Transient gain of function of cannabinoid CB1 receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes

Joana Reis Pedro, Liane I.F. Moura, Ângela Valério-Fernandes, Filipa I. Baptista, Joana M. Gaspar, Bárbara S. Pinheiro, Cristina Lemos, Fernanda Neutzling Kaufmann, Carla Morgado, Carla S. da Silva-Santos, Isaura Tavares, Samira G. Ferreira, Eugénia Carvalho, António F. Ambrósio, Rodrigo A. Cunha, João M.N. Duarte, Attila Köfalvi
Brain Research Bulletin. 2020-08-01; 161: 106-115
DOI: 10.1016/j.brainresbull.2020.05.004

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Here we aimed to unify some previous controversial reports on changes in both
cannabinoid CB1 receptor (CB1R) expression and glucose metabolism in the
forebrain of rodent models of diabetes. We determined how glucose metabolism and
its modulation by CB1R ligands evolve in the frontal cortex of young adult male
Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes
(T1D). We report that frontocortical CB1R protein density was biphasically
altered in the first month of T1D, which was accompanied with a reduction of
resting glucose uptake ex vivo in acute frontocortical slices that was normalized
after eight weeks in T1D. This early reduction of glucose uptake in slices was
also restored by ex vivo treatment with both the non-selective CB1R agonists,
WIN55212-2 (500 nM) and the CB1R-selective agonist, ACEA (3 μM) while it was
exacerbated by the CB1R-selective antagonist, O-2050 (500 nM). These results
suggest a gain-of-function for the cerebrocortical CB1Rs in the control of
glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities
remained unaffected, phosphorylated GSKα and GSKβ levels showed different
profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the
biphasic response in frontocortical CB1R density within a month after T1D
induction resolves previous controversial reports on forebrain CB1R levels in T1D
rodent models. Furthermore, this study also hints that cannabinoids may be useful
to alleviate impaired glucoregulation in the diabetic cortex.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.brainresbull.2020.05.004
PMID: 32428627

Conflict of interest statement: Declaration of Competing Interest The authors
declare no conflict of interest. The funding agencies had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the
writing of the manuscript, or in the decision to publish the results.

Auteurs Bordeaux Neurocampus