Effects of glucagon-like peptide-1 receptor stimulation and blockade on food consumption and body weight in rats treated with a cannabinoid CB1 receptor agonist WIN 55,212-2

Abstract

BackgroundGlucagon-like peptide-1 (GLP-1) and endocannabinoids are involved in appetite control. Recently we have demonstrated that cannabinoid (CB)1 receptor antagonist and GLP-1 receptor agonist synergistically suppress food intake in the rat. The aim of the present study was to determine the effects of GLP-1 receptor stimulation or blockade on feeding behavior in rats treated with WIN 55,212-2, a CB1 receptor agonist.Material/MethodsExperiments were performed on adult male Wistar rats. In the first experiment the effects of increasing doses (0.5–4.0 mg/kg) of WIN 55,212-2 injected intraperitoneally on 24-hour food consumption were tested. In further experiments a GLP-1 receptor antagonist, exendin (9-39), and WIN 55,212-2 or a GLP-1 receptor agonist, exendin-4, and WIN 55,212-2 were injected intraperitoneally at subthreshold doses (that alone did not change food intake and body weight) to investigate whether these agents may interact to affect food intake in rats.ResultsWIN 55,212-2 administered at low doses (0.5–2 mg/kg) did not markedly change 24-hour food consumption; however, at the highest dose, daily food intake was inhibited. Combined administration of WIN 55,212-2 and exendin (9-39) did not change the amount of food consumed compared to either the control group or to each agent injected alone. Combined injection of WIN 55,212-2 and exendin-4 at subthreshold doses resulted in a significant decrease in food intake and body weight in rats.ConclusionsStimulation of the peripheral CB1 receptor by its agonist WIN 55,212-2 can induce anorexigenic effects or potentiate, even at a subthreshold dose, the effects of exendin-4, a known anorectic agent. Hence, this dual action of the cannabinoid system should be considered in the medical use of CB1 agonists.

Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study

“…The majority of previous evidence suggest that orexigenic actions of cannabinoids are linked to CB 1 receptors located in the hypothalamus [32][33][34] , with some research also implicating the role of CB 2 receptors in increased food consumption 35 . A close relationship also exists between the endocannabinoid system and endocrine pathways involved in metabolic regulation and food seeking behaviors [36][37][38][39] . For example, investigators found that orexigenic effects of systemically administered ghrelin (also known as the "hunger hormone") were abolished in CB 1 receptor knockout mice 40 , and pharmacological blockade of the CB 1 receptor, via rimonabant administration, attenuated ghrelin-induced activation of the mesolimbic dopamine systema key pathway involved in reward processing 41 .…”

What Role Does the Endocannabinoid System Play in the Pathogenesis of Obesity?

“…In the study by Radiszewska et al on Wistar rats, a stimulation of peripheral CB 1 R by its agonist (WIN 55,212-2) had an anorexigenic effect and induced activity of exendin-4, a peptide agonist of the glucagon-like-peptide 1 [ 216 ]. It suggests a double activity of the ECS and could be used in the pharmacotherapy of obesity.…”

Obesity as a Condition Determined by Food Addiction: Should Brain Endocannabinoid System Alterations Be the Cause and Its Modulation the Solution?

“…In addition to these data, studies have shown interactions between endocannabinoid-like molecules and GLP-1 [145]. Preclinical results demonstrated that CB1 antagonism could enhance GLP-1 receptor agonists activity [146] and improve GLP-1R mediated insulin secretion [147], suggesting that new drugs acting on the ECS system may have a synergic effect and ameliorate the results obtained with liraglutide treatment. For these reasons, research on anti-obesogenic drugs acting on the ECS is still an option that must not be discarded.…”