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 CB1 receptor (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.
Highlights
Food intake and energy homeostasis are controlled by a dynamic interplay of gut-brain signaling pathways that are not well-defined but are thought to become dysregulated in obesity (Steinert et al, 2017)
We reported that eCB levels are increased in the upper smallintestinal epithelium from mice maintained on a Western Diet (WD; high-fat and sucrose diet) for 60 days when compared to lean controls maintained on a low-fat and low-sugar diet, and inhibiting peripheral Cannabinoid receptor subtype 1 (CB1R) blocked overeating associated with consumption of western diet (WD) (Argueta and DiPatrizio, 2017)
Our studies suggest that eCB activity at CB1Rs in the upper small intestinal epithelium is upregulated in mice chronically fed a WD, which in turn, promotes overeating by a mechanism that includes inhibiting nutrient-induced gut-brain satiation signaling
Summary
Food intake and energy homeostasis are controlled by a dynamic interplay of gut-brain signaling pathways that are not well-defined but are thought to become dysregulated in obesity (Steinert et al, 2017). CB1Rs in the brain control food intake and energy homeostasis (DiPatrizio and Piomelli, 2012; Simon and Cota, 2017); targeting central CB1Rs with antagonists for the treatment of human obesity led to psychiatric side-effects that preclude their use as safe and effective anti-obesity therapeutics (Christensen et al, 2007). Peripheral mechanisms influence brain function [e.g., signals from the gut microbiome (Cani and Knauf, 2016)]; the impact of disrupting endocannabinoid signaling at peripheral CB1Rs on these functions is largely unknown and warrants future investigation
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