Naunyn Schmiedebergs Arch Pharmacol. 2013 Aug;386(8):721-32.
Effects of CB1 receptor blockade on monosodium glutamate induced hypometabolic and hypothalamic obesity in rats.
Chen W, Chen Z, Xue N, Zheng Z, Li S, Wang L.
Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
Effects of cannabinoid receptor 1 (CB1R) blockade were observed by comparing 9-day and 6-week SR141716 treatments in monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity (HO) in rats for the first time and molecular mechanisms were investigated. Compared with normal rats, the MSG rats display typical symptoms of the metabolic syndrome, i.e., excessive abdominal obesity, hypertriglyceridemia, hyperinsulinemia, insulin resistance, and hepatic steatosis, but with lower food intake. Although both the 9-day and 6-week treatments with the specific CB1R antagonist SR141716 effectively lowered body weight, intraperitoneal adipose tissue mass, serum triglyceride (TG), and insulin level, the effect of chronic treatment is more impressive. Moreover, serum cholesterol, free fatty acids (FFA), fasted and postprandial blood glucose, and insulin insensitivity were more effectively improved by 6-week exposure to SR141716, whereas hypophagia was only effective within the initial 2 weeks. In addition, hepatic steatosis as well as hepatic and adipocyte morphology was improved. Western blot analysis revealed that the markedly increased CB1R expression and decreased insulin receptor (INR) expression in liver and adipose tissues were effectively corrected by SR141716. Consistent with this, deregulated gene expression of lipogenesis and lipolysis as well as glucose metabolic key enzymes were also restored by SR141716. In conclusion, based on present data we found that: (1) alteration of the hypothalamus in MSG rats leads to a lower expression of INR in crucially insulin-targeted tissues and hyperinsulinemia that was reversed by SR141716, (2) the abnormally increased expression of CB1R in liver and adipose tissues plays a vital role in the pathophysiological process of MSG rats, and (3) chronic CB1R blockade leads to a sustained improvement of the metabolic dysfunctions of MSG rats.
The cannabinoid receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation composed the endocannabinoid system (ECS) that is involved in physiological regulation of many functions, including metabolism and energy homeostasis. The cannabinoid receptors are G-protein coupled receptors (GPCRs). Two cannabinoid receptors, CB1 and CB2, have been characterized. Besides widely expressed in the central nervous system (CNS), cannabinoid-1 receptor (CB1R) also located in peripheral tissues, including liver, adipose tissue, gut and muscle. CB2 receptor exists dominantly in the immune system.
CB1R has been considered as an extremely attractive therapeutic target for obesity and type 2 diabetes over the past two decades. CB1R antagonism displayed good therapeutic effects in obese and/or diabetic rodents and humans. The first-in-class selective CB1R antagonist SR141716A (rimonabant) discovered by Sanofi in 1994, had been successfully approved by the European Medicines Agency in 2006, and was once anticipated to be a blockbuster anti-obesity drug. However, undesirable CNS-based neuropsychiatric side effects such as depression and suicidality had led to its final withdrawal from market in October 2008. The anti-obesity effect of CB1R antagonist could be ascribed to a reduction of food intake by hypothalamic CB1R blockade and an increase of energy expenditure by peripheral CB1R blockade. Recently, numerous studies indicated the sustained weight loss after administration of rimonabant was maintained by chronic treatment, because the inhibition on food intake is transient (about 2~3 weeks). The persistent anti-obesity effect of the CB1R antagonist is mainly peripheral dependent. Thoroughly understanding the mechanisms of CB1R antagonism in weight reduction would contribute more to the development of next generation of CB1R antagonists.
To circumvent the undesired CNS side effects that have beset the brain-penetrant CB1R antagonists, and uncover safer compounds that preferentially target CB1R in peripheral tissues rather than central CB1R, a number of potential strategies can be used, which include proportionately lowering the logD and lipophilicity, increasing the polarity and polar surface area (PSA) of compounds. Compound TM38857 (7TM) with little potential to cross the blood brain barrier (BBB), represents the most advanced peripheral restricted CB1R blocker. TM38857 exerts its therapeutic effects exclusively through CB1 receptors located in the peripheral tissue and displays a substantial and robust weight reduction effect in various obese animal models. Recently, TM38857 had undergone phaseⅠclinical evaluation. Thus the new generation of peripheral restricted CB1R antagonist showed promise as a new therapy for controlling obesity and related metabolic functions.
Figure 1: Pharmacological mechanism of CB1R antagonist. The first generation brain-penetrant CB1R antagonists exert their anti-obesity action through both central and peripheral CB1R blockade mediated effects. In contrast, the new generation peripheral restricted CB1R antagonists hold the promise to combat obesity and related metabolic disorders, yet without CNS liabilities. CB1R: cannabinoid-1 receptor, BBB, blood-brain-barrier. TAG, triglycerides.