Peripheral cannabinoid CB 1 receptors control nutrient‐induced incretin secretion in vivo

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Enteroendocrine cells along the intestinal epithelium secrete incretins and related hormones (i.e. GIP, GLP‐1, and CCK‐8) following ingestion of nutrients. Incretins bind and activate their respective receptors on cells located in – but not limited to – the endocrine pancreas, which enhances insulin secretion and maintains a tight window of circulating blood glucose. The ability to adequately regulate circulating glucose levels is lost in patients living with prediabetes and type 2 diabetes. The endocannabinoid system controls food intake and glucose homeostasis, and its activity becomes upregulated in the proximal small‐intestinal epithelium of Western‐diet induced obese mice. Cannabinoid subtype‐1 receptors (CB 1 Rs) are present in various incretin‐producing cells in the intestinal epithelium (e.g. K, L, I‐cells), yet their function in these cell types are poorly characterized. In the current investigation, we examined the ability for CB 1 Rs to control incretin secretion in vivo in male C57CL/6N mice. We administered the cannabinoid receptor agonist, WIN 55,212‐2 (WIN, 3 mg per kg), alone and in combination with the peripherally‐restricted neutral CB 1 R antagonist, AM6545 (10 mg per kg). Incretin secretion was then stimulated via corn oil gavage (0.5 mL 30 minutes after drug treatment) and circulating incretins were quantified by sensitive enzyme‐linked immunosorbent assays from plasma obtained 30 minutes later. Activating CB 1 Rs with WIN blunted corn‐oil induced secretion of GIP, active GLP‐1 and CCK‐8. Co‐administration of WIN with AM6545 completely reversed the inhibitory actions of WIN on incretin release. Collectively, our results suggest that CB 1 Rs in the small‐intestinal epithelium control nutrient induced incretin release. The functional consequences of these findings on glucose homeostasis are currently under investigation. Support or Funding Information Acknowledgements Funded by the National Institutes of Health, USA (Grant no. DK119498, DK114978, and DA034009)

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