title: 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.
authors.affiliation: Unidad de Gestion Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga 29009, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Málaga 29009, Spain INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France javier.bermudez@ibima.eu daniela.cota@inserm.fr.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Bermudez-Silva
authors.affiliation: Unidad de Gestion Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga 29009, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Málaga 29009, Spain.
authors.forename: Silvana Y
authors.initials: SY
authors.lastname: Romero-Zerbo
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France.
authors.forename: Magalie
authors.initials: M
authors.lastname: Haissaguerre
authors.affiliation: Unidad de Gestion Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga 29009, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Málaga 29009, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ruz-Maldonado
authors.affiliation: Unidad de Gestion Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga 29009, Spain.
authors.forename: Said
authors.initials: S
authors.lastname: Lhamyani
authors.affiliation: Unidad de Gestion Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga 29009, Spain.
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Bekay
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France Service d'endocrinologie, diabétologie, maladies métaboliques et nutrition, Hôpital Haut-Lévêque, Pessac F-33604, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Tabarin
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France javier.bermudez@ibima.eu daniela.cota@inserm.fr.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cota
mesh_terms: D000818:Animals; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D000077285:Rimonabant; D015398:Signal Transduction; D020123:Sirolimus / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007328:Insulin; D046912:Multiprotein Complexes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D005947:Glucose; D000077285:Rimonabant; D020123:Sirolimus
keywords: CB1; Cannabinoids; Insulin secretion; Islets; Rapamycin; Rimonabant; S6K1