Peripheral modulation of the endocannabinoid system in metabolic disease

Abstract

Dysfunction of the endocannabinoid system (ECS) has been identified in metabolic disease. Cannabinoid receptor 1 (CB) is abundantly expressed in the brain but also expressed in the periphery. Cannabinoid receptor 2 (CB) is more abundant in the periphery, including the immune cells. In obesity, global antagonism of overexpressed CB reduces bodyweight but leads to centrally mediated adverse psychological outcomes. Emerging research in isolated cultured cells or tissues has demonstrated that targeting the endocannabinoid system in the periphery alleviates the pathologies associated with metabolic disease. Further, peripheral specific cannabinoid ligands can reverse aspects of the metabolic phenotype. This Keynote review will focus on current research on the functionality of peripheral modulation of the ECS for the treatment of obesity.

Phytocannabinoids: Useful Drugs for the Treatment of Obesity? Special Focus on Cannabidiol

“…In previous studies it was shown that, hepatocytes produce endocannabinoids, AEA and 2-AG, and possess CB 1 and CB 2 receptors (80,91). A study carried out by Liu et al revealed that liver specific CB 1 receptor knockout mice were protected from the development of both insulin resistance and hepatosteatosis but not obesity (55).…”

“…Many scientists are looking for new therapeutic strategies, including expanded ECS, which can be a useful tool in preventing and treating the above mentioned diseases. Therefore, the components of eCBome are emerging as potent therapeutic targets due to their wellestablished role in the regulation of food consumption and energy balance as well as lipid and glucose metabolism (79,80). Literature data indicated, that ECS is upregulated during obesity and associated diseases (81)(82)(83)(84).…”

The effect of high maternal linoleic acid on endocannabinoid signalling in rodent hearts

“…20 Cannabinoid receptors interact with additional targets that may either inhibit inflammation (including leptin 21 ) or promote inflammation (including tumour necrosis factor alpha (TNFα). 22 Although the ECS influences development and plays a role in regulating cardiovascular function, 23 there is a paucity of data concerning the effects of high LA exposure on cardiomyocyte viability and development. Based on prior studies, we therefore predict that 1) exposure to elevated LA will alter cardiomyocyte viability and 2) consumption of elevated concentrations of LA upregulates LA metabolic by-products, 3 which leads to altered expression of LA metabolic enzymes and increased downstream pro-inflammatory mediators.…”

Gastrointestinal Adverse Events of Cannabinoid 1 Receptor Inverse Agonists suggest their Potential Use in Irritable Bowel Syndrome with Constipation: A Systematic Review and Meta-Analysis

“…The CB1-RAN rimonabant and taranabant exerted great efficacy in reducing weight in clinical trials. However, the phase III studies were suspended and rimonabant was eventually withdrawn from the market due to the serious psychiatric AEs including depression and suicidal intentions [35]. Nevertheless, other applications of CB1-RAN are being investigated.…”