight that outlives the inhibition of food intake, which is significant for only ∼1 week after the start of the treatment (6). Thus, it is possible that the part of the endocannabinoid system that controls the peripheral aspects of energy balance becomes more active with obesity and for a longer time as compared to what might happen in the brain.
