Insulin disrupts β-adrenergic signalling to protein kinase A in adipocytes

Abstract

Hormones mobilize intracellular second messengers and initiate signalling cascades involving protein kinases and phosphatases, which are often spatially compartmentalized by anchoring proteins to increase signalling specificity¹. These scaffold proteins may themselves be modulated by hormones^2,3,4. In adipocytes, stimulation of β-adrenergic receptors increases cyclic AMP levels and activates protein kinase A (PKA)⁵, which stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin^6,7,8. Acute insulin treatment activates phosphodiesterase 3B, reduces cAMP levels and quenches β-adrenergic receptor signalling⁹. In contrast, chronic hyperinsulinaemic conditions (typical of type 2 diabetes) enhance β-adrenergic receptor-mediated cAMP production¹⁰. This amplification of cAMP signalling is paradoxical because it should enhance lipolysis, the opposite of the known short-term effect of hyperinsulinaemia. Here we show that in adipocytes, chronically high insulin levels inhibit β-adrenergic receptors (but not other cAMP-elevating stimuli) from activating PKA. We measured this using an improved fluorescent reporter and by phosphorylation of endogenous cAMP-response-element binding protein (CREB). Disruption of PKA scaffolding mimics the interference of insulin with β-adrenergic receptor signalling. Chronically high insulin levels may disrupt the close apposition of β-adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways.