“Obesity, an impending global pandemic, is not being effectively controlled by current measures such as lifestyle modifications, bariatric surgery or available medications. Its toll on health and economy compels us to look for more effective measures. Fortunately, the advances in biology and molecular technology have been in our favour for delineating new pathways in the pathophysiology of obesity and have led to subsequent development of new drug targets. Development of anti-obesity drugs has often been riddled with problems in the past. Some of the recently approved drugs for pharmacotherapy of obesity have been lorcaserin, phentermine/topiramate and naltrexone/bupropion combinations. Several promising new targets are currently being evaluated, such as amylin analogues (pramlintide, davalintide), leptin analogues (metreleptin), GLP-1 analogues (exenatide, liraglutide, TTP-054), MC4R agonists (RM-493), oxyntomodulin analogues, neuropeptide Y antagonists (velneperit), cannabinoid type-1 receptor blockers (AM-6545), MetAP2 inhibitors (beloranib), lipase inhibitors (cetilistat) and anti-obesity vaccines (ghrelin, somatostatin, Ad36). Many of these groups of drugs act as “satiety signals” while others act by antagonizing orexigenic signals, increasing fat utilisation and decreasing absorption of fats. Since these targets act through various pathways, the possibility of combined use of two or more classes of these drugs unlocks numerous therapeutic avenues. Hence, the dream of personalized management of obesity might be growing closer to reality.” https://www.ncbi.nlm.nih.gov/pubmed/28245771]]>
Category Archives: Obesity
Cannabinoid receptor-1 blockade attenuates acute pancreatitis in obesity by an adiponectin mediated mechanism.
“Obesity is a risk factor for increased severity of acute pancreatitis.
Adipocytes produce adiponectin, an anti-inflammatory molecule that is paradoxically decreased in the setting of obesity. We have shown that adiponectin concentration inversely mirrors the severity of pancreatitis in obese mice.
Cannabinoid receptor CB-1 blockade increases circulating adiponectin concentration. We, therefore, hypothesize that blockade of CB-1 would increase adiponectin and attenuate pancreatitis severity.
Rimonabant treatment significantly increased circulating adiponectin concentration in obese mice.
In obese mice, cannabinoid receptor CB-1 blockade with rimonabant attenuates the severity of acute pancreatitis by an adiponectin-mediated mechanism.” https://www.ncbi.nlm.nih.gov/pubmed/19225848Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome
“Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans.
We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice.
Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.
In conclusion, the current study provides the first evidence that the eCB system may contribute to severe obesity both in PWS children and adults and in an established mouse model for this syndrome. Our results confirm that the eCB system contributes to the metabolic phenotype associated with PWS. Moreover, specifically targeting the peripheral eCB system in obese Magel2-null mice was found to be as efficacious as in DIO animals, and, therefore, it may represent a novel approach to treating obesity and its complications in PWS. This would also provide the rationale for the development and clinical testing of peripherally restricted CB1R antagonists for treating obesity in PWS.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123200/
“Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists.” https://www.ncbi.nlm.nih.gov/pubmed/22335400
“The phytocannabinoid, Delta(9)-tetrahydrocannabivarin (THCV), can block cannabinoid CB(1) receptors” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931567/]]>GPR55: a new promising target for metabolism?
“GPR55 is a G-protein coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans. The potential of GPR55 to become a new pharmaceutical target to treat obesity and type 2 diabetes, as well as the foreseeing difficulties are also discussed.” https://www.ncbi.nlm.nih.gov/pubmed/28196832
“GPR55 – a putative “type 3” cannabinoid receptor in inflammation.” https://www.ncbi.nlm.nih.gov/pubmed/26669245
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“Increased food consumption following ∆(9)-tetrahydrocannabinol-induced cannabinoid type 1 receptor agonism is well documented.
However, possible non-∆(9)-tetrahydrocannabinol phytocannabinoid-induced feeding effects have yet to be fully investigated. Therefore, we have assessed the effects of the individual phytocannabinoids, 
“The physiological control of appetite and satiety, in which numerous neurotransmitters and neuropeptides play a role, is extremely complex. Here we describe the involvement of endocannabinoids in these processes.
These endogenous neuromodulators enhance appetite in animals.
The same effect is observed in animals and in humans with the psychotropic plant cannabinoid Delta(9)-tetrahydrocannabinol, which is an approved appetite-enhancing drug.
The CB(1) cannabinoid receptor antagonist SR141716A blocks the effects on feeding produced by the endocannabinoids. If administered to mice pups, this antagonist blocks suckling.
In obese humans, it causes weight reduction.
Very little is known about the physiological and biochemical mechanisms involved in the effects of Delta(9)-tetrahydrocannabinol and the cannabinoids in feeding and appetite.”
