Weeks

Fig. 3. SR141716 (rimonabant) decreases body weight in overweight and obese humans over the course of 1 yr. In RIO-Europe, a total of 1507 patients with body-mass index 30 kg/m2 or greater, or body-mass index greater than 27 kg/m2 with treated or untreated dyslipidemia, hypertension, or both, were randomized to receive double-blind treatment with placebo, 5 mg rimonabant, or 20 mg rimonabant once daily in addition to a mild hypocaloric diet (600 kcal/d deficit). (*p < 0.05; ** p < 0.01; redrawn from ref. 120).

lipid profiles (120). There were no interactions among weight loss and sex, changes in metabolic parameters, or reduction in waist circumference. Importantly, analyses of both studies suggest that the improvement in the lipid and glycemic profiles is greater than could be explained by the decrease of body weight. Hence, as has also been observed in animal experiments, rimonabant causes improved metabolic parameters beyond its effects on food intake and body weight. In summary, the first data obtained from clinical trials indicate that the pharmacological blockade of CB1 has therapeutic potential for the treatment of obesity and its associated risk factors.

Endocannabinoids are fatty acid signals derived from cell membranes in the brain and many other tissues. Although they influence numerous systems and behaviors, this review has focused on their coordinated action at multiple tissues to act at CB1 receptors and promote increased food intake, lipogenesis, and the storage of fat. Within the brain, endocannabinoids interact with hypothalamic circuits as well as with reward areas to enhance intake of palatable foods. Within adipose tissue and liver, endocannabinoids increase expression of enzymes that remove fat from the blood and store it in cells, as well as enzymes that facilitate the de novo generation of fatty acids. There is also evidence that cannabinoid activity in the gastrointestinal tract and in skeletal muscle also contributes to the net anabolic action. Converging evidence indicates that activity of the endocannabinoid system is tonically increased in animal and human obesity, and that animals lacking cannabinoid receptors are resistant to becoming obese. Consistent with these findings, acute or chronic administration of selective synthetic CB1 antagonists to overweight or obese individuals results in weight loss, reduced waist circumference, and an improved lipid and glycemic profile. Developing ligands for endocannabinoid receptors is an important novel therapeutic strategy for the treatment of metabolic dysregulation.

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