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

Pedro, Joana Reis ; Moura, Liane I.F. ; Valério-Fernandes, Ângela ; Baptista, Filipa I. ; Gaspar, Joana M. ; Pinheiro, Bárbara S. ; Lemos, Cristina ; Kaufmann, Fernanda Neutzling ; Morgado, Carla and Silva-Santos, Carla S.da , et al. (2020) In Brain Research Bulletin 161. p.106-115
Abstract

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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Cannabinoid CBreceptor, Cerebral glucose metabolism, Frontal cortex, Goto-Kakizaki rat, type-1 diabetes, Wistar rat
in
Brain Research Bulletin
volume
161
pages
10 pages
publisher
Elsevier
external identifiers
  • pmid:32428627
  • scopus:85085035596
ISSN
0361-9230
DOI
10.1016/j.brainresbull.2020.05.004
language
English
LU publication?
yes
id
e9b477ee-f150-47bf-80aa-e6e11be1687a
date added to LUP
2020-06-11 12:39:58
date last changed
2024-03-04 21:40:01
@article{e9b477ee-f150-47bf-80aa-e6e11be1687a,
  abstract     = {{<p>Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB<sub>1</sub> receptor (CB<sub>1</sub>R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB<sub>1</sub>R 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 CB<sub>1</sub>R 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 CB<sub>1</sub>R agonists, WIN55212−2 (500 nM) and the CB<sub>1</sub>R-selective agonist, ACEA (3 μM) while it was exacerbated by the CB<sub>1</sub>R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB<sub>1</sub>Rs 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 CB<sub>1</sub>R density within a month after T1D induction resolves previous controversial reports on forebrain CB<sub>1</sub>R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex.</p>}},
  author       = {{Pedro, Joana Reis and Moura, Liane I.F. and Valério-Fernandes, Ângela and Baptista, Filipa I. and Gaspar, Joana M. and Pinheiro, Bárbara S. and Lemos, Cristina and Kaufmann, Fernanda Neutzling and Morgado, Carla and Silva-Santos, Carla S.da and Tavares, Isaura and Ferreira, Samira G. and Carvalho, Eugénia and Ambrósio, António F. and Cunha, Rodrigo A. and Duarte, João M.N. and Köfalvi, Attila}},
  issn         = {{0361-9230}},
  keywords     = {{Cannabinoid CBreceptor; Cerebral glucose metabolism; Frontal cortex; Goto-Kakizaki rat; type-1 diabetes; Wistar rat}},
  language     = {{eng}},
  pages        = {{106--115}},
  publisher    = {{Elsevier}},
  series       = {{Brain Research Bulletin}},
  title        = {{Transient gain of function of cannabinoid CB<sub>1</sub> receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes}},
  url          = {{http://dx.doi.org/10.1016/j.brainresbull.2020.05.004}},
  doi          = {{10.1016/j.brainresbull.2020.05.004}},
  volume       = {{161}},
  year         = {{2020}},
}