UC Riverside

The endocannabinoid (eCB) system is an important regulator of food intake and energy conservation both within the central nervous system and in key metabolically relevant peripheral organs. Recent findings have shown the peripheral eCB system to be an important contributor in regulating energy homeostasis. With the increasing obesity epidemic, we sought to determine whether this system is altered during maternal obesity which might explain some predispositions for later weight gain. Notably, these studies were met with unexpected high neonate mortality, emphasizing how detrimental obesity can be and the further need for therapeutic targets to curtail this disease. Thus, we examined the eCB system in the context of obesity. Previous evidence shows an increase in eCB signaling in the proximal small intestine during obesity. We further examined these findings and determined that these changes occur in the same region as enteroendocrine I-cells, which secrete satiation factor cholecystokinin (CCK). Indeed, I-cells were shown to express cannabinoid receptor subtype 1 (CB1Rs). Using pharmacological agents or increased endogenous signaling (as seen during diet-induced obesity), we showed that CB1R signaling controls CCK secretion. This suggests that CB1R signaling in the proximal small intestine controls satiation through a CCK dependent mechanism. Furthermore, we examined the role of CB1Rs on glucose regulatory peptides glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP1), which are produced by enteroendocrine K- and L-cells, respectively, and both express CB1Rs. CB1R activation inhibited incretin secretion, an effect that was restored by co-administering a peripherally-restricted CB1R antagonist. Lastly, through the use of transgenic mouse models, we demonstrate that CB1R on enteroendocrine K- cells control GIP release, but CB1R on enteroendocrine L-cells do not, suggesting an alternative CB1R dependent, intestinal independent mechanism for GLP1. This body of work begins to elucidate eCB signaling in the small intestine as regulators of enteroendocrine incretin release, which regulate both food intake (CCK) and energy homeostasis (GIP, GLP1).