Live-cell imaging identifies cAMP microdomains regulating β-adrenoceptor-subtype-specific lipolytic responses in human white adipocytes
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Live-cell imaging identifies cAMP microdomains regulating β-adrenoceptor-subtype-specific lipolytic responses in human white adipocytes. / De Jong, Kirstie A; Ehret, Sandra; Heeren, Joerg; Nikolaev, Viacheslav O.
in: CELL REP, Jahrgang 42, Nr. 5, 30.05.2023, S. 112433.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -