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

Sajjad Khani, Hande Topel, Ronja Kardinal, Ana Rita Tavanez, Ajeetha Josephrajan, Bjørk Ditlev Marcher Larsen, Michael James Gaudry, Philipp Leyendecker, Nadia Meincke Egedal, Aylin Seren Güller, Natasa Stanic, Phillip M.M. Ruppert, Isabella Gaziano, Nils Rouven Hansmeier, Elena Schmidt, Paul Klemm, Lara Marie Vagliano, Rainer Stahl, Fraser Duthie, Jens Henning KrauseAna Bici, Christoph Andreas Engelhard, Sabrina Gohlke, Peter Frommolt, Thorsten Gnad, Alvaro Rada-Iglesias, Marta Pradas-Juni, Tim Julius Schulz, Frank Thomas Wunderlich, Alexander Pfeifer, Alexander Bartelt, Martin Jastroch, Dagmar Wachten*, Jan Wilhelm Kornfeld*


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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.

TidsskriftNature Metabolism
StatusE-pub ahead of print - 2024


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