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Krier, J. ; Spähn, D.* ; Lopez, D.A.J. ; Nono, J.L. ; Seigner, J. ; Ussar, S. ; Lukowski, R.* ; Birkenfeld, A.L. ; Sancar, G.

PDE4D and PDE3B orchestrate distinct cAMP microdomains in 3T3-L1 adipocytes.

Br. J. Pharmacol., DOI: 10.1111/bph.70216 (2025)
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BACKGROUND AND PURPOSE: Lipolysis is tightly regulated by pro-lipolytic β-adrenoceptor signalling, which activates the cAMP/PKA pathway, and by antilipolytic hormones like insulin and FGF1, which counter-regulate lipolysis through cAMP-degrading phosphodiesterases (PDEs). While the spatial compartmentalization of cAMP signalling is recognized, comparisons between distinct cAMP pools remain under-investigated in adipocytes. Moreover, the dynamics of cAMP around lipid droplets (LD) where lipolysis occurs, are particularly intriguing. Thus, we studied whether adipose FGF1/PDE4D and insulin/PDE3B pathways regulate distinct cAMP microdomains to execute their antilipolytic actions. EXPERIMENTAL APPROACH: We evaluated the role of subcellular cAMP pools in lipolysis regulation by PDEs, or antilipolytic hormones, by utilizing EPAC1-based FRET cAMP biosensors specifically designed to localize in the cytoplasm or at the plasma membrane of living cells. Additionally, we developed the first LD-associated cAMP biosensor by fusing the lipid droplet-associated protein perilipin-1 to the EPAC1-based probe. KEY RESULTS: We identified previously unrecognized cAMP pools surrounding LDs that are distinct from cytoplasmic cAMP and resistant to PDE inhibition or antilipolytic stimuli. PDE4D exhibits a stronger effect on all three cAMP pools investigated than PDE3B. FGF1 mainly inhibits the cAMP in the initiation of the signalling at the plasma membrane, whereas insulin targets mainly cytoplasmic cAMP pools. CONCLUSION AND IMPLICATIONS: The discovery of LD-associated cAMP as a distinct subcellular pool suggests that cAMP signalling in adipocytes is more compartmentalized than previously recognized. The distinct pathways by which FGF1 and insulin regulate adipose cell cAMP levels highlight that antilipolytic signalling is not uniform, refining our understanding of lipolysis regulation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Fgf1 ; Fret ; Pde3b ; Pde4d ; Camp ; Insulin ; Lipolysis; Protein-kinase-a; Cyclic-nucleotide Phosphodiesterases; Adipose-tissue; Beta(2)-adrenergic Receptors; Insulin-resistance; Rat Adipocytes; Concise Guide; Lipolysis; Phosphorylation; Activation
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Journal British Journal of Pharmacology
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
Adipocytes & Metabolism (ADM)
POF-Topic(s) 90000 - German Center for Diabetes Research
30205 - Bioengineering and Digital Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502400-001
G-507200-001
Grants German Center for Diabetes Research (DZD)
Deutsches Zentrum fur Diabetesforschung
DOI 10.1111/bph.70216
WOS ID 001592690900001
Scopus ID 105019079268
PubMed ID 41082906
Erfassungsdatum 2025-10-15
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