Peripheral Metabolic Effects of Endocannabinoids and Cannabinoid Receptor Blockade

Abstract

The endocannabinoid system consists of endogenous arachidonic acid derivates that activate cannabinoid receptors. The two most prominent endocannabinoids are anandamide and 2-arachidonoyl glycerol. In obesity, increased concentrations of circulating and tissue endocannabinoid levels have been described, suggesting increased activity of the endocannabinoid system. Increased availability of endocannabinoids in obesity may over-stimulate cannabinoid receptors. Blockade of cannabinoid type 1 (CB1) receptors was the only successful clinical development of an anti-obesity drug during the last decade. Whereas blockade of CB1 receptors acutely reduces food intake, the long-term effects on metabolic regulation are more likely mediated by peripheral actions in liver, skeletal muscle, adipose tissue, and the pancreas. Lipogenic effects of CB1 receptor signalling in liver and adipose tissue may contribute to regional adipose tissue expansion and insulin resistance in the fatty liver. The association of circulating 2-arachidonoyl glycerol levels with decreased insulin sensitivity strongly suggests further exploration of the role of endocannabinoid signalling for insulin sensitivity in skeletal muscle, liver, and adipose tissue. A few studies have suggested a specific role for the regulation of adiponectin secretion from adipocytes by endocannabinoids, but that has to be confirmed by more experiments. Also, the potential role of CB1 receptor blockade for the stimulation of energy expenditure needs to be studied in the future. Despite the current discussion of safety issues of cannabinoid receptor blockade, these findings open a new and exciting perspective on endocannabinoids as regulators of body weight and metabolism.

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

“…Circulating eCBs have been implicated in the pathogenesis of obesity and the metabolic syndrome both in humans and in animal models [36]. Here, we show, for the first time, that the circulating levels of 2-AG and its endogenous precursor ligand and breakdown product AA are markedly elevated in individuals with PWS.…”

Deletion of G-protein-coupled receptor 55 promotes obesity by reducing physical activity

“…Cannabinoids are implicated in the regulation of feeding behavior and energy balance, and their functions are mediated through cannabinoid receptors 1 (CB1) and 2 (CB2) [1][2][3] . CB1 is the best characterized cannabinoid receptor.…”

Acute and subacute antidiabetic studies of ENP-9, a new 1,5-diarylpyrazole derivative

“…[14] Regarding the above, some of the remarkable effects related to type-2 diabetes management include the reduction in adipogenesis, thermogenesis, hypoglycaemia and adiponectin upregulation, [15,16] which ultimately lead to insulin sensitization and lipid homoeostasis. [17] Considering the potential benefits of CB1 receptor antagonists against metabolic diseases, our group has recently focused on the design and synthesis of 1,5-diarylpyrazole analogues with enhanced hypoglycaemic and antidiabetic effects with less adverse consequences. Accordingly, we constructed a series of poli-substituted pyrazolic compounds with improved antidiabetic effect on an in vivo in a non-insulin-dependent diabetes model (NIDDM).…”