A10

A10 Project movie

A10

Inflammatory processes occurring in adipose tissues have been studied by project A10. A complex paracrine network between white or brown adipocytes with tissue-resident endothelial cells, macrophages and other immune cells maintains adipose homeostasis in response to metabolic cues such as high fat diet feeding, but also contributes to inflammation and the etiology of obesity-associated cardiometabolic disease. Preliminary data generated in the first funding period suggest a prominent role of endothelial CD73, myeloid P2X4 and P2X7 as well as adipocyte P2X5 for metabolic and inflammatory responses in WAT and BAT. Notably, in transgenic mice lacking CD38, project A10 detected a substantial increase in NAD levels in brown adipose tissue (BAT) and white adipose tissue (WAT), respectively, especially under conditions of thermogenic adaptation. These effects were associated with increased expression of thermogenic and mitochondrial genes, such as uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1α), suggesting that the absence of CD38 improved adaptation to a cold environment. Further, project A10 found that thermoneutral housing leading to a state of low energy expenditure and lipid accumulation in adipose tissues resulted in enhanced uptake of glucose into WAT of mice lacking endothelial CD73. This effect was associated with elevated expression levels of de novo lipogenesis marker genes in adipocytes. On the other hand, ADO supplementation reduced de novo lipogenesis gene expression in cultured mouse and human primary white adipocytes, which is line with the observation that AAV-mediated CD73 expression in adipocytes protected mice from diet-induced obesity. Overall, these data indicate that in a physiological setting endothelial CD73 is involved in the paracrine regulation of lipid accumulation in adipocytes and thus may serve a novel therapeutic target for the treatment of obesity-associated diseases.

Since accumulating data suggested that P2X7 deficiency may be compensated by P2X4 under conditions of diet-induced inflammation, project A10 examined the effects of futile thermogenic activation in mice deficient for both P2X4 and P2X7. Due to the chromosomal proximity of these genes, generation of P2x4/P2x7 double knockout mice by conventional breeding of single knockout mice is nearly impossible. Accordingly, project A10 blocked P2X7 receptor activity in P2x4-deficient mice by injecting the inhibitory nanobody 13A7 in collaboration with project Z02. Notably, the absence of both purinergic receptors prevented macrophage infiltration in response to futile thermogenic activation, an effect maintaining high UCP1 protein levels in BAT and energy expenditure. These results strongly suggest that ATP released by thermogenic adipocytes acts as a danger signal that triggers the involution of BAT.

In contrast to P2X4 and P2X7, the purinergic receptor P2X5 is a marker for thermogenic adipocytes. It is of note that in contrast to African populations, a SNP found in the 3’ splice site of human P2x5 exon 10 is present in nearly the entire European population. This SNP results in a truncated dysfunctional protein, questioning from a European perspective to what extent P2X5 regulates human physiology. Accordingly, project A10 proposes that reduced BAT activity and lower basal metabolic rates described for populations with African ancestry are explained, at least in part, by the expression of the functional P2X5 protein.

Prof. Dr. Jörg Heeren

Selected publications (*equal contribution)

 

  1. Fischer AW*, Jaeckstein MY*, Gottschling K, Heine M, Sass F, Mangels N, Schlein C, Worthmann A, Bruns OT, Yuan Y, Zhu H, Chen O, Ittrich H, Nilsson SK, Stefanicka P, Ukropec J, Balaz M, Dong H, Sun W, Reimer R, Scheja L, Heeren J (2020) Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation. Cell Metab S1550-4131(20)30656-2
  2. Scheja L, Heeren J (2019) The endocrine function of adipose tissues in health and cardiometabolic disease. Nature Rev Endocrinol 15(9):507-524.
  3. Heine M, Fischer AW, Schlein C, Jung C, Straub LG, Gottschling K, Mangels N, Yuan Y, Nilsson SK, Liebscher G, Chen O, Schreiber R, Zechner R, Scheja L, Heeren J (2018) Lipolysis Triggers a Systemic Insulin Response Essential for Efficient Energy Replenishment of Activated Brown Adipose Tissue in Mice. Cell Metab 28(4):644-655.
  4. Worthmann A, John C, Rühlemann MC, Baguhl M, Heinsen FA, Schaltenberg N, Heine M, Schlein C, Evangelakos I, Mineo C, Fischer M, Dandri M, Kremoser C, Scheja L, Franke A, Shaul PW, Heeren J (2017) Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat Med 23:839-849.
  5. Bartelt A, John C, Schaltenberg N, Berbée JFP, Worthmann A, Cherradi ML, Schlein C, Piepenburg J, Boon MR, Rinninger F, Heine M, Toedter K, Niemeier A, Nilsson SK, Fischer M, Wijers SL, van Marken Lichtenbelt W, Scheja L, Rensen PCN, Heeren J (2017) Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport. Nat Commun 8:15010.
  6. Schlein C, Talukdar S, Heine M, Fischer AW, Krott LM, Nilsson SK, Brenner MB, Heeren J, Scheja L (2016) FGF21 Lowers Plasma Triglycerides by Accelerating Lipoprotein Catabolism in White and Brown Adipose Tissues. Cell Metab 23:441-453.
  7. Berbée JF, Boon MR, Khedoe PP, Bartelt A, Schlein C, Worthmann A, Kooijman S, Hoeke G, Mol IM, John C, Jung C, Vazirpanah N, Brouwers LP, Gordts PL, Esko JD, Hiemstra PS, Havekes LM, Scheja L, Heeren J*, Rensen PC* (2015) Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun 6:6356.
  8. Bartelt A, Heeren J (2014) Adipose tissue browning and metabolic health. Nat Rev Endocrinol 10: 24-36.
  9. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmüller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J (2011) Brown adipose tissue activity controls triglyceride clearance. Nat Med 17:200-205.
  10. Bruns OT, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Lauterwasser J, Nikolic MS, Mollwitz B, Merkel M, Bigall NC, Sapra S, Reimer R, Hohenberg H, Weller H, Eychmüller A, Adam G, Beisiegel U, Heeren J (2009) Real-time magnetic resonance imaging and quantification of lipoprotein metabolism in vivo using nanocrystals. Nature Nanotechnol 4, 193-201.

Prof. Dr. Friedrich Nolte (geb. Koch)

Selected publications

 

  1. Bertin E, Deluc T, Pilch KS, Martinez A, Pougnet JT, Doudnikoff E, Allain AE, Bergmann P, Russeau M, Toulmé E, Bezard E, Koch-Nolte F, Séguéla P, Lévi S, Bontempi B, Georges F, Bertrand SS, Nicole O, Boué-Grabot E (2020) Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice. Mol Psychiatry 
  2. Linden J, Koch-Nolte F, Dahl G (2019) Purine Release, Metabolism, and Signaling in the Inflammatory Response. Annu Rev Immunol 37:325-347
  3. Danquah W, Meyer-Schwesinger C, Rissiek B, Pinto C, Serracant-Prat A, Amadi M, Iacenda D, Knop JH, Hammel A, Bergmann P, Schwarz N, Assunçao J, Rotthier W, Haag F, Tolosa E, Bannas P, BouéGrabot E, Magnus T, Laeremans T, Stortelers C, Koch-Nolte F (2016) Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation. Sci Trans Med 8:366ra162.
  4. Menzel S, Rissiek B, Bannas P, Jakoby T, Miksiewicz M, Schwarz N, Nissen M, Haag F, Tholey A, Koch-Nolte F (2015) Nucleotide-Induced Membrane-Proximal Proteolysis Controls the Substrate Specificity of T Cell Ecto-ADP-Ribosyltransferase ARTC2.2. J Immunol 195:2057-2066.
  5. Teege S, Hann A, Miksiewicz M, MacMillan C, Rissiek B, Buck F, Menzel S, Nissen M, Bannas P, Haag F, Boyer O, Seman M, Adriouch S, Koch-Nolte F (2015) Tuning IL-2 signaling by ADP-ribosylation of CD25. Sci Rep5:8959.
  6. Unger M, Eichhoff AM, Schumacher L, Strysio M, Menzel S, Schwan C, Alzogaray V, Zylberman V, Seman M, Brandner J, Rohde H, Zhu K, Haag F, Mittrücker HW, Goldbaum F, Aktories K, Koch-Nolte F (2015) Selection of Nanobodies that Block the Enzymatic and Cytotoxic Activities of the Binary Clostridium Difficile Toxin CDT. Sci Rep 5:7850.
  7. Bannas P, Lenz A, Kunick V, Well L, Fumey W, Rissiek B, Haag F, Schmid J, Schütze K, Eichhoff A, Trepel M, Adam G, Ittrich H, Koch-Nolte F (2015) Molecular imaging of tumors with nanobodies and antibodies: Timing and dosage are crucial factors for improved in vivo detection. Contrast Media Mol Imaging 10:367-378.
  8. Rissiek B, Danquah W, Haag F, Koch-Nolte F (2014) A new cell preparation strategy that greatly improves the yield of vital and functional Tregs and NKT cells. J Leukoc Biol 95:543-549.
  9. Schwarz N, Drouot L, Nicke A, Fliegert R, Boyer O, Guse AH, Haag F, Adriouch S, Koch-Nolte F (2012) Alternative splicing of the N-terminal cytosolic and transmembrane domains of P2X7 controls gating of the ion channel by ADP-ribosylation. PLoS One 7:e41269.
  10. Hubert S, Rissiek B, Klages K, Huehn J, Sparwasser T, Haag F, Koch-Nolte F, Boyer O, Seman M, Adriouch S (2010) Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. J Exp Med 207:2561-2568.

Our Team

Prof. Dr. Jörg Heeren

Department of Biochemistry and Molecular Cell Biology

University Medical Center Hamburg-Eppendorf (UKE)

Prof. Dr. Friedrich Koch-Nolte

Institute of Immunology

University Medical Center Hamburg-Eppendorf (UKE)

M.Sc. Michelle Jäckstein

Department of Biochemistry and Molecular Cell Biology

University Medical Center Hamburg-Eppendorf (UKE)

M.Sc. Tobias Schäfer

Institute of Immunology

University Medical Center Hamburg-Eppendorf (UKE)

Alumni

Dr. Tian Tian

Department of Biochemistry and Molecular Cell Biology

University Medical Center Hamburg-Eppendorf (UKE)

Contact

University Medical Center Hamburg-Eppendorf 
Department of Biochemistry and Molecular Cell Biology 
Martinistrasse 52
20246 Hamburg

Scientific Coordinator

Dr. Björn-Philipp Diercks
Fon: +49  (0) 40 7410 54338
E-Mail: b.diercks©uke.de

Administration

Laura Mitsching
Fon: +49  (0) 40 7410 50301
E-Mail: l.mitsching©uke.de