α1- and β1-adrenoceptor signaling fully compensates for β3-adrenoceptor deficiency in brown adipocyte norepinephrine-stimulated glucose uptake

To assess the relative roles and potential contribution of adrenergic receptor subtypes other than the beta(3)-adrenergic receptor in norepinephrine-mediated glucose uptake in brown adipocytes, we have here analyzed adrenergic activation of glucose uptake in primary cultures of brown adipocytes from wild-type and beta(3)-adrenergic receptor knockout (KO) mice. In control cells in addition to high levels of beta(3)-adrenergic receptor mRNA, there were relatively low alpha(1A)-, alpha(1D)-, and moderate beta(1)-adrenergic receptor mRNA levels with no apparent expression of other adrenergic receptors. The levels of alpha(1A)-, alpha(1D)-, and beta(1)-adrenergic receptor mRNA were not changed in the beta(3)-KO brown adipocytes, indicating that the beta(3)-adrenergic receptor ablation does not influence adrenergic gene expression in brown adipocytes in culture. As expected, the beta(3)-adrenergic receptor agonists BRL-37344 and CL-316 243 did not induce 2-deoxy-D-glucose uptake in beta(3)-KO brown adipocytes. Surprisingly, the endogenous adrenergic neurotransmitter norepinephrine induced the same concentration-dependent 2-deoxy-D-glucose uptake in wild-type and beta(3)-KO brown adipocytes. This study demonstrates that beta(1)-adrenergic receptors, and to a smaller degree beta(1)-adrenergic receptors, functionally compensate for the lack of beta(3)-adrenergic receptors in glucose uptake. beta(1)-Adrenergic receptors activate glucose uptake through a cAMP/protein kinase A/phosphatidylinositol 3-kinase pathway, stimulating conventional and novel protein kinase Cs. The alpha(1)-adrenergic receptor component ( that is not evident in wild-type cells) stimulates glucose uptake through a phosphatidylinositol 3-kinase and protein kinase C pathway in the beta(3)-KO cells.