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Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function
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Number of Authors: 342024 (English)In: Nature Metabolism, E-ISSN 2522-5812Article in journal (Refereed) Epub ahead of print
Abstract [en]

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. 

Place, publisher, year, edition, pages
2024.
National Category
Cell and Molecular Biology Endocrinology and Diabetes
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URN: urn:nbn:se:su:diva-228971DOI: 10.1038/s42255-024-01033-8ISI: 001209548100001PubMedID: 38684889Scopus ID: 2-s2.0-85191850631OAI: oai:DiVA.org:su-228971DiVA, id: diva2:1857496
Available from: 2024-05-14 Created: 2024-05-14 Last updated: 2024-05-14

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Gaudry, Michael JamesJastroch, Martin

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Department of Molecular Biosciences, The Wenner-Gren Institute
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