Cannabinoids block fat-induced incretin release via CB1-dependent and CB1-independent pathways in intestinal epithelium

Abstract

Background and AimsGlucose homeostasis is regulated by a dynamic interplay between hormones along the gastro-insular axis. For example, enteroendocrine L- and K- cells that line the intestine produce the incretins glucagon-like polypeptide-1 (GLP1) and glucose-dependent insulinotropic peptide (GIP), respectively, which are secreted following a meal. Broadly, incretin signaling enhances insulin release from the endocrine pancreas and participates in the control of food intake, and therapeutics that mimic their activity have recently been developed for the treatment of type-2 diabetes and obesity. Notably, genes for cannabinoid subtype-1 receptor (CB1R) are expressed in these cell subpopulations; however, roles for CB1Rs in controlling fat-induced incretin release are unclear. To address this gap in our understanding, we tested the hypothesis that intestinal epithelial CB1Rs control fat-induced incretin secretion. MethodsWe treated mice with conditional deletion of CB1Rs in the intestinal epithelium (IntCB1-/-) or controls (IntCB1+/+) with oil gavage to stimulate incretin release in the presence of the cannabinoid receptor agonists, WIN55,212-2 or Δ9-tetrahydrocannabinol (THC), and the peripherally-restricted CB1R antagonist AM6545. Circulating incretin levels were measured in plasma. ResultsOral gavage of corn oil increased levels of bioactive GLP1 and GIP in IntCB1+/+ mouse plasma. Pretreatment with the WIN55,212-2 or THC blocked this response, which was largely reversed by co-administration with AM6545. WIN55,212-2 failed to inhibit fat-induced GIP release, but not aGLP1, in IntCB1-/- mice. In contrast, THC inhibited the secretion of incretins irrespective of CB1R expression in intestinal epithelial cells. ConclusionsThese results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB1R-dependent and CB1R-independent mechanisms.