α1- and β1-Adrenoceptor Signaling Fully Compensates for β3-Adrenoceptor Deficiency in Brown Adipocyte Norepinephrine-Stimulated Glucose Uptake

Abstract

AbstractTo assess the relative roles and potential contribution of adrenergic receptor subtypes other than the β3-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 β3-adrenergic receptor knockout (KO) mice. In control cells in addition to high levels of β3-adrenergic receptor mRNA, there were relatively low α1A-, α1D-, and moderate β1-adrenergic receptor mRNA levels with no apparent expression of other adrenergic receptors. The levels of α1A-, α1D-, and β1-adrenergic receptor mRNA were not changed in the β3-KO brown adipocytes, indicating that the β3-adrenergic receptor ablation does not influence adrenergic gene expression in brown adipocytes in culture. As expected, the β3-adrenergic receptor agonists BRL-37344 and CL-316 243 did not induce 2-deoxy-d-glucose uptake in β3-KO brown adipocytes. Surprisingly, the endogenous adrenergic neurotransmitter norepinephrine induced the same concentration-dependent 2-deoxy-d-glucose uptake in wild-type and β3-KO brown adipocytes. This study demonstrates that β1-adrenergic receptors, and to a smaller degree α1-adrenergic receptors, functionally compensate for the lack of β3-adrenergic receptors in glucose uptake. β1-Adrenergic receptors activate glucose uptake through a cAMP/protein kinase A/phosphatidylinositol 3-kinase pathway, stimulating conventional and novel protein kinase Cs. The α1-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 β3-KO cells.