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

Francisco J. Bermudez-Silva, Silvana Y. Romero-Zerbo, Magalie Haissaguerre, Inmaculada Ruz-Maldonado, Said Lhamyani, Rajaa El Bekay, Antoine Tabarin, Giovanni Marsicano, Daniela Cota
Dis. Model. Mech.. 2015-11-12; 9(1): 51-61
DOI: 10.1242/dmm.020750

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1. Dis Model Mech. 2016 Jan;9(1):51-61. doi: 10.1242/dmm.020750. Epub 2015 Nov 12.

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

Bermudez-Silva FJ(1), Romero-Zerbo SY(2), Haissaguerre M(3), Ruz-Maldonado I(2),
Lhamyani S(4), El Bekay R(4), Tabarin A(5), Marsicano G(3), Cota D(6).

Author information:
(1)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 .
(2)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.
(3)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.
(4)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.
(5)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.
(6)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
.

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.

© 2016. Published by The Company of Biologists Ltd.

DOI: 10.1242/dmm.020750
PMCID: PMC4728331
PMID: 26563389 [Indexed for MEDLINE]

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