The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice

Abstract

The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases.

Biphasic effects of methanandamide on murine gastric vagal afferent mechanosensitivity

“…Activation of CB1 inhibits mTOR activity, presumably via Gα i/o (Bermudez‐Silva et al . ), subsequently increasing ghrelin release from gastric cells. Further, endogenous ghrelin, acting at GHSR (Page et al .…”

The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling

“…The effects of SR141716A on insulin secretion in vitro and in vivo in rodents have been a point of controversy in the literature. Thus, it is reported to decrease insulin hypersecretion in islets isolated from diabetic rats [36] and glucose-induced insulin secretion from mouse islets [37], but another study showed that SR141716A did not significantly affect insulin secretion from mouse islets [38]. Conversely, SR141716A was found to reversibly stimulate insulin secretion from human islets [39], and its chronic administration improved islet function and morphology in diabetic rats [40].…”

LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling

“…Despite confirmation of the expression of CB1 and GPR55 by both rodent and human β-cells, 10,14,18,19,47,48 the role played by the endocannabinoid system in the modulation of islet secretory activity is still far from being completely understood. For example, while the majority of studies suggest that activation of CB1 receptors increases insulin secretion, 47,[49][50][51] others point to the opposite effects. 19,20 The reasons for the controversies are likely to lie in the experimental models used, the selectivity of the ligands and the difficulties in addressing intracellular coupling where cannabinoid receptors signal via more than one heterotrimeric G-protein.…”