MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

Abstract

The endocannabinoid system (ECS), including cannabinoid type 1 and type 2 receptors (CB 1 R and CB 2 R), endogenous ligands called endocannabinoids and their related enzymatic machinery, is known to have a role in the regulation of energy balance. Past information generated on the ECS, mainly focused on the involvement of this system in the central nervous system regulation of food intake, while at the same time clinical studies pointed out the therapeutic efficacy of brain penetrant CB 1 R antagonists like rimonabant for obesity and metabolic disorders. Rimonabant was removed from the market in 2009 and its obituary written due to its psychiatric side effects. However, in the meanwhile a number of investigations had started to highlight the roles of the peripheral ECS in the regulation of metabolism, bringing up new hope that the ECS might still represent target for treatment. Accordingly, peripherally restricted CB 1 R antagonists or inverse agonists have shown to effectively reduce body weight, adiposity, insulin resistance and dyslipidemia in obese animal models. Very recent investigations have further expanded the possible toolbox for the modulation of the ECS, by demonstrating the existence of endogenous allosteric inhibitors of CB 1 R, the characterization of the structure of the human CB 1 R, and the likely involvement of CB 2 R in metabolic disorders. Here we give an overview of these findings, discussing what the future may hold in the context of strategies targeting the ECS in metabolic disease.

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…The harmful psychiatric effects have been linked to the antagonizing effect of rimonabant on constitutively active CB1Rs in the ventral tegmental area, and in the amygdala (Meye et al, 2013). Before the clinical development was stopped, rimonabant showed promising effects to improve glycemic control and lessen cardiometabolic risk factors (Despres et al, 2005;Nissen et al, 2008;Van Gaal et al, 2008) Research continues to uncouple the metabolic benefits from the harmful events of CB1R targeting (Simon and Cota, 2017), providing hope that a new generation of safe and efficacious CB1R-based agonists might still be possible.…”

The protective effects of Δ9-tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia

“…we observed that the body weight values were not changed with fructose intake. It is known that THC has the regulatory effect on body weight and food intake . Recently, Brierley et al .…”

“…It is known that THC has the regulatory effect on body weight and food intake. [24] Recently, Brierley et al [25] reported that purified cannabigerol from the cannabis plant is a novel appetite stimulant. However, Cluny et al [26] clarified that chronic THC administration reduced energy intake in diet-induced obese mice.…”

Molecular neuroscience at its “high”: bibliometric analysis of the most cited papers on endocannabinoid system, cannabis and cannabinoids

“…However, rimonabant was withdrawn for treatment due to its adverse effects such as causing mood swings and suicide (Christensen et al 2007). Research is still ongoing for food intake regulation and it is proposed that peripherally restricted CB1 receptor blockers may be therapeutic in the future (Simon and Cota 2017). Moreover, the CB1 receptor was frequently the focus of research, with frequent recurrence of keywords: "CB1" (n = 6), "cannabinoid CB1 receptor" (n = 5), and anandamide (n = 17, citations per manuscript = 823.6), its famous agonist reported by the manuscript with the highest citation count (Devane et al 1992).…”