Hierarchical glucocorticoid-endocannabinoid interplay regulates the activation of the nucleus accumbens by insulin.
Brain Research Bulletin. 2016-06-01; 124: 222-230
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Here we asked if insulin activation of the nucleus accumbens in vitro is
reflected by an increase in (3)H-deoxyglucose ([(3)H]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 [(3)H]DG uptake. The synthetic cannabinoid agonist,
WIN55212-2 (500nM) and the glucocorticoid dexamethasone (10μM), impaired insulin
(300nM) action on [(3)H]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 heteromer, thus impeding insulin signaling.