Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes.
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 specificity. These scaffold proteins may themselves be modulated by hormones. In adipocytes, stimulation of beta-adrenergic receptors increases cyclic AMP levels and activates protein kinase A (PKA), which stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin. Acute insulin treatment activates phosphodiesterase 3B, reduces cAMP levels and quenches beta-adrenergic receptor signalling. In contrast, chronic hyperinsulinaemic conditions (typical of type 2 diabetes) enhance beta-adrenergic receptor-mediated cAMP production. 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 beta-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 beta-adrenergic receptor signalling. Chronically high insulin levels may disrupt the close apposition of beta-adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways.
Zhang
Jin
J
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA.
Hupfeld
Christopher J
CJ
Taylor
Susan S
SS
Olefsky
Jerrold M
JM
Tsien
Roger Y
RY
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008066:Lipolysis; D051379:Mice; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D007328:Insulin; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases