A09
In the 1st funding period, project A09 identified several chemokines/chemokine receptors that are differentially regulated in BAT by diet (13% fat vs 60% fat) or housing temperature (23°C vs 4°C), e.g.: Cxcl12, Cxcl10, Ccr10, Cxcl14, Ccl2, Ccl5, Ccl6, Ccl7, Cxcr4 and Cxcr5. Cxcl12 (C-X-C motif chemokine ligand-12) was significantly upregulated in BAT from mice exposed to cold. Upon treatment of mature brown adipocytes with CXCL12, a reduction of Ucp-1 mRNA expression (the major thermogenic marker) was observed. In contrast to Cxcl12, Cxcl10 (C-X-C motif chemokine ligand-10) transcript was downregulated in BAT isolated from mice exposed to cold. Interestingly, Cxcl10 mRNA levels were significantly upregulated in BAT upon HFD diet and in brown adipocytes treated with TNFα to mimic adipose tissue inflammation. Collectively, project A09’s results suggest that Cxcl10 might be a possible macrophage-recruiting factor released by BAT. Further, in project A09 the spatiotemporal organization of cAMP signaling in adipocytes was studied by real-time live cell imaging in pre- and mature brown adipocytes in close collaboration with Prof. Nikolaev (project A06). Cytosolic cAMP microdomains generated during stimulation of individual β-adrenoceptor subtypes (β1, β2 and β3) as well as cAMP degradation by PDEs were visualized revealing PDE3 or 4 differentially regulate cAMP microdomains initiated by β1 or β3 adrenoceptors depending on the stage of adipocytes differentiation (pre- versus mature). Functionally, β1/2 receptor-induced lipolysis was controlled more by PDE3/4 than β3-receptor-induced lipolysis, which might be explained by the changes of both PDE3- and 4-mediated regulation of individual β adrenoceptor-dependent cAMP pools. Project A09 also studies the downstream effectors of cAMP-mediated regulation of BAT, and discovered a so far unknown biological role of the effector receptor EPAC1 in thermogenic fat. Using pharmacological and genetic tools EPAC1 was identified as a potent enhancer of BAT thermogenic capacity that significantly reduces diet-induced obesity and enhances human brown adipocyte differentiation. Thus, EPAC1 is apotentially promising target for obesity prevention and treatment. Also, project A09 studied ADO signaling and found that ADO receptor A2B induces BAT activation and browning of white fat. Human data also revealed that A2BAdoR expression correlates inversely with obesity. Further preliminary data of project A09relate to cAMP signaling organization in murine and human brown/beige adipocytes, the role of A-kinase anchoring proteins for the cAMP signaling architecture, and ADO signaling in adipocyte-macrophage communication.
Prof. Dr. Alexander Pfeifer
E-Mail: alexander.pfeifer©uni-bonn.de
www: Department of Pharmacology and Toxicology, University of Bonn/ Biomedical Center
Prof. Dr Alexander Pfeifer
Selected publications
- Elschner T, Grein S, Sander J, Hildebrand S, Heubach L, Pannwitz N, Mircea M, Raimundez E, Karagiannakou V, Georgiadi A, Heeren J, Hasenauer J, Pfeifer A, Wilhelm-Jüngling K. From brown to white: Brown adipose tissue endothelial cells whiten in culture conditions. Mol Metab. 2026 Mar 12;107:102349.
- Grein S, Elschner T, Kardinal R, Bruder J, Strohmeyer A, Gunasekaran K, Witt J, Hermannsdóttir H, Behrens J, U-Din M, Yu J, Heldmaier G, Schreiber R, Rozman J, Heine M, Scheja L, Worthmann A, Heeren J, Wachten D, Wilhelm-Jüngling K, Pfeifer A, Hasenauer J, Klingenspor M. Shiny-Calorie: a context-aware application for indirect calorimetry data analysis and visualization using R. Bioinform Adv. 2025 Oct 29;6(1):vbaf270.
- Chaible L, Preillon J, Philippart C, Canevat A, Saerens L, Kondratow D, Deligny M, Goffaux A, Michaux AC, Letellier MC, Rosewick N, Carbonez D, Marchante J, Strozzi F, Houthuys E, Marillier R, McGrath Y, Van der Plas S, Pfeifer A, Chesné J. ENT1 inhibition enhances weight control and metabolic health in diet-induced obesity. Biomed Pharmacother. 2025 Dec 9;193:118848.
- Jaeckstein MY, Fischer AW, Rissiek B, Staehler T, Heine M, Behrens J, Mann O, Pfeifer A, Magnus T, Schlein C, Worthmann A, Scheja L, Koch-Nolte F, Heeren J. Purinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic brown adipose tissue. EMBO Rep. 2025 Dec;26(24):6460-6493.
- Hübner MP, de Coninck D, Lenz B, Surendar J, Koschel M, Gandjui NVT, Andrew BA, Nchang LC, Ebob AOB, Fombad FF, Springer LM, Eppe L, Schildberg FA, Wanji S, Hoerauf A, Pfeifer A, Karunakaran I. The role of the IL-9‒NLRP3 axis in insulin resistance and adipose tissue inflammation during diet-induced obesity. Cell Mol Immunol. 2025 Sep 18.
- Pfeifer A, Langer T, Lusic M, Wickström SA, Frezza C, Trifunovic A. 2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction. Nat Metab. 2025 Aug 1.
- Khani S, Topel H, Kardinal R, Tavanez AR, Josephrajan A, Larsen BDM, Gaudry MJ, Leyendecker P, Egedal NM, Güller AS, Stanic N, Ruppert PMM, Gaziano I, Hansmeier NR, Schmidt E, Klemm P, Vagliano LM, Stahl R, Duthie F, Krause JH, Bici A, Engelhard CA, Gohlke S, Frommolt P, Gnad T, Rada-Iglesias A, Pradas-Juni M, Schulz TJ, Wunderlich FT, Pfeifer A, Bartelt A, Jastroch M, Wachten D, Kornfeld JW. Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function. Nat Metab. 2024 Jun;6(6):1053-1075.
- Jaeckstein MY, Schulze I, Zajac MW, Heine M, Mann O, Pfeifer A, Heeren J. CD73-dependent generation of extracellular adenosine by vascular endothelial cells modulates de novo lipogenesis in adipose tissue. Front Immunol. 2024 Jan 9;14:1308456.
- Reverte-Salisa L, Siddig S, Hildebrand S, Yao X, Zurkovic J, Jaeckstein MY, Heeren J, Lezoualc'h F, Krahmer N, Pfeifer A. EPAC1 enhances brown fat growth and beige adipogenesis. Nat Cell Biol. 2024 Jan;26(1):113-123.
- Birte Niemann, Saskia Haufs-Brusberg, Laura Puetz, Martin Feickert, Michelle Y Jaeckstein, Anne Hoffmann, Jelena Zurkovic, Markus Heine, Eva-Maria Trautmann, Christa E Müller, Anke Tönjes, Christian Schlein, Azin Jafari, Holger K Eltzschig, Thorsten Gnad, Matthias Blüher, Natalie Krahmer, Peter Kovacs, Joerg Heeren, Alexander Pfeifer. Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine. Nature, 2022, Sep; 609(7926):361-368.
Prof. Dr. Alexander Pfeifer
Institute of Pharmacology and Toxicology
University Hospital, University of Bonn,
M.Sc. Linghui Wang
Institute of Pharmacology and Toxicology
University Hospital, University of Bonn
Proposed PI 3rd funding Period
Prof. Dr. Tong Tong Wang
Institute of Pharmacology and Toxicology
University Hospital, University of Bonn
Alumni
Sana Siddig, PhD
Institute of Pharmacology and Toxicology
University Hospital, University of Bonn
M.Sc. Mickel Mikhael
Institute of Pharmacology and Toxicology
University Hospital, University of Bonn