Cannabinoid CB1 receptors and mTORC1 signalling pathway interact to modulate glucose homeostasis

Abstract

The endocannabinoid system (ECS) is an inter-cellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and beta-cell mass expansion. The downstream signalling pathways mediating these effects are poorly understood. The mammalian target of rapamycin complex 1 (mTORC1) is a key intra-cellular pathway involved in energy homeostasis and known to importantly affect pancreatic islet's physiology. We investigated the possible relationship between cannabinoid type 1 (CB1) receptors signalling and the mTORC1 pathway in the endocrine pancreas by using pharmacology as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, p70S6K1 kinase. In vitro static secretion experiments on islets, western blots and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1µM while increasing phosphorylation of p70S6K1 and rpS6 within the islets. Specific pharmacological blockade of mTORC1 by 3nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3mg/kg 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 (0.1mg/kg), 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 beta-cell diseases.