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

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...

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Published in:	Nature metabolism Vol. 6; no. 6; pp. 1053 - 1075
Main Authors:	Khani, Sajjad, Topel, Hande, Kardinal, Ronja, Tavanez, Ana Rita, Josephrajan, Ajeetha, Larsen, Bjørk Ditlev Marcher, Gaudry, Michael James, Leyendecker, Philipp, Egedal, Nadia Meincke, Güller, Aylin Seren, Stanic, Natasa, Ruppert, Phillip M. M., Gaziano, Isabella, Hansmeier, Nils Rouven, Schmidt, Elena, Klemm, Paul, Vagliano, Lara-Marie, Stahl, Rainer, Duthie, Fraser, Krause, Jens-Henning, Bici, Ana, Engelhard, Christoph Andreas, Gohlke, Sabrina, Frommolt, Peter, Gnad, Thorsten, Rada-Iglesias, Alvaro, Pradas-Juni, Marta, Schulz, Tim Julius, Wunderlich, Frank Thomas, Pfeifer, Alexander, Bartelt, Alexander, Jastroch, Martin, Wachten, Dagmar, Kornfeld, Jan-Wilhelm
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-06-2024
Subjects:	13/51 13/89 14 38 38/91 42 45 45/15 45/41 631/443/319 631/443/319/1642 631/443/319/2723 631/45/173 692/4017 Adenylyl Cyclases - genetics Adenylyl Cyclases - metabolism Adipose Tissue, Brown - metabolism Animals Biomedical and Life Sciences Cold Temperature Cyclic AMP - metabolism Energy Metabolism Humans Life Sciences Male Mice Mice, Knockout Thermogenesis - genetics
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Summary:	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. Truncated version of adenylyl cyclase 3 acts as a cold-induced rheostat during long-term brown adipose tissue activation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2522-5812 2522-5812
DOI:	10.1038/s42255-024-01033-8