Endogenous cannabinoids acting at CB 1 receptors stimulate appetite, and CB 1 antagonists show promise in the treatment of obesity. CB 1 -/-mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB 1 in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB 1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB 1 . High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB 1 density, and basal rates of fatty acid synthesis, and the latter is reduced by CB 1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB 1 ligands. We conclude that anandamide acting at hepatic CB 1 contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation. IntroductionMaintenance of energy homeostasis and body weight involves the coordinated regulation of appetitive behavior and peripheral energy metabolism (1), as illustrated by the ability of the appetitereducing hormone leptin to regulate fat metabolism in the liver (2). Endocannabinoids are novel lipid mediators that modulate appetitive behavior through the activation of CB 1 (3-11). Sites in the hypothalamus (4, 10, 12), limbic forebrain (11-13), and peripheral sensory nerve terminals (7) have been implicated in mediating the orexigenic effect of endocannabinoids, which is potentiated by hunger or in hyperphagia associated with obesity (4-6, 9) and antagonized by CB 1 blockade. Indeed, CB 1 antagonists show promise in the treatment of obesity (14). A number of recent observations suggest that reduction of food intake alone cannot fully account for the antiobesity effects of CB 1 antagonists. In a mouse model of diet-induced obesity, chronic treatment with the CB 1 antagonist SR141716 caused a transient reduction in food intake and a more prolonged reduction in body weight (15). Mice lacking CB 1 are resistant to diet-induced obesity even though their total caloric intake is similar to that of wild-type littermates, which become obese on the same diet (16). CB 1 -/-mice display a moderately lean phenotype throughout adulthood but only a temporary hypophagia in the first few weeks of life (17). These observations suggest that endocannabinoids and CB 1 also regulate peripheral energy metabolism. Indeed, adipocytes have been found to express

Endogenous cannabinoids acting at CB 1 receptors stimulate appetite, and CB 1 antagonists show promise in the treatment of obesity. CB 1 -/-mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB 1 in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB 1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB 1 . High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB 1 density, and basal rates of fatty acid synthesis, and the latter is reduced by CB 1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB 1 ligands. We conclude that anandamide acting at hepatic CB 1 contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation. IntroductionMaintenance of energy homeostasis and body weight involves the coordinated regulation of appetitive behavior and peripheral energy metabolism (1), as illustrated by the ability of the appetitereducing hormone leptin to regulate fat metabolism in the liver (2). Endocannabinoids are novel lipid mediators that modulate appetitive behavior through the activation of CB 1 (3-11). Sites in the hypothalamus (4, 10, 12), limbic forebrain (11-13), and peripheral sensory nerve terminals (7) have been implicated in mediating the orexigenic effect of endocannabinoids, which is potentiated by hunger or in hyperphagia associated with obesity (4-6, 9) and antagonized by CB 1 blockade. Indeed, CB 1 antagonists show promise in the treatment of obesity (14). A number of recent observations suggest that reduction of food intake alone cannot fully account for the antiobesity effects of CB 1 antagonists. In a mouse model of diet-induced obesity, chronic treatment with the CB 1 antagonist SR141716 caused a transient reduction in food intake and a more prolonged reduction in body weight (15). Mice lacking CB 1 are resistant to diet-induced obesity even though their total caloric intake is similar to that of wild-type littermates, which become obese on the same diet (16). CB 1 -/-mice display a moderately lean phenotype throughout adulthood but only a temporary hypophagia in the first few weeks of life (17). These observations suggest that endocannabinoids and CB 1 also regulate peripheral energy metabolism. Indeed, adipocytes have been found to express

Background-Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension. Methods and Results-In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB 1 ) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB 1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB 1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB 1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats. Conclusions-We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB 1 -mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.