2016 May 18. pii: S0361-9230(16)30114-9. doi: 10.1016/j.brainresbull.2016.05.009. [Epub ahead of print]
Pinheiro BS1, Lemos C1, Neutzling-Kaufmann F1, Marques JM1, da Silva-Santos CS1, Carvalho E1, Mackie K2, Rodrigues RJ3, Cunha RA4, Köfalvi A5.
Abstract
Here we asked if insulin activation of the nucleus accumbens in vitro is reflected by an increase in 3H-deoxyglucose ([3H]DG) uptake, thus subserving a new model to study molecular mechanisms of central insulin actions. Additionally, we investigated the dependence of this insulin effect on endocannabinoids and corticosteroids, two major culprits in insulin resistance. We found that in acute accumbal slices, insulin (3 and 300nM but not at 0.3nM) produced an increase in [3H]DG uptake. The synthetic cannabinoid agonist, WIN55212-2 (500nM) and the glucocorticoid dexamethasone (10μM), impaired insulin (300nM) action on [3H]DG uptake. The glucocorticoid receptor (GcR) antagonist, mifepristone (10μM) prevented dexamethasone from inhibiting insulin’s action. Strikingly, this anti-insulin action of dexamethasone was also blocked by two CB1 cannabinoid receptor (CB1R) antagonists, O-2050 (500nM) and SR141716A (500nM), as well as by tetrahydrolipstatin (10μM), an inhibitor of diacylglycerol lipases – the enzymes responsible for the synthesis of the endocannabinoid, 2-arachidonoyl-glycerol (2-AG). On the other hand, the blockade of the post-synaptic 2-AG metabolizing enzymes, α,β-serine hydrolase domain 6/12 by WWL70 (1μM) also prevented the action of insulin, probably via increasing endogenous 2-AG tone. Additionally, an anti-insulin receptor (InsR) antibody immunoprecipitated CB1Rs from accumbal homogenates, indicating a physical complexing of CB1Rs with InsRs that supports their functional interaction. Altogether, insulin stimulates glucose uptake in the nucleus accumbens. Accumbal GcR activation triggers the synthesis of 2-AG that in turn binds to the known CB1R-InsR heterodimer, thus impeding insulin signaling.
Copyright © 2016 Elsevier Inc. All rights reserved.
Copyright © 2016 Elsevier Inc. All rights reserved.
KEYWORDS:
2-Arachidonoylglycerol; CB(1)R cannabinoid receptor; Glucocorticoid receptor; Glucose uptake; Insulin; Nucleus accumbens
- PMID: 27208730
- [PubMed – as supplied by publisher]