Posted by Quintal on October 5, 2007, at 19:00:25
In reply to Re: Rimonabant - New Appetite Suppressant » Quintal, posted by Phillipa on October 4, 2007, at 19:33:33
Getting back to the original topic, I was surprised by the amount of research available on rimonabant and the cannabinoid system. There are literally thousands of studies. It's a shame about the adverse psychiatric profile of rimonabant. I wondered if a selective CB1 antagonist that did not cross the blood-brain barrier (like ceterizine etc) would have fewer side effects, and naturally it seems other researchers have had the same idea.
__________________________________________________1: Int J Obes (Lond). 2006 Apr;30 Suppl 1:S30-2.Click here to read Links
The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action?
Horvath TL.Department of Ob/Gyn and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510-8016, USA.
Presentations in this symposium addressed effects and modes of action of endocannabinoids in various tissues in relation to metabolic disorders. Endocannabinoids are produced and exert their effect in various brain sites, including the mesolimbic reward circuitry and the hypothalamus. Both of these regions have direct ties to energy metabolism regulation, particularly food intake and energy expenditure. These data clearly suggest that the observed beneficial effects of CB1 (cannabinoid receptor 1) receptor antagonists on obesity may be related to the central endocannabinoid system. On the other hand, data presented on cannabinoid action in the liver and white adipose tissues clearly indicate that CB1-mediated events in affecting metabolic phenotype may occur in peripheral tissues as well. This together with the reported results from human trials on CB1 antagonists showing that the initial anorectic effect of rimonabant is diminished after the first weeks while longer lasting weight loss is achieved do indicate that peripheral action of cannabinoids are very important in body weight regulation. Should this hold true in the long run, antagonizing CB1 receptors with compound not crossing the blood-brain barrier could revolutionize pharmaceutical approaches to obesity by offering a tool that short cuts the central nervous system.
PMID: 16570102 [PubMed - indexed for MEDLINE]
--------------------------------------------------2: Am J Med. 2007 Sep;120(9 Suppl 1):S18-24; discussion S24.Click here to read Links
Understanding metabolic homeostasis and imbalance: what is the role of the endocannabinoid system?
Kunos G.National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20817, USA. gkunos@mail.nih.gov
Endogenous endocannabinoids (ECs) (anandamide and 2-arachidonoyl glycerol) are part of the leptin-regulated neural circuitry involved in appetite regulation. One of the sites of the orexigenic action of ECs involves activation of cannabinoid-1 (CB1) receptors in the lateral hypothalamus, from which neurons involved in mediating food reward project into the limbic system. In animal models of obesity, pharmacologic blockade or genetic ablation of CB1 receptors causes a transient reduction in food intake accompanied by sustained weight loss, reduced adiposity, and reversal of hormonal/metabolic changes, such as elevated levels of plasma leptin, insulin, glucose, and triglyceride, and reduced levels of plasma adiponectin (Acrp30). However, the beneficial effects of CB1 blockade on weight and metabolism cannot be explained by appetite suppression alone. Animal studies suggest that CB1 blockade exerts a direct peripheral as well as a central effect on fat metabolism. CB1 receptor blockade with rimonabant has been shown to not only reduce weight and adiposity but also to directly modulate fat metabolism at peripheral sites in skeletal muscle, adipose tissue, and the liver. Preclinical animal studies suggest that CB1 blockade acts on adipocytes to increase Acrp30 expression, on hepatocytes to decrease de novo lipogenesis and increase fatty acid oxidation, and on skeletal muscle to reduce blood glucose and insulin levels. Extrapolating from animal studies to the clinic, CB1 receptor blockade offers a promising strategy not only for reducing weight and abdominal adiposity but also for preventing and reversing its metabolic consequences.
PMID: 17720356 [PubMed - in process]
--------------------------------------------------3: Crit Pathw Cardiol. 2007 Jun;6(2):46-50.Click here to read Links
The endocannabinoid system: a new target for the regulation of energy balance and metabolism.
Després JP.Québec Heart Institute, Québec QC, Canada. jean-pierre.despres@crhl.ulaval.ca
Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism through the central control of appetite and by affecting peripheral metabolism. Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor, is believed to be responsible for the majority of the central effects of endocannaboids on appetite. Chronic positive energy balance and obesity have been associated with an overactivation of the endocannaboid system which has been suggested to contribute to the development of abdominal obesity and to associated metabolic abnormalities which increase the risk of cardiovascular disease and type 2 diabetes. Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver. Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss. Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly, to "fix" the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk.
PMID: 17667864 [PubMed - indexed for MEDLINE]
--------------------------------------------------4:Nat Neurosci. 2005 May;8(5):585-9.Click here to read Links
Endocannabinoid control of food intake and energy balance.
Di Marzo V, Matias I.Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy. vdimarzo@icmib.na.cnr.it
Marijuana and its major psychotropic component, Delta(9)-tetrahydrocannabinol, stimulate appetite and increase body weight in wasting syndromes, suggesting that the CB(1) cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in controlling energy balance. The endocannabinoid system controls food intake via both central and peripheral mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes.
PMID: 15856067 [PubMed - indexed for MEDLINE]
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It seems to me that rimonabant might be producing behavioral patterns that I associate with naturally thin persons, i.e. worry, nervousness, melancholia, introversion, hypersensitivity, agitation etc. Contrast this with the stereotype of the 'jolly fat person' and you can see where there might be a link. Not only in behavioral patterns, but energy metabolism, body shape etc. They seem to be linked, maybe because they are indeed linked in some way via the endocannabionoid system.I eat mostly soft, fatty, palatable foods but never gain much weight (unless on medication). This is the first piece of evidence to shed light on this phenomena. I know of a few overweight people who never seem to change much despite doing more physical exercise than me, and eating a low-calorie, low-fat diet. Thinness seems to imply pain and un-ease (if not dis-ease) to me, and these cannabinoid receptor antagonists seems to be producing a sense of mental un-ease. It makes sense. No such thing as a free lunch they say... I think it's largely a myth that thin people feel better. And in order to be thin, naturally obese people may have to 'pay the price' in mental un-ease - as naturally thin people do, at least if they use rimonabant. I note that dietary restriction also tends to produce much the same effect in naturally large people.
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1: Int J Obes Relat Metab Disord. 2004 Apr;28(4):640-8.Click here to read Links
CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity.
Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrié P.Central Nervous System Research, Sanofi-Synthélabo, Toulouse Cedex, France. christine.ravinet-trillou@sanofi-synthelabo.com
OBJECTIVE: There is growing evidence for an implication of the CB1 receptor subtype of the endocannabinoid system in the regulation of eating and fat deposition. To further define the physiological role of these receptors in the control of energy balance, we characterized the phenotype of CB1 receptor knockout (CB1(-/-)) mice maintained on an obesity-prone regimen or on a standard chow. DESIGN: CB1(-/-) male mice were compared to wild-type animals (CB1(+/+) male mice) in two feeding paradigms: (1) with a standard laboratory regimen (3.5 kcal/g, 14.5% of energy as fat) and (2) on a free-choice paradigm consisting of offering both the standard laboratory chow and a high-fat diet (HFD) (4.9 kcal/g, 49% of energy as fat). RESULTS: When maintained on the standard diet, CB1(-/-) mice are lean. At the age of 20 weeks, their body weight and adiposity are, respectively, 24 and 60% lower than that of CB1(+/+) mice. They are slightly hypophagic, but when expressed as percent of body weight, their relative energy intake is similar to that of the wild-type animals. Furthermore, inactivation of CB1 receptors reduces plasma insulin and leptin levels, and enhances the response to intracerebroventricular leptin injection. The free-choice paradigm shows that the preference for a high-fat highly palatable chow is slightly delayed in onset but maintained in CB1(-/-) mice. However, loading CB1(-/-) mice with this obesity-prone diet does not result in development of obesity. Knockout mice do not display hyperphagia or reduction of their relative energy intake in contrast to CB1(+/+) mice, and their feeding efficiency remains low. These data suggest an improved energetic metabolism with the high-fat regimen. Furthermore, the insulin resistance normally occurring in HFD-fed mice is not present in CB1(-/-) mice. CONCLUSION: These results provide evidence that the stimulation of CB1 receptors is a key component in the development of diet-induced obesity, and that these receptors and their endogenous ligands are implicated not only in feeding control but also in peripheral metabolic regulations. The lack of effect of SR141716, a selective CB1 receptor antagonist, in CB1(-/-) mice further supports this hypothesis, as this compound was previously shown to display potent anti-obesity properties in diet-induced obese C57BL/6 mice.
PMID: 14770190 [PubMed - indexed for MEDLINE]
--------------------------------------------------2 FASEB J. 2005 Sep;19(11):1567-9. Epub 2005 Jul 11.Click here to read Links
The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance.
Jbilo O, Ravinet-Trillou C, Arnone M, Buisson I, Bribes E, Péleraux A, Pénarier G, Soubrié P, Le Fur G, Galiègue S, Casellas P.Oncology Research Department, Sanofi-Synthelabo Recherche, Montpellier, France.
We investigated the molecular events involved in the long-lasting reduction of adipose mass by the selective CB1 antagonist, SR141716. Its effects were assessed at the transcriptional level both in white (WAT) and brown (BAT) adipose tissues in a diet-induced obesity model in mice. Our data clearly indicated that SR141716 reversed the phenotype of obese adipocytes at both macroscopic and genomic levels. First, oral treatment with SR141716 at 10 mg/kg/d for 40 days induced a robust reduction of obesity, as shown by the 50% decrease in adipose mass together with a major restoration of white adipocyte morphology similar to lean animals. Second, we found that the major alterations in gene expression levels induced by obesity in WAT and BAT were mostly reversed in SR141716-treated obese mice. Importantly, the transcriptional patterns of treated obese mice were similar to those obtained in the CB1 receptor knockout mice fed a high-fat regimen and which are resistant to obesity, supporting a CB1 receptor-mediated process. Functional analysis of these modulations indicated that the reduction of adipose mass by the molecule resulted from an enhanced lipolysis through the induction of enzymes of the beta-oxidation and TCA cycle, increased energy expenditure, mainly through futile cycling (calcium and substrate), and a tight regulation of glucose homeostasis. These changes accompanied a significant cellular remodeling and contributed to a reduction of the obesity-related inflammatory status. In addition to a transient reduction of food consumption, increases of both fatty acid oxidation and energy expenditure induced by the molecule summate leading to a sustained weight loss. Altogether, these data strongly indicate that the endocannabinoid system has a major role in the regulation of energy metabolism.
PMID: 16009704 [PubMed - indexed for MEDLINE]
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poster:Quintal
thread:786700
URL: http://www.dr-bob.org/babble/20070929/msgs/787125.html