1. Department of Pharmacology,
2. Division of Endocrinology and Metabolism,
3. Department of Chemistry and Biochemistry, and
4. Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093, USA
5. †Present address: Department of Pharmacology and Molecular Sciences and Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
6. *These authors contributed equally to this work

Correspondence to: Roger Y. Tsien^1,3,4 Correspondence and requests for materials should be addressed to R.Y.T. (Email: rtsien@ucsd.edu).

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 -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 -adrenergic receptor signalling⁹. In contrast, chronic hyperinsulinaemic conditions (typical of type 2 diabetes) enhance -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 -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 -adrenergic receptor signalling. Chronically high insulin levels may disrupt the close apposition of -adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways.

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