The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice
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...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2016-01-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/9/1/51 |
| _version_ | 1818543117828096000 |
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| author | Francisco J. Bermudez-Silva Silvana Y. Romero-Zerbo Magalie Haissaguerre Inmaculada Ruz-Maldonado Said Lhamyani Rajaa El Bekay Antoine Tabarin Giovanni Marsicano Daniela Cota |
| author_facet | Francisco J. Bermudez-Silva Silvana Y. Romero-Zerbo Magalie Haissaguerre Inmaculada Ruz-Maldonado Said Lhamyani Rajaa El Bekay Antoine Tabarin Giovanni Marsicano Daniela Cota |
| author_sort | Francisco J. Bermudez-Silva |
| collection | DOAJ |
| description | 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. |
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| format | Article |
| id | doaj.art-69494151f06440d4ad56164e45d6b46d |
| institution | Directory Open Access Journal |
| issn | 1754-8411 1754-8403 |
| language | English |
| last_indexed | 2024-12-11T22:31:07Z |
| publishDate | 2016-01-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-69494151f06440d4ad56164e45d6b46d2022-12-22T00:48:08ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032016-01-0191516110.1242/dmm.020750020750The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in miceFrancisco J. Bermudez-Silva0Silvana Y. Romero-Zerbo1Magalie Haissaguerre2Inmaculada Ruz-Maldonado3Said Lhamyani4Rajaa El Bekay5Antoine Tabarin6Giovanni Marsicano7Daniela Cota8 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 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 INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France 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 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 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 INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux F-33000, France 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.http://dmm.biologists.org/content/9/1/51CannabinoidsInsulin secretionRapamycinRimonabantIsletsCB1S6K1 |
| spellingShingle | Francisco J. Bermudez-Silva Silvana Y. Romero-Zerbo Magalie Haissaguerre Inmaculada Ruz-Maldonado Said Lhamyani Rajaa El Bekay Antoine Tabarin Giovanni Marsicano Daniela Cota The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice Disease Models & Mechanisms Cannabinoids Insulin secretion Rapamycin Rimonabant Islets CB1 S6K1 |
| title | The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice |
| title_full | The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice |
| title_fullStr | The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice |
| title_full_unstemmed | The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice |
| title_short | The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice |
| title_sort | cannabinoid cb1 receptor and mtorc1 signalling pathways interact to modulate glucose homeostasis in mice |
| topic | Cannabinoids Insulin secretion Rapamycin Rimonabant Islets CB1 S6K1 |
| url | http://dmm.biologists.org/content/9/1/51 |
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