- Email: [email protected]
Discussion Following Dr. Kunos’s Presentation
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The American Journal of Medicine, Vol 120 (9A), September 2007
11. Ravinet Trillou C, Arnone M, Delgorge C, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol. 2003;284:R345–R353. 12. Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298 – 1305. 13. Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lepob/Lepob mice. Int J Obes (Lond). 2005;29:183–187. 14. Bensaid M, Gary-Bobo M, Esclangon A, Moffrand JP, LeFur G, Oury-Donat F, Soubrie P. The cannabinoid CB1 receptor antagonist SR141716 increases acrp20 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol. 2003;63:908 –914. 15. Jo YH, Chen YJ, Chua SC Jr, Talmage DA, Role LW. Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron. 2005;48:1055–1066. 16. Poirier B, Bidouard J-P, Cadrouvele C, et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab. 2005;7:65–72. 17. Pocai A, Obici S, Schwartz GJ, Rossetti L. A brain-liver circuit regulates glucose homeostasis. Cell Metab. 2005;1:53– 61.
18. Diraison F, Yankah V, Letexier D, Dusserre E, Jones P, Beylot M. Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans. J Lipid Res. 2003;44:846 – 853. 19. Brown MS, Goldstein JL. Sterol regulatory element binding proteins (SREBPs): controllers of lipid synthesis and cellular uptake. Nutr Rev. 1998;56(pt 2):S1–S3. 20. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73–100. 21. Biddinger SB, Almind K, Miyazaki M, Kokkotou E, Ntambi JM, Kahn CR. Effects of diet and genetic background on sterol response element binding protein 1c and stearoyl CoA-desaturase-1 and the development of the metabolic syndrome. Diabetes. 2005;54:1314 –1323. 22. Savage DB, Choi S, Samuel VT, et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. 2006; 116:817– 824. 23. Sampath H, Miyazaki M, Dobrzyn A, Ntambi JM. Stearoyl CoAdesaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. J Biol Chem. 2007;282:2483–2493. 24. Lin J, Yang R, Tarr PT, et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1 coactivation of SREBP. Cell. 2005;120:261–273.
Discussion Following Dr. Kunos’s Presentation Question: What is the effect of the cannabinoid-1 (CB1) receptor pathway on behavioral factors other than appetite, such as mood? George Kunos, MD, PhD (Bethesda, Maryland): The antianxiety effect of CB1 receptor activation has generated interest. Of course, in this paradigm the desirable therapeutic goal would be a CB1 receptor agonist, and, in fact, a CB1 antagonist may actually aggravate underlying anxiety and depression. Because no medication is without side effects, we have to be aware of this possibility when treating obese individuals, who may have an underlying anxiety or depressive disorder, with a CB1 antagonist, particularly if dosage increase precipitates effects on mood. However, in certain animal models of depression, CB1 antagonists were reported to have an antidepressant effect, so the situation is complicated as far as depression is concerned. Conversely, preliminary animal studies suggest that amplification of the endogenous endocannabinoid (EC) system may unmask an antianxiety effect mediated by CB1 receptors that could be further developed for therapeutic use. Question: Is serotonin reuptake the mechanism responsible for the effects of CB1 receptor upregulation on mood?
Dr. Kunos: The downstream mechanisms have not yet been explored. However, because serotonin and catecholamines play fundamental roles in regulating mood, I would not be surprised if there was a link. Question: Is the EC system involved in reinforcing or propagating addictive behavior? Dr. Kunos: Because the cannabinoid marijuana is an addictive substance, it was not surprising to learn that ECs, as well as CB1 receptors, are components of the mesolimbic reward pathway. This pathway is activated not only by natural rewards, such as food and sex, but also by chemical rewards, such as drugs and alcohol. Animal studies indicate that the rewarding effects of opiates, nicotine, and alcohol are interrupted by rimonabant.* In the case of nicotine addiction, this forms the basis for the potential usefulness of rimonabant as an adjunct to smoking-cessation therapy. In terms of alcoholism, we have almost completed the first North American study, which is evaluating whether rimonabant can reduce alcohol cravings. We expect to have the results next year. *
Recently an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in future studies.
The American Journal of Medicine, Vol 120 (9A), September 2007
11. Ravinet Trillou C, Arnone M, Delgorge C, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol. 2003;284:R345–R353. 12. Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298 – 1305. 13. Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lepob/Lepob mice. Int J Obes (Lond). 2005;29:183–187. 14. Bensaid M, Gary-Bobo M, Esclangon A, Moffrand JP, LeFur G, Oury-Donat F, Soubrie P. The cannabinoid CB1 receptor antagonist SR141716 increases acrp20 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol. 2003;63:908 –914. 15. Jo YH, Chen YJ, Chua SC Jr, Talmage DA, Role LW. Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron. 2005;48:1055–1066. 16. Poirier B, Bidouard J-P, Cadrouvele C, et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab. 2005;7:65–72. 17. Pocai A, Obici S, Schwartz GJ, Rossetti L. A brain-liver circuit regulates glucose homeostasis. Cell Metab. 2005;1:53– 61.
18. Diraison F, Yankah V, Letexier D, Dusserre E, Jones P, Beylot M. Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans. J Lipid Res. 2003;44:846 – 853. 19. Brown MS, Goldstein JL. Sterol regulatory element binding proteins (SREBPs): controllers of lipid synthesis and cellular uptake. Nutr Rev. 1998;56(pt 2):S1–S3. 20. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73–100. 21. Biddinger SB, Almind K, Miyazaki M, Kokkotou E, Ntambi JM, Kahn CR. Effects of diet and genetic background on sterol response element binding protein 1c and stearoyl CoA-desaturase-1 and the development of the metabolic syndrome. Diabetes. 2005;54:1314 –1323. 22. Savage DB, Choi S, Samuel VT, et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. 2006; 116:817– 824. 23. Sampath H, Miyazaki M, Dobrzyn A, Ntambi JM. Stearoyl CoAdesaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. J Biol Chem. 2007;282:2483–2493. 24. Lin J, Yang R, Tarr PT, et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1 coactivation of SREBP. Cell. 2005;120:261–273.
Discussion Following Dr. Kunos’s Presentation Question: What is the effect of the cannabinoid-1 (CB1) receptor pathway on behavioral factors other than appetite, such as mood? George Kunos, MD, PhD (Bethesda, Maryland): The antianxiety effect of CB1 receptor activation has generated interest. Of course, in this paradigm the desirable therapeutic goal would be a CB1 receptor agonist, and, in fact, a CB1 antagonist may actually aggravate underlying anxiety and depression. Because no medication is without side effects, we have to be aware of this possibility when treating obese individuals, who may have an underlying anxiety or depressive disorder, with a CB1 antagonist, particularly if dosage increase precipitates effects on mood. However, in certain animal models of depression, CB1 antagonists were reported to have an antidepressant effect, so the situation is complicated as far as depression is concerned. Conversely, preliminary animal studies suggest that amplification of the endogenous endocannabinoid (EC) system may unmask an antianxiety effect mediated by CB1 receptors that could be further developed for therapeutic use. Question: Is serotonin reuptake the mechanism responsible for the effects of CB1 receptor upregulation on mood?
Dr. Kunos: The downstream mechanisms have not yet been explored. However, because serotonin and catecholamines play fundamental roles in regulating mood, I would not be surprised if there was a link. Question: Is the EC system involved in reinforcing or propagating addictive behavior? Dr. Kunos: Because the cannabinoid marijuana is an addictive substance, it was not surprising to learn that ECs, as well as CB1 receptors, are components of the mesolimbic reward pathway. This pathway is activated not only by natural rewards, such as food and sex, but also by chemical rewards, such as drugs and alcohol. Animal studies indicate that the rewarding effects of opiates, nicotine, and alcohol are interrupted by rimonabant.* In the case of nicotine addiction, this forms the basis for the potential usefulness of rimonabant as an adjunct to smoking-cessation therapy. In terms of alcoholism, we have almost completed the first North American study, which is evaluating whether rimonabant can reduce alcohol cravings. We expect to have the results next year. *
Recently an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in future studies.