Cannabinoids Block Fat-induced Incretin Release via CB₁-dependent and CB₁-independent Pathways in Intestinal...

Glucose 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 peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (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.

We 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.

Oral 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 coadministration with AM6545. WIN55,212-2 failed to inhibit fat-induced GIP release, but not GLP1, in IntCB₁-/- mice. In contrast, THC inhibited the secretion of incretins irrespective of CB₁R expression in intestinal epithelial cells.

These results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB₁R-dependent and CB₁R-independent mechanisms.