Taranabant Cuts the Fat: New Hope for Cannabinoid-Based Obesity Therapies?
2008; Cell Press; Volume: 7; Issue: 1 Linguagem: Inglês
10.1016/j.cmet.2007.12.006
ISSN1932-7420
Autores Tópico(s)Neurotransmitter Receptor Influence on Behavior
ResumoEndocannabinoid/cannabinoid receptor signaling acts centrally and peripherally to govern appetite and energy balance. While system stimulation promotes eating and energy storage, receptor blockade can reduce food intake and facilitate weight loss. In this issue of Cell Metabolism, Addy et al., 2008Addy C. Wright H. Van Laere K. Gantz I. Erondu N. Musser B.J. Lu K. Yuan J. Sanabria-Bohórquez S.M. Stoch A. et al.Cell Metab. 2008; 7 (this issue): 68-78Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar test the therapeutic antiobesity potential of taranabant, a cannabinoid 1 receptor inverse agonist. Endocannabinoid/cannabinoid receptor signaling acts centrally and peripherally to govern appetite and energy balance. While system stimulation promotes eating and energy storage, receptor blockade can reduce food intake and facilitate weight loss. In this issue of Cell Metabolism, Addy et al., 2008Addy C. Wright H. Van Laere K. Gantz I. Erondu N. Musser B.J. Lu K. Yuan J. Sanabria-Bohórquez S.M. Stoch A. et al.Cell Metab. 2008; 7 (this issue): 68-78Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar test the therapeutic antiobesity potential of taranabant, a cannabinoid 1 receptor inverse agonist. Work over recent years has identified the cannabinoid receptors as mediators of the pharmacological actions of the phytocannabinoid molecules present in Cannabis sativa. Additional efforts have uncovered biologically active lipid compounds, the endogenous cannabinoids, that are these receptors' natural ligands. The "endocannabinoids" have now been linked to numerous physiological and psychological processes, from nociception, thermoregulation, and cell proliferation to emotion and cognition. Importantly, the rapid advances in this field have been greatly aided by the availability of antagonists/inverse agonists selective for cannabinoid 1 receptors (CB1Rs) expressed in the brain and peripheral tissues. Among marijuana's many psychological effects, a well-recognized action is the induction of a strong desire to eat, together with an increased anticipation of the delights of food and enhanced enjoyment of its sensory properties. These effects reflect the role of anandamide and other endocannabinoids in the normal, physiological processes that govern appetite. Endocannabinoids appear to be directly involved in the central mechanisms that give rise to hunger, food craving and anticipation, and the hedonic evaluation of food (Kirkham, 2005Kirkham T.C. Behav. Pharmacol. 2005; 16: 297-313Crossref PubMed Scopus (170) Google Scholar). The clinical potential of these pathways was highlighted by early reports that the CB1 antagonist rimonabant could suppress food intake in animal models—presumably by blocking the actions of endocannabinoids within feeding- and reward-related brain circuits (Arnone et al., 1997Arnone M. Maruani J. Chaperon F. Thiebot M.H. Poncelet M. Soubrie P. Le Fur G. Psychopharmacology (Berl.). 1997; 132: 104-106Crossref PubMed Scopus (540) Google Scholar). Pharmaceutical companies were thus alerted to a potential new class of antiobesity drugs that could, by modifying endocannabinoid actions, reduce the drive to eat and the tendency to overconsume. Rimonabant is currently licensed in many countries (although not the USA) as an adjunct to diet and exercise for the treatment of overweight or obese patients with associated conditions, such as type 2 diabetes and dyslipidemia, and has proven reasonably effective in improving these parameters. The mechanism of action, initially predicated on its anorectic actions, remains uncertain, with recent attention focusing on peripheral metabolic factors. In preclinical studies, rimonabant's anorectic effects were relatively short lived, while weight loss persisted with continued treatment (Ravinet-Trillou et al., 2003Ravinet Trillou C. Arnone M. Delgorge C. Gonalons N. Keane P. Maffrand J.P. Soubrie P. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003; 284: R345-R353PubMed Google Scholar). In addition, the drug's beneficial effects (including improved plasma glucose, low-density lipoprotein cholesterol, and free fatty acid profiles) exceeded the consequences expected solely from reduced food consumption and lowered body weight. In fact, endocannabinoids appear to act at receptors in adipocytes, liver, pancreas, and muscle to modulate the regulation of energy utilization and fuel storage, with rimonabant and its analogs promoting lipolysis and increasing energy expenditure (Kunos, 2007Kunos G. Am. J. Med. 2007; 120: S18-S24Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, Cota, 2007Cota D. Diabetes Metab. Res. Rev. 2007; 23: 507-517Crossref PubMed Scopus (111) Google Scholar). In this issue, Heymsfield and colleagues (Addy et al., 2008Addy C. Wright H. Van Laere K. Gantz I. Erondu N. Musser B.J. Lu K. Yuan J. Sanabria-Bohórquez S.M. Stoch A. et al.Cell Metab. 2008; 7 (this issue): 68-78Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar) report preliminary findings on the weight-reducing and metabolic effects of Merck's novel CB1R inverse agonist taranabant in overweight and obese subjects. In an acute 24-hour food intake study, taranabant (12 mg) was found to significantly suppress ad libitum food intake, reducing caloric intake over 24 hr by approximately 20% compared to placebo. A parallel indirect calorimetry study also found a modest increase in resting energy expenditure with a significant decrease in respiratory quotient, implying a drug-induced increase in fat oxidation. In a 12-week dose range-finding study, taranabant was administered in conjunction with a reduced-calorie diet plan. Here, each dose produced a persistent decline in body weight over the full course of the experiment. In those subjects completing the treatment, doses of 0.5 to 6 mg taranabant produced weight loss between 3.6 and 6.3 kg, compared to 1.4 kg with placebo. These effects compare favorably with the weight loss obtained in far longer phase 3 clinical trials of 10 or 20 mg doses of rimonabant (Van Gaal et al., 2005Van Gaal L.F. Rissanen A.M. Scheen A.J. Ziegler O. Rossner S. for the RIO-Europe Study Group.Lancet. 2005; 365: 1389-1397Abstract Full Text Full Text PDF PubMed Scopus (1413) Google Scholar, Pi-Sunyer et al., 2006Pi-Sunyer F.X. Aronne L.J. Heshmati H.M. Devin J. Rosenstock J. JAMA. 2006; 295: 761-775Crossref PubMed Scopus (1115) Google Scholar). In light of the current regulatory climate and continuing concerns over the safety of this class of drugs, Addy et al., 2008Addy C. Wright H. Van Laere K. Gantz I. Erondu N. Musser B.J. Lu K. Yuan J. Sanabria-Bohórquez S.M. Stoch A. et al.Cell Metab. 2008; 7 (this issue): 68-78Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar are rightly cautious in describing the relative efficacy of taranabant for weight loss and the incidence and nature of the drug's side effects—particularly psychiatric consequences reminiscent of those hindering rimonabant in its bid for FDA approval (Christensen et al., 2007Christensen R. Kristensen P.K. Bartels E.M. Bliddal H. Astrup A. Lancet. 2007; 370: 1706-1713Abstract Full Text Full Text PDF PubMed Scopus (870) Google Scholar). Reflecting the ubiquity of CB1Rs in the gastrointestinal tract, taranabant treatment was associated with an increase in gastrointestinal symptoms. More influential in determining treatment continuation, however, were adverse psychiatric effects, including anxiety, irritability, and depressed mood—again, consistent with the central distribution of cannabinoid receptors. Although the trends in these and related factors were small and not statistically reliable, any increase in incidence would have potentially immense clinical significance when multiplied across a potential patient population of many millions. More detailed analyses of the effects of taranabant on mood-related factors are therefore imperative. Overall, the Addy et al., 2008Addy C. Wright H. Van Laere K. Gantz I. Erondu N. Musser B.J. Lu K. Yuan J. Sanabria-Bohórquez S.M. Stoch A. et al.Cell Metab. 2008; 7 (this issue): 68-78Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar report confirms that CB1-selective antagonists/inverse agonists may provide a relatively effective alternative to existing antiobesity drugs through possible effects on food intake, and also on energy storage and metabolism. However, as the authors observe, many aspects of cannabinoid antagonist action remain to be elucidated. In particular, better characterizations of the effects on appetite and behavior are needed. What changes in hunger, sensory evaluation of food, and/or satiety underpin the observed reduction in food intake? Do the effects reflect changes in routine appetite-related psychological factors, or are there nonspecific, indirect effects of the drug? As a not altogether facetious aside, pruritus (itching) was a side effect reported by a large number of taranabant patients and in some cases led to discontinuation from the trial. Increased levels of scratching contribute to the intake suppression observed in rodents treated with this class of drugs (Tallett et al., 2007Tallett A.J. Blundell J.E. Rodgers J.R. Psychopharmacology (Berl.). 2007; 195: 27-39Crossref PubMed Scopus (49) Google Scholar), suggesting an alternative explanation that may subvert accepted notions of how the drugs affect eating. This example highlights the need, when evaluating cannabinoid-based pharmacotherapies, to consider the broad spectrum of physiological and behavioral processes subserved by endocannabinoids and to determine the specificity of their actions. In the animal laboratory, motivational specificity can only be inferred indirectly from behavior. Clinical trials thus provide an important opportunity to obtain subjective reports about drug effects and, crucially, apply fine-resolution measures of appetite and eating behavior. Although Addy et al., 2008Addy C. Wright H. Van Laere K. Gantz I. Erondu N. Musser B.J. Lu K. Yuan J. Sanabria-Bohórquez S.M. Stoch A. et al.Cell Metab. 2008; 7 (this issue): 68-78Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar indicate that ratings of hunger and other appetite-related parameters were assessed for the acute study, no data are reported. In the chronic study, only periodic, retrospective measures of appetite and satiety were made, which detected no significant trends. However, we cannot discount important, possibly subtle changes potentially identifiable by more detailed, proximal measures of eating behavior. Laboratory animals treated repeatedly with rimonabant or taranabant show markedly diminished anorectic effects over time; it remains unclear whether this same effect is observed clinically, but such data are clearly crucial to our understanding of the drug's antiobesity action. If taranabant does act separately on appetite and metabolic factors, their relative contributions to weight loss need to be carefully assessed. Ultimately, only a deeper knowledge of central and peripheral endocannabinoid mechanisms can improve our theoretical models and allow better targeting and more effective administration of these drugs for obesity/metabolic syndrome management. The current state of our knowledge is highlighted by a literature search for "cannabinoids and obesity": nearly half the articles are reviews. Many of these speculate on the therapeutic potential of CB1 antagonists/inverse agonists, extrapolating from relatively sparse empirical data from animal or in vitro models. Endocannabinoids do appear to be important in the control of appetite and regulation of energy balance and could be key to the future pharmaceutical management of obesity and its comorbidities; the recent work by Addy et al., 2008Addy C. Wright H. Van Laere K. Gantz I. Erondu N. Musser B.J. Lu K. Yuan J. Sanabria-Bohórquez S.M. Stoch A. et al.Cell Metab. 2008; 7 (this issue): 68-78Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar indicates this potential clearly. But the race to market might be reined in to follow, rather than lead, the development of satisfactory theoretical models about their function. The Acyclic CB1R Inverse Agonist Taranabant Mediates Weight Loss by Increasing Energy Expenditure and Decreasing Caloric IntakeAddy et al.Cell MetabolismJanuary, 2008In BriefCannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [18F]MK-9470 confirmed central nervous system receptor occupancy levels (∼10%–40%) associated with energy balance/weight-loss effects in animals. Full-Text PDF Open Archive
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