Cannabinoid CB1 Receptors Inhibit Gut-Brain Satiation Signaling in Diet-Induced Obesity
Argueta DA, Perez PA, Makriyannis A, DiPatrizio NV (2019) Front. Physiol. 2019 June; doi.org/10.3389/fphys.2019.00704
Web URL: Read the research on Frontiers here
Abstract:
Gut-brain signaling controls feeding behavior and energy homeostasis; however, the underlying molecular mechanisms and impact of diet-induced obesity (DIO) on these pathways are poorly defined.We tested the hypothesis that elevated endocannabinoid activity at cannabinoid CB1receptor (CB1Rs) in the gut of mice rendered DIO by chronic access to a high fat and sucrose diet for 60 days inhibits nutrient-induced release of satiation peptides and promotes overeating.
Immunoreactivity for CB1Rs was present in enteroendocrine cells in the mouse’s upper small-intestinal epithelium that produce and secrete the satiation peptide, cholecystokinin (CCK), and expression of mRNA for CB1Rs was greater in these cells when compared to non-CCK producing cells. Oral gavage of corn oil increased levels of bioactive CCK (CCK-8) in plasma from mice fed a low fat no-sucrose diet. Pretreatment with the cannabinoid receptor agonist, WIN55,212-2, blocked this response, which was reversed by co-administration with the peripherally-restricted CB1R neutral antagonist, AM6545.
Furthermore, monoacylglycerol metabolic enzyme function was dysregulated in the upper small-intestinal epithelium from DIO mice, which was met with increased levels of a variety of monoacylglycerols including the endocannabinoid, 2-arachidonoyl-sn-glycerol. Corn oil failed to affect levels of CCK in DIO mouse plasma; however, pretreatment with AM6545 restored the ability for corn oil to stimulate increases in levels of CCK, which suggests that elevated endocannabinoid signaling at small intestinal CB1Rs in DIO mice inhibits nutrient-induced CCK release. Moreover, the hypophagic effect of AM6545 in DIO mice was reversed by co-administration with the CCKA receptor antagonist, devazepide.
Collectively, these results provide evidence that hyperphagia associated with DIO is driven by a mechanism that includes CB1R-mediated inhibition of gut-brain satiation signaling.
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