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PreprintCited by 24Adipose Tissue and MetabolismPeroxisome Proliferator-Activated ReceptorsLipid metabolism and biosynthesis

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Cold-induced expression of a truncated Adenylyl Cyclase 3 acts as rheostat to brown fat function

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Khani, Sajjad, Topel, Hande, Josephrajan, Ajeetha, Larsen, Bjørk Ditlev Marcher, de Almeida Tavanez, Ana Rita Albuquerque, Gaudry, Michael James, Leyendecker, Philipp, Stanic, Natasa, Gaziano, Isabella, Hansmeier, Nils Rouven, Schmidt, Elena, Klemm, Paul, Vagliano, Lara-Marie, Engelhard, Christoph Andreas, Nielsen, Søren, Jespersen, Naja Zenius, Rehimi, Rizwan, Gohlke, Sabrina, Frommolt, Peter, Gnad, Thorsten, Rada-Iglesias, Alvaro, Pradas-Juni, Marta, Schulz, Tim Julius, Wunderlich, Frank Thomas, Pfeifer, Alexander, Jastroch, Martin, Wachten, Dagmar, Kornfeld, Jan-Wilhelm·2022·Nature Metabolism
DOI 10.1101/2022.08.01.502156PMC PMC11971047

Preprint — published as 10.1038/s42255-024-01033-8

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Abstract

Promoting brown adipose tissue (BAT) activity has been recognized as innovative therapeutic approach to improve obesity and metabolic disease. Whilst the molecular circuitry underlying thermogenic activation of BAT is well understood, the processes underlying rheostatic regulation of BAT to maintain homeostasis and avoid excessive energy dissipation remain ill-defined. Increasing cyclic AMP (cAMP) biosynthesis is key for BAT activation. Here, we demonstrate that ADCY3, an adenylyl cyclase whose expression is induced during cold exposure and regulates cAMP homeostasis in thermogenic fat, is dispensable for BAT function in lean mice, but becomes critical during obesity. Furthermore, by combining RNA-seq with epigenomic H3K4me3 profiling, we detected a novel, cold-inducible promoter that generates a 5’ truncated Adcy3-at mRNA isoform, Adcy3-at . Mice lacking only Adcy3-at , but not full-length Adcy3 , displayed increased energy expenditure already under lean conditions and were protected against obesity and ensuing metabolic imbalances. Subcellularly, translated ADCY3-AT proteins are retained in the endoplasmic reticulum (ER), did not translocate to the cell membrane, and lacked enzymatic activity. By interacting with ADCY3, ADCY3-AT retained ADCY3 in the ER and, thereby, reduced the plasma membrane pool of ADCYs available for G-protein mediated cAMP synthesis. Thereby, ADCY3-AT acts as a signaling rheostat in BAT, limiting adverse consequences of uncurbed cAMP activity after long-term BAT activation. Adcy3-at induction was driven by a cold-induced, truncated isoform of the transcriptional cofactor PPARGC1A (PPARG Coactivator 1 Alpha, PPARGC1A-AT). Expression of Ppargc1a-at and Adcy3-at are evolutionary conserved, indicating that transcriptional rewiring by commissioning of alternative promoters is key for thermogenic fat function.

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Metadata

Authors
Khani, S., Topel, H., Josephrajan, A., Larsen, B. D. M., de Almeida Tavanez, A. R. A., Gaudry, M. J., Leyendecker, P., Stanic, N., Gaziano, I., Hansmeier, N. R., Schmidt, E., Klemm, P., Vagliano, L.-M., Engelhard, C. A., Nielsen, S., Jespersen, N. Z., Rehimi, R., Gohlke, S., Frommolt, P., Gnad, T., Rada-Iglesias, A., Pradas-Juni, M., Schulz, T. J., Wunderlich, F. T., Pfeifer, A., Jastroch, M., Wachten, D., & Kornfeld, J.-W.
Affiliations
  • University of Cologne (DE)
  • University of Southern Denmark (DK)
  • Stockholm University (SE)
  • University of Bonn (DE)
  • Max Planck Institute for Metabolism Research (DE)
  • University of Copenhagen (DK)
  • German Institute of Human Nutrition (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Novo Nordisk Foundation Center for Basic Metabolic Research (DK)
  • German Center for Diabetes Research (DE)
Corresponding author
  • Wachten, Dagmar
  • Kornfeld, Jan-Wilhelm
ORCID
Venue
Nature Metabolism
Publisher
openRxiv
Published
2022-08-01
Volume
6
Issue
6
Pages
1053-1075
ISSN
2522-5812 (ISSN-L)
DOI
10.1101/2022.08.01.502156
PMC
PMC11971047
OpenAlex
W4395959987
Cited by
24
References
1
Citations by year
2026: 15 · 2025: 7 · 2024: 1 · 2023: 1
FWCI
6.49
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Metabolism (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
  • bonndoc (University of Bonn) (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
  • UCrea (University of Cantabria) (submittedVersion, cc-by)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
Funders
  • European Molecular Biology Organization (676-2021)
  • Danish Diabetes Academy
  • Deutscher Akademischer Austauschdienst
  • Deutsche Forschungsgemeinschaft (SFB1454, SPP 1726, 432325352, TRR333, FOR 2743, TRR333/1, SPP 1926, 169331223, EXC 2151, 112927078, TRR 83, 450149205, 388159768, SFB1123-B10, 390873048)
  • Novo Nordisk
  • Syddansk Universitet
  • Rheinische Friedrich-Wilhelms-Universität Bonn
  • Novo Nordisk Fonden (NNF21OC0070263, NNF23OC0086800, NNF17OC0028416, 33444, NNF18OC0033444, 28416)
Topics
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
brown adipose tissue, cold exposure, PGC-1α, endoplasmic reticulum retention, cAMP signaling, thermogenesis, energy expenditure, obesity resistance, metabolic disorders, G protein signaling
MeSH terms
Cyclic AMP, Adenylyl Cyclases, Animals, Adipose Tissue, Brown, Cold Temperature, Energy Metabolism, Humans, Male, Mice, Knockout, Thermogenesis, Mice

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