RT Journal Article
T1 The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice.
A1 Bermudez-Silva, Francisco J
A1 Romero-Zerbo, Silvana Y
A1 Haissaguerre, Magalie
A1 Ruz-Maldonado, Inmaculada
A1 Lhamyani, Said
A1 El Bekay, Rajaa
A1 Tabarin, Antoine
A1 Marsicano, Giovanni
A1 Cota, Daniela
K1 Cannabinoids
K1 Insulin secrection
K1 Rapamycin
K1 Rimonabant
K1 Islets
K1 CB1
K1 S6K1
K1 Animales
K1 Inmunotransferencia Western
K1 Peso corporal
K1 Endocannabinoides
K1 Glucosa
K1 Intolerancia a la glucosa
K1 Homeostasis
K1 Resistencia a la insulina
K1 Células secretoras de insulina
K1 Insulinas
K1 Islotes pancreáticos
K1 Ratones
K1 Complejos multiproteicos
K1 Fosforilación
K1 Piperidinas
K1 Pirazoles
K1 Receptor cannabinoide CB1
K1 Proteína S6 ribosómica
K1 Sirolimus
K1 TOR serina-treonina cinasas
AB 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.
PB The Company of Biologists
SN 1754-8403
YR 2016
FD 2016-01
LK http://hdl.handle.net/10668/2431
UL http://hdl.handle.net/10668/2431
LA en
NO Bermudez-Silva FJ, Romero-Zerbo SY, Haissaguerre M, Ruz-Maldonado I, Lhamyani S, El Bekay R, et al. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice. Dis Model Mech. 2016; 9(1):51-61
NO Journal Article; Research Support, Non-U.S. Gov't;
DS RISalud
RD Apr 5, 2025