Cannabinoid CB1 Receptors Inhibit Gut-Brain Satiation Signaling in Diet-Induced Obesity

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 CB 1 receptor (CB 1 Rs) 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 CB 1 Rs 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 CB 1 Rs 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 CB 1 R 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 CB 1 Rs in DIO mice inhibits nutrient-induced CCK release. Moreover, the hypophagic effect of AM6545 in DIO mice was reversed by co-administration with the CCK A receptor antagonist, devazepide. Collectively, these results provide evidence that hyperphagia associated with DIO is driven by a mechanism that includes CB 1 R-mediated inhibition of gut-brain satiation signaling.

Maternal Transfer of Environmentally Relevant Polybrominated Diphenyl Ethers (PBDEs) Produces a Diabetic Phenotype and Disrupts Glucoregulatory Hormones and Hepatic Endocannabinoids in Adult Mouse Female Offspring

“…Ultra-performance liquid chromatography-tandem mass spectrometry. Hepatic lipids were extracted following a modification of the Folch method 96 Glutamate dehydrogenase (GDH) activity. GDH is a key enzyme bridging amino acid-toglucose pathways.…”

Cannabinoid CB1 Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice

“…In response, these cells release several satiation-and satiety-related molecules that communicate with the brain via a mechanism that includes the afferent vagus nerve [30][31][32][33][34][35][36][37][38]. We recently reported that eCB signaling in the gut controls nutrient-induced release of satiation peptides [16]. Gene transcripts for CB 1 Rs were enriched in a subpopulation of enteroendocrine cells in the upper small-intestinal epithelium that secrete the satiation peptide, cholecystokinin [16,39].…”

“…We recently reported that eCB signaling in the gut controls nutrient-induced release of satiation peptides [16]. Gene transcripts for CB 1 Rs were enriched in a subpopulation of enteroendocrine cells in the upper small-intestinal epithelium that secrete the satiation peptide, cholecystokinin [16,39]. Notably, the ability for nutrients to stimulate an increase in levels of circulating cholecystokinin was impaired in mice fed WD for eight weeks when compared to lean control mice, and pharmacological inhibition of overactive eCB signaling at peripheral CB 1 Rs in mice fed WD restored the ability for nutrients to induce release of cholecystokinin [16].…”

“…Gene transcripts for CB 1 Rs were enriched in a subpopulation of enteroendocrine cells in the upper small-intestinal epithelium that secrete the satiation peptide, cholecystokinin [16,39]. Notably, the ability for nutrients to stimulate an increase in levels of circulating cholecystokinin was impaired in mice fed WD for eight weeks when compared to lean control mice, and pharmacological inhibition of overactive eCB signaling at peripheral CB 1 Rs in mice fed WD restored the ability for nutrients to induce release of cholecystokinin [16]. Furthermore, the appetite-suppressing effects of peripheral CB 1 R inhibition in mice maintained on WD were attenuated by co-treatment with an antagonist for cholecystokinin-A receptors [16], which are expressed by sensory vagal neurons and other organs [40].…”

“…Notably, the ability for nutrients to stimulate an increase in levels of circulating cholecystokinin was impaired in mice fed WD for eight weeks when compared to lean control mice, and pharmacological inhibition of overactive eCB signaling at peripheral CB 1 Rs in mice fed WD restored the ability for nutrients to induce release of cholecystokinin [16]. Furthermore, the appetite-suppressing effects of peripheral CB 1 R inhibition in mice maintained on WD were attenuated by co-treatment with an antagonist for cholecystokinin-A receptors [16], which are expressed by sensory vagal neurons and other organs [40]. Collectively, these studies suggest that eCB signaling in upper small-intestinal epithelium is dysregulated in WD-induced obese mice and promotes overeating by a mechanism that includes blocking nutrient-induced gut-brain satiation signaling.…”