Live-cell imaging identifies cAMP microdomains regulating β-adrenoceptor-subtype-specific lipolytic responses in human white adipocytes

TY - JOUR

T1 - Live-cell imaging identifies cAMP microdomains regulating β-adrenoceptor-subtype-specific lipolytic responses in human white adipocytes

AU - De Jong, Kirstie A

AU - Ehret, Sandra

AU - Heeren, Joerg

AU - Nikolaev, Viacheslav O

N1 - Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2023/5/30

Y1 - 2023/5/30

N2 - Lipolysis of stored triglycerides is stimulated via β-adrenergic receptor (β-AR)/3',5'-cyclic adenosine monophosphate (cAMP) signaling and inhibited via phosphodiesterases (PDEs). In type 2 diabetes, a dysregulation in the storage/lipolysis of triglycerides leads to lipotoxicity. Here, we hypothesize that white adipocytes regulate their lipolytic responses via the formation of subcellular cAMP microdomains. To test this, we investigate real-time cAMP/PDE dynamics at the single-cell level in human white adipocytes with a highly sensitive florescent biosensor and uncover the presence of several receptor-associated cAMP microdomains where cAMP signals are compartmentalized to differentially regulate lipolysis. In insulin resistance, we also detect cAMP microdomain dysregulation mechanisms that promote lipotoxicity, but regulation can be restored by the anti-diabetic drug metformin. Therefore, we present a powerful live-cell imaging technique capable of resolving disease-driven alterations in cAMP/PDE signaling at the subcellular level and provide evidence to support the therapeutic potential of targeting these microdomains.

AB - Lipolysis of stored triglycerides is stimulated via β-adrenergic receptor (β-AR)/3',5'-cyclic adenosine monophosphate (cAMP) signaling and inhibited via phosphodiesterases (PDEs). In type 2 diabetes, a dysregulation in the storage/lipolysis of triglycerides leads to lipotoxicity. Here, we hypothesize that white adipocytes regulate their lipolytic responses via the formation of subcellular cAMP microdomains. To test this, we investigate real-time cAMP/PDE dynamics at the single-cell level in human white adipocytes with a highly sensitive florescent biosensor and uncover the presence of several receptor-associated cAMP microdomains where cAMP signals are compartmentalized to differentially regulate lipolysis. In insulin resistance, we also detect cAMP microdomain dysregulation mechanisms that promote lipotoxicity, but regulation can be restored by the anti-diabetic drug metformin. Therefore, we present a powerful live-cell imaging technique capable of resolving disease-driven alterations in cAMP/PDE signaling at the subcellular level and provide evidence to support the therapeutic potential of targeting these microdomains.

KW - Humans

KW - Lipolysis/physiology

KW - Adipocytes, White/metabolism

KW - Diabetes Mellitus, Type 2

KW - Cyclic AMP/metabolism

KW - Receptors, Adrenergic, beta/metabolism

U2 - 10.1016/j.celrep.2023.112433

DO - 10.1016/j.celrep.2023.112433

M3 - SCORING: Journal article

C2 - 37099421

VL - 42

SP - 112433

JO - CELL REP

JF - CELL REP

SN - 2211-1247

IS - 5

ER -