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Khani, S.* ; Topel, H.* ; Kardinal, R.* ; Tavanez, A.R.* ; Josephrajan, A.* ; Larsen, B.D.M.* ; Gaudry, M.J.* ; Leyendecker, P.* ; Egedal, N.M.* ; Güller, A.S.* ; Stanic, N.* ; Ruppert, P.M.M.* ; Gaziano, I.* ; Hansmeier, N.R.* ; Schmidt, E.* ; Klemm, P.* ; Vagliano, L.M.* ; Stahl, R.* ; Duthie, F.* ; Krause, J.H.* ; Bici, A.* ; Engelhard, C.A.* ; Gohlke, S.* ; Frommolt, P.* ; Gnad, T.* ; Rada-Iglesias, A.* ; Pradas-Juni, M.* ; Schulz, T.J.* ; Wunderlich, F.T.* ; Pfeifer, A.* ; Bartelt, A. ; Jastroch, M.* ; Wachten, D.* ; Kornfeld, J.W.*

Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.

Nat. Metab., DOI: 10.1038/s42255-024-01033-8 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5′ truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adipose-tissue; Transcriptional Regulation; Gene; Obesity; Camp; Differentiation; Thermogenesis; Disruption; Metabolism; Activation
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Publisher Springer
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Grants European Molecular Biology Organization (EMBO)
EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activit
Novo Nordisk Fonden (Novo Nordisk Foundation)
Deutscher Akademischer Austauschdienst (German Academic Exchange Service)
Deutsche Forschungsgemeinschaft (German Research Foundation)