title: Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers.
abstract: Long-term exposure to peroxisome proliferator-activated receptor γ (PPARγ) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated. Browning triggers reprogramming of PPARγ binding, leading to the formation of PPARγ "superenhancers" that are selective for brown-in-white (brite) adipocytes. These are highly associated with key brite-selective genes. Based on such an association, we identified an evolutionarily conserved metabolic regulator, Kruppel-like factor 11 (KLF11), as a novel browning transcription factor in human adipocytes that is required for rosiglitazone-induced browning, including the increase in mitochondrial oxidative capacity. KLF11 is directly induced by PPARγ and appears to cooperate with PPARγ in a feed-forward manner to activate and maintain the brite-selective gene program.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark;
authors.forename: Anne
authors.initials: A
authors.lastname: Loft
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark;
authors.forename: Isabel
authors.initials: I
authors.lastname: Forss
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark;
authors.forename: Majken Storm
authors.initials: MS
authors.lastname: Siersbæk
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark;
authors.forename: Søren Fisker
authors.initials: SF
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark;
authors.forename: Ann-Sofie Bøgh
authors.initials: AS
authors.lastname: Larsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark;
authors.forename: Jesper Grud Skat
authors.initials: JG
authors.lastname: Madsen
authors.affiliation: UMR 7277, Centre National de la Recherche Scientifique, U1091, Institut National de la Santé et de la Recherche Médicale, Institute of Biology Valrose, University Nice Sophia Antipolis, 06100 Nice, France;
authors.forename: Didier F
authors.initials: DF
authors.lastname: Pisani
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark;
authors.forename: Ronni
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark;
authors.forename: Mads Malik
authors.initials: MM
authors.lastname: Aagaard
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Angela
authors.initials: A
authors.lastname: Mathison
authors.affiliation: National Institute for Health Research, Oxford Biomedical Research Centre, OX3 7LE Oxford, United Kingdom.
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Neville
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: National Institute for Health Research, Oxford Biomedical Research Centre, OX3 7LE Oxford, United Kingdom.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.affiliation: UMR 7277, Centre National de la Recherche Scientifique, U1091, Institut National de la Santé et de la Recherche Médicale, Institute of Biology Valrose, University Nice Sophia Antipolis, 06100 Nice, France;
authors.forename: Ez-Zoubir
authors.initials: EZ
authors.lastname: Amri
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark; s.mandrup@bmb.sdu.dk.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D052437:Adipocytes, Brown / Q000166:cytology; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D065150:Cellular Reprogramming; D002843:Chromatin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D007004:Hypoglycemic Agents; C115117:KLF11 protein, human; D047495:PPAR gamma; D012097:Repressor Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: KLF11; PPARγ; browning of human adipocytes; genomic reprogramming; rosiglitazone; superenhancer