Hierarchical glucocorticoid-endocannabinoid interplay regulates the activation of the nucleus accumbens by insulin

Abstract

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.

Anandamide Effects in a Streptozotocin-Induced Alzheimer’s Disease-Like Sporadic Dementia in Rats

“…Our results further indicated a tendency for lower CB1R levels only in Veh/STZ. This might be a consequence of the tight interaction between endocannabinoids, CB1R and insulin receptors and their signaling that was previously reported in different systems and brain areas ( Kim et al, 2011 ; Labouèbe et al, 2013 ; Osmanovic Barilar et al, 2015 ; Pinheiro et al, 2016 ). Yet, it is important to remind that AEA also activates CB2R, transient receptor potential vanilloid channels ( Rodella et al, 2005 ) and has membrane and intracellular targets, since it is a hydrophobic molecule that can easily cross lipid membranes ( Glaser et al, 2005 ).…”

Cannabis: A Treasure Trove or Pandora's Box?

“…GcR activation in the prefrontal cortex triggers endocannabinoid release [966], which in turn downregulates the hypothalamo-pituitary-adrenal (HPA) axis to decrease circulating corticosteroid levels [967,968], facilitate the extinction and impair the retrieval of aversive memories [965,967,[969][970][971]. A similar phenomenon was suspected based on a pharmacological approach in the rat nucleus accumbens: dexamethasone via GcR activation stimulated 2-AG production, and consequently, activated CB 1 Rs in heteromeric complexes with insulin receptors, thus impairing insulin-stimulated accumbal glucose uptake [880]. Such mechanism could explain how chronic stress, Cushingsyndrome or chronic glucocorticoid treatment could impair the regulation of food intake or even, cerebral insulin sensitivity.…”

“…As a footnote, interactions between trophic factors and the endocannabinoid systems also occur beyond the RTK-CB 1 R heterodimers: CB 1 R activation stimulates insulin release in pancreatic β-cells [892] while insulin triggers 2-AG release onto accumbal glutamatergic terminals, with a consequent LTD on these excitatory afferents [893]. A CB 1 R antibody has been shown by us to immunoprecipitate the insulin receptor β chain in accumbal homogenates of the rat, and CB 1 R activation impaired the insulin-stimulated glucose uptake in rat accumbal slices [880] (see also Section 3.3.9).…”

“…At the current level of evidence, CB 1 Rs most probably control RTKs via adapter proteins or converging intracellular signaling. Nevertheless, it has been shown that CB 1 Rs form heteromeric complexes in the presence of agonists with the TrkB [879] and the insulin receptor [878,880]. Whether these complexes involve "bridges" of intracellular or intramembranal proteins or the two receptors are directly connected to each other, is unclear.…”

El Sistema de Endocannabinoides como regulador de la lipogénesis y su posible modulación por la mangiferina

“…En los ratones CB1 -/-, ocurre una desregulación generalizada del eje hipotalámicohipofisario-adrenal (HPA). Estos animales exhiben un aumento de los niveles de corticosterona en el pico circadiano y aumento de la expresión del RNAm de la CRH en el PVN, así como la sobre activación en la liberación de ACTH y la fosfoserina hipofisaria, lo cual también explicaría la resistencia a cortisol presente en algunos pacientes con diabetes y obesidad (47,50). También se ha demostrado que el SR141716A estimula los niveles de corticosterona circulantes basales y la actividad del eje HPA en ratas obesas privadas de alimento (51).…”