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Submitted on July 10, 2003
Accepted on September 25, 2003
3-adrenoceptors through a cAMP, PKA and PI3-kinase-dependent pathway stimulating conventional and novel PKCs
1 The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: Tore.Bengtsson{at}zoofys.su.se.
To identify the signaling pathways that mediate the adrenergic stimulation of glucose uptake in BAT, we have used mouse brown adipocytes in culture. The endogenous adrenergic neurotransmitter norepinephrine (NE) induced 2-deoxy-D-glucose uptake 3-fold in a concentration-dependent manner (pEC50 
6.5). The uptake was abolished by high doses of propranolol. The NE effect was mimicked by isoprenaline (pEC50 6.9), BRL 37344 (pEC50 8.6), CL 316243 (pEC50 9.7) and CGP 12177 (pEC50 7.3) and was thus mediated by 
3-adrenergic receptors. The NE-induced effect on 2-deoxy-D-glucose uptake was mediated by adenylyl cyclase and cAMP, since responses were inhibited by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine (DDA) and the PKA inhibitor 4-cyano-3-methylisoquinoline (4CM). Cholera toxin and 8-Br cAMP were both able to increase 2-deoxy-D-glucose uptake. Involvement of other adrenergic signaling pathways (
1-and 2-adrenergic receptors) were excluded. The PI3K inhibitor LY294002, abolished -adrenergic- or 8-Br cAMP-stimulated 2-deoxy-D-glucose uptake, demonstrating that a cAMP dependent PI3K-mediated pathway is positively connected to glucose uptake. Inhibition of the -adrenergically stimulated response with PKC inhibitors (Gö 6983 which inhibits (, , 
), (
) and (
) isoforms and Ro-31-8220 which inhibits (, 1, 2, ) and (
) but not atypical isoforms) indicated that cAMP-mediated glucose uptake is stimulated via conventional and novel PKCs. These results demonstrate that adrenergic stimulation, through 3-adrenergic receptors /cAMP/protein kinase A, recruits a PI3K pathway stimulating conventional and novel PKCs which mediate glucose uptake in brown adipocytes.
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