beta(3)-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes

Activity of the sympathetic nervous system is an important factor involved in the pathogenesis of insulin resistance and associated metabolic and vasc ular abnormalities. In this study, we investigate the molecular basis of cr oss-talk between beta(2)-adrenergic and insulin signaling systems in mouse brown adipocytes immortalized by SV40 T infection. Insulin-induced tyrosine phosphorylation of the insulin receptor, insulin receptor substrate 1 (IRS -1), and IRS-S was reduced by prestimulation of beta(3)-adrenergic receptor s (CL316243). Similarly, insulin-induced IRS-1-associated and phosphotyrosi ne-associated phosphatidylinositol S-kinase (PI 3-kinase) activity, but not IRS-2-associated PI 3-kinase activity, was reduced by beta(3)-adrenergic p restimulation, Furthermore, insulin-stimulated activation of Akt, but not m itogen-activated protein kinase, was diminished. Insulin-induced glucose up take was completely inhibited by beta(3)-adrenersc prestimulation. These ef fects appear to be protein kinase A-dependent. Furthermore inhibition of pr otein kinase C restored the beta(3)-receptor-mediated reductions in insulin -induced IRS-1 tyrosine phosphorylation and IRS-1-associated PI 3-kinase ac tivity. Together, these findings indicate cross-talk between adrenergic and insulin signaling pathways. This interaction is protein kinase A-dependent and, at least in part, protein kinase C-dependent, and could play an impor tant role in the pathogenesis of insulin resistance associated with sympath etic overactivity and regulation of brown fat metabolism.