title: ARTD1-induced poly-ADP-ribose formation enhances PPARγ ligand binding and co-factor exchange.
abstract: PPARγ-dependent gene expression during adipogenesis is facilitated by ADP-ribosyltransferase D-type 1 (ARTD1; PARP1)-catalyzed poly-ADP-ribose (PAR) formation. Adipogenesis is accompanied by a dynamic modulation of the chromatin landscape at PPARγ target genes by ligand-dependent co-factor exchange. However, how endogenous PPARγ ligands, which have a low affinity for the receptor and are present at low levels in the cell, can induce sufficient co-factor exchange is unknown. Moreover, the significance of PAR formation in PPARγ-regulated adipose tissue function is also unknown. Here, we show that inhibition of PAR formation in mice on a high-fat diet reduces weight gain and cell size of adipocytes, as well as PPARγ target gene expression in white adipose tissue. Mechanistically, topoisomerase II activity induces ARTD1 recruitment to PPARγ target genes, and ARTD1 automodification enhances ligand binding to PPARγ, thus promoting sufficient transcriptional co-factor exchange in adipocytes. Thus, ARTD1-mediated PAR formation during adipogenesis is necessary to adequately convey the low signal of endogenous PPARγ ligand to effective gene expression. These results uncover a new regulatory mechanism of ARTD1-induced ADP-ribosylation and highlight its importance for nuclear factor-regulated gene expression.
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, 8057 Zurich, Switzerland Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Mareike
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Pirinen
authors.affiliation: Competence Centre for Applied Biotechnology and Molecular Medicine, University of Zurich, 8057 Zurich, Switzerland Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Ali
authors.initials: A
authors.lastname: Mirsaidi
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, 8057 Zurich, Switzerland Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Kunze
authors.affiliation: Competence Centre for Applied Biotechnology and Molecular Medicine, University of Zurich, 8057 Zurich, Switzerland Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Richards
authors.affiliation: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, 8057 Zurich, Switzerland Competence Centre for Applied Biotechnology and Molecular Medicine, University of Zurich, 8057 Zurich, Switzerland Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland hottiger@vetbio.uzh.ch.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
mesh_terms: D050156:Adipogenesis / Q000235:genetics*; D052436:Adipose Tissue, White / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D059305:Diet, High-Fat; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000037:antagonists & inhibitors; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D020218:Response Elements; D015533:Transcriptional Activation; D015430:Weight Gain / Q000187:drug effects
chemical_list: D008024:Ligands; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D011064:Poly Adenosine Diphosphate Ribose; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D004250:DNA Topoisomerases, Type II